Thesis Andy Temmerman by Karen De Rycke

â&#x20AC;&#x153;

Impaired Bone Quality

â&#x20AC;?

& Quantity and Oral Implants:

Evaluation of treatment strategies.

Andy Temmerman

KU Leuven Biomedical Sciences Group Department of Oral Health Sciences Section of Periodontology

DOCTORAL SCHOOL BIOMEDICAL SCIENCES

Kapucijnenvoer 7 – box 7001 B-3000 Leuven Belgium

“Impaired Bone Quality & Quantity and Oral Implants: Evaluation of treatment strategies.” Andy TEMMERMAN Promoter:

Prof. Dr. M. Quirynen Katholieke Universiteit Leuven, Belgium (Section of Periodontology)

Co-Promoters: Prof. Dr. R. Jacobs Prof. Dr. J. Duyck

Katholieke Universiteit Leuven, Belgium (OMFS Impath Research Group) Katholieke Universiteit Leuven, Belgium (Section of Restorative Dentistry)

Chair:

Prof. Dr. D. Declerck Katholieke Universiteit Leuven, Belgium (Section of Restorative Dentistry)

Secretary:

Prof. Dr. R. Hermans Katholieke Universiteit Leuven, Belgium (Department of Pathology and Imaging)

Jury Members: Prof. Dr. C. Politis

Katholieke Universiteit Leuven, Belgium (Department of Oral & Maxillofacial Surgery)

Prof. Dr. R. Hermans Katholieke Universiteit Leuven, Belgium (Department of Pathology and Imaging) Prof. Dr. F. Lambert

Prof. Dr. F. Schwarz Prof. Dr. S. Renvert

University de Liège, Belgium (Department of Periodontology) Heinrich Heine University, Düsseldorf, Germany (Department of Oral Surgery) Kristianstad University, Kristianstad, Sweden (Department of Oral Health Sciences)

31/05/17, The Leuven Institute for Ireland in Europe, Leuven. Doctoral Thesis in Medical Sciences

This thesis has been submitted in partial fulfilment of the requirements in achieving the degree of <<Doctor in de Medische Wetenschappen >>

ÂŠ Andy Temmerman All rights reserved. No parts of this book may be reproduced or transmitted in any form by any means, electronical, mechanical, photocopying nor recording without the written permission of the author. Grafische design. Karen De Rycke (www.karenderycke.be) Correspondance should be addressed to: andy.temmerman@uzleuven.be - andy_temmerman@hotmail.com Katholieke Universiteit Leuven Department of Oral Health Sciences â&#x20AC;&#x201C; Section of Periodontology Kapucijnenvoer 7 B-3000 Leuven Belgium +32 16 33 24 83 or +32 16 33 24 84

“The Only Thing That Is Constant Is Change.” Heraclitus (540 B.C. - 480 B.C.)

Dankwoord Toen ik in 2010 de opleiding parodontologie afrondde, samen met mijn mede-assistenten

in opleiding Koen en Kim, was het zeker niet de bedoeling om hierna nog een doctoraat

te starten. Erger nog: ik heb zelfs ooit gezegd dat men mij mocht vastbinden op een stoel wanneer ik het wel zou doen. Ik ben Koen en Kim nog steeds dankbaar deze woorden niet letterlijk op te vatten…

Ongeveer 6 jaar, 90000 kilometer in de auto en talloze uren in de file later kan ik, met een zekere trots, deze thesis afleveren. Tien jaar aan de afdeling parodontologie in Leuven zijn voorbij gevlogen.

Op het einde van dit ‘hoofdstuk in mijn leven’ kan ik niet anders dan een heel aantal mensen oprecht bedanken en even in de spreekwoordelijke bloemetjes zetten.

Waarschijnlijk zal ik bij het ter perse gaan van dit boekje denken van ‘Oh nee, ik ben nog zoveel mensen vergeten te bedanken in mijn dankwoord!’. Aan hen op voorhand reeds mijn verontschuldigingen en mijn dank. Weet vooral dat ik dit niet met opzet heb gedaan.

Mijn promotor: Prof. Marc Quirynen. Voor de eerste keer zal ik ‘Beste Marc’ zeggen en de titel ‘Professor’ weglaten.

Bedankt om mij destijds de kans te geven om de opleiding parodontologie in Leuven te kunnen volgen. U gaf mij snel de kans aan onderzoek te doen en ik raakte hier geleidelijk

aan meer en meer in geïnteresseerd. Ik herinner mij nog Uw reactie toen ik 6 jaar geleden

over een doctoraat begon te praten. Ik wist van toen af dat ik de goede keuze had gemaakt. Ik wens U te bedanken voor de begeleiding, de motivatie en kansen die ik heb gekregen

op professioneel vlak en binnen de wondere wereld van de parodontologie. Maar ook

voor de leuke babbels, waardoor we ook op persoonlijk vlak een goede en toffe band hebben opgebouwd.

Tijdens het ENHD congres in Leuven (oktober 2016) zag ik nog maar eens een fantastische afdeling – een fantastisch team. U mag gerust fier zijn om aan het roer van te staan van dit schip!

Mijn co-promotoren: Prof. Reinhilde Jacobs en Prof. Joke Duyck. Beste Joke en Reinhilde. Alle input, hulp en steun (ook op moeilijkere momenten) werd enorm geapprecieerd! Bedankt om mijn co-promotoren te willen zijn. Het voelt altijd goed aan te weten dat er een back-up is van mensen met heel grote wetenschappelijke bagage en kwaliteit.

Prof. Wim Teughels en Mevr. Dekeyser. Beste Wim en Christel. Als draaischijven van

de afdeling wil ik jullie danken om mij altijd thuis te hebben laten voelen aan de afdeling. Jullie interesse in wat ik deed, zowel professioneel als privé, maakte van mijn dagen in Leuven meer dan alleen ‘werken’. Ook jullie mogen fier zijn op de afdeling zoals ze nu is en draait!

Dear members of the internal and external jury: Prof. C. Politis, Prof. R. Hermans, Prof. F. Schwarz, Prof. S. Renvert and Prof. F. Lambert. Thank you so much for your time and effort to elevate this thesis to a higher level and for accepting the invitation to be part of my jury. It is a real honour to have been interrogated by you!

Dr. Wim Coucke en Prof. Hertelé. Beste Wim, beste Stijn, dank voor jullie snelle & deskundige statistische analyses. Het maakte mijn leven als doctoraatstudent een heel pak eenvoudiger!

Gedurende de 10 jaar aan de afdeling zijn er natuurlijk heel wat mensen de revue gepasseerd. Elk jaar nieuwe assistenten in opleiding, assistenten die afstuderen, consulenten die komen en gaan… Ook al zie ik heel wat mensen niet zo vaak meer, toch is het altijd een leuke aangelegendheid wanneer we elkaar eens ontmoeten op één of ander congres.

Met een aantal mensen werd in de loop der jaren een speciale band opgebouwd, die veel verder reikt dan de afdeling parodontologie alleen.

Drs. Joe Merheb. Bro, bedankt voor je steun, de fantastische momenten die we al hebben beleefd (en nog zullen beleven) en de onvoorwaardelijke vriendschap!

Dr. Marjolein Vercruyssen. Marjolein, ook al ben je niet meer aan de afdeling, toch wens ik je te bedanken voor de leuke ‘educational’ momenten in het begin van de opleiding, talloze

‘surgical guides’ die we (meestal) tot een goed einde brachten en vooral de leuke babbels tijdens de lunch op maandag en zoveel meer!

Rutger Dhondt, Ilya Grosjean, Willem-Frederik Simons: Boykes, ook al zijn we het meestal niet eens over behandelingen bij patiënten, toch ben ik uitermate vereerd met de goede

band en vrienschap die we hebben opgebouwd in de laatste jaren! Rutger, veel succes met je doctoraat!

Karina Vranckx & Andrea Vanobberghen. Karine & Andrea, de aanspreekpunten van de afdeling! Bedankt voor de steun, de babbels en het indekken van mijn administratieve tekortkomingen.

Marie Hoflack. Beste Marie, dank voor de leuke momenten, de opbeurende gesprekken en je vriendschap!

Nederlandse vrienden Hans en Richard, dank voor de toffe Belgische, Nederlandse en Europese ‘vergaderingen’.

Drs. Jeroen Van Dessel. Zoals ik tijdens lezingen al vaak heb verteld aan het publiek, zouden

veel van de studies besproken in deze thesis niet zijn wat ze nu zijn, zonder jouw professionele en zeer gewaardeerde inbreng. Het is fantastisch om te zien hoe je van, op zich eenvoudige klinische studies, 3D meesterwerkjes hebt gemaakt. Bedankt Jeroen, voor jouw inzet en kunde. Ik hoop nog veel met je te kunnen samenwerken tijdens nieuwe projecten!

Verder gaan mijn dank uit naar alle vroegere en huidige medewerkers, consulten (in het bijzonder Marc Meeus, Carl Spaas en Greet De Mars) en assistenten in opleiding. Iedereen afzonderlijk bedanken zou het aantal bladzijden te hoog doen oplopen, echter

is mijn dank daarom niet kleiner! Mijn mede-doctoraatsstudenten op het 6de verdiep wens ik echter toch speciaal te vernoemen: drs. Ana Castro, drs. Isabelle Laleman en

drs. Simone Cortellini. Ik wens jullie veel succes met de verderzetting van jullie doctoraat. Dank om ‘af en toe’ mijn gezaag te aanhoren!

Naast de KU Leuven bestaat mijn professioneel leven uit niets anders dan ‘ParoPlus’. Ik ben zeer vereerd mee aan het roer te staan van praktijken die kwaliteit hoog in het vaandel dragen. Dank aan mijn collegae in de praktijken om mij de kans te geven om deel te zijn van het ParoPlus-team! Dank U, Nathalie, Luc en Stefan!

ParoPlus Aalst is zo een beetje mijn tweede (of derde) thuis geworden. Ik wens in het bijzonder Stefan Matthijs te bedanken om mij na mijn stage de kans te geven om mij in te

werken in de praktijk. Verder wens ik je te bedanken voor de aangename samenwerking, collegialiteit en je interesse in mijn academische projecten. Je mag terecht fier zijn op wat

ParoPlus Aalst is geworden in de laatste jaren: een bloeiende praktijk! De nieuwe locatie zal het alleen maar beter laten worden!

Natuurlijk mag ik ook de assistentes in de praktijk niet vergeten: Ilse, Anita, Veerle, Julitta en Synthia. Bedankt om van ParoPlus Aalst een succesverhaal te maken.

En natuurlijk zijn er een aantal mensen te bedanken die niets met tandheelkunde te maken hebben (al klopt dit niet volledig…).

Karen De Rycke. Dank U Karen, om van Word-documenten een mooi grafisch geheel te maken.

Beste vrienden, Thomas en Alexander. Zoveel jaren later nog steeds bevriend! Ook al

zien we elkaar niet zo vaak meer als vroeger. Het blijft een waar genoegen jullie tot mijn

allerbeste vrienden te kunnen rekenen. Bedankt voor alle fantastische momenten en onvoorwaardelijke vriendschap!

Stefan, Louis en Guy. Jullie hebben natuurlijk wel iets met tandheelkunde te maken, maar ik denk dat onze vrienschap hier ver buiten gaat. Ook jullie wens te ik danken voor de steun en alle leuke dingen die mijn leven meer kleur geven.

Stefaan Six. Bedankt voor het kritisch nalezen van mijn thesis en jouw opmerkingen. Veel succes met de verderzetting van je doctoraat. Er komen nog meer dan genoeg momenten (tussen de schaakstukken en de Leffe glazen) om er over te ‘discussiëren’.

Natuurlijk mag ik mijn familie niet vergeten: Hugo & Carine. Bedankt om er altijd te zijn voor ons gezin.

Mijn ouders. Spijtiggenoeg kan mama dit zelf niet meer meemaken, maar ik weet, dat jullie echte fans van mij zijn. Dank voor alle kansen die ik van jullie gekregen heb. Jullie opvoeding

en steun heeft mij in de juiste richting geduwd. Woorden schieten tekort om te beschrijven wat jullie voor mij hebben gedaan. Nu ik zelf vader ben, dringt dit steeds dieper tot mij door… Dank U!

En dan ‘last but not least’, mijn 2 kostbaarste ‘bezittingen’: Inge en Matéo. Ik weet dat jullie mij veel moeten missen. Ik ben weinig thuis en als ik thuis ben dan ben

ik soms ook nog eens aan het werk. Hoe jullie het met mij uithouden is mij een raadsel.

Desalniettemin, ik zie jullie beiden doodgraag! Ik wens jullie vanuit het diepste van mijn hart te bedanken voor alles tot nu toe en voor alles wat we nog tegoed hebben. Dank jullie om mijn zonnetjes in mijn leven te willen zijn…

TABLE of CONTENTS List of Abbreviations

Hypothesis & Preface

General Introduction

PART 1: Impaired Bone Quantity

Chapter 1:

Assessment of the reliability of panoramic images in

the planning of sinus augmentation procedures.

Chapter 2:

The influence of various surgical techniques for sinus augmentation

on the amount of augmented bone & on the Schneiderian membrane.

Chapter 3:

Chapter 4:

122

The use of extra-short oral implants in patients with extreme bone resorption.

The use of small diameter oral implants in patients with narrow bucco-oral alveolar ridge width.

PART 2: Impaired Bone Quality Chapter 5:

The use of oral implants in post-menopausal women over 60 years of age

suffering from osteoporosis/osteopenia.

Chapter 6:

The use of Leucocyte & Platelet Rich Fibrin in ridge preservation techniques

148

180

and socket management.

Chapter 7:

147

The influence of remaining bone pathologies after tooth extraction on oral implant

220

outcome and retrograde peri-implantitis: a literature review

General Discussion and Future Perspectives

247

Summary

267

Samenvatting

273

Curriculum Vitae

279

List of Abbreviations

List of Abbreviations 2D 3D ASAN BIC BMD BOP BP BS/TV BV/TV C/I ratio CAL CBCT cm3 Conn.Dn CSR CT DXA EGF FDP FGF g GBR HU IAC IL ISQ L-PRF lSFE MBL mm MRONJ MSCT n PAN PDGF

Two Dimensional Three Dimensional Anterior Superior Alveolar Nerve Bone-to-Implant Contact Bone Mineral Density Bleeding on Probing Bisphosphonates Bone Surface/Total Volume Bone Volume/Total Volume Crown/Implant ratio Clinical Attachment Level Cone-Beam Computed Tomography Cubic centimetre Connective Densisty Cumulative Survival Rate Computed Tomography Dual X-ray Absorptiometry Epidermal Growth Factor Fixed Dental Prothesis Fibroblast Growth Factor gram Guided Bone Regeneration Hounsfield Unit Integrated Abutment Crown Interleukin Implant Stability Quotient Leucocyte & Platelet Rich Fibrin Lateral Sinus Floor Elevation Marginal Bone Level Millimetre Medication Related Osteonecrosis of the Jaws Multi-Slice Computed Tomography Number Panoramic Radiograph Platelet Derived Growth Factor

Po[tot]; PPD PRP PSAA PTV RBH RCT RFA RQ SD SFE SMI SMV SR Tb.N Tb.Pf Tb.Th TGF TNF tSFE VAS VEGF µCT µm

Total Porosity Pocket Probing Depth Platelet Rich Plasma Posterior Superior Alveolar Artery Perio Test Value Residual Bone Height Randomised Controlled Trial Resonance Frequency Analysis Research Question Standard Deviation Sinus Floor Elevation Structural Model Index Schneiderian Membrane Volume Systematic Review Trabecular Number Trabecular Profile Thickness Trabecular Thickness Transforming Growth Factor Tumor Necrosis Factor Transcrestal Sinus Floor Elevation Visual Analogue Scale Vascular Endothelial Growth Factor Micro-Computed Tomography micrometre

Hypothesis & Preface

Hypothesis & Preface The overall aim of this thesis was to evaluate different pre-surgical diagnostic tools and surgical techniques in patients with impaired bone quantity or bone quality. Whenever possible a prospective study design was used, in the form of a RCT. Split-mouth designs were used whenever these could enhance the power of the respective studies. To obtain the overall aim 2 general hypotheses were pointed out: â&#x20AC;˘ Major bone augmentation procedures can, to some extent, be avoided by using different, less invasive treatment options, without interfering with long-term implant outcomes. â&#x20AC;˘ Alveolar bone quality can, to some extent, be influenced by using specific treatment modalities but does not seem to interfere with long-term oral implant outcome. To obtain these aims 5 specific hypotheses, which are intertwined to some extent, were created. These hypotheses resulted in a number of RQ. PART 1: Impaired Bone Quantity 1) Panoramic imaging is not able to overcome fundamental diagnostic limitations in order to achieve sufficient pre-operative information on the need of sinus augmentation procedures. RQ1a: Does panoramic imaging overestimate the need for sinus augmentation procedures? And if so: to what extent? RQ1b: Which anatomical features are deformed or masked on panoramic images?

These RQ are addressed in: Chapter 1, page 41 Material & Methods: retrospective radiological study Are panoramic images reliable in planning sinus augmentation procedures? Temmerman Andy, Hertelé Stijn, Teughels Wim, Dekeyser Christel, Jacobs Reinhilde & Quirynen Marc. (2011) Clinical Oral Implants Research 22: 189-94. 2) Extra short implants and internal sinus augmentation procedures can overcome the limitations of insufficient bone height without major surgical interventions in order to decrease patient morbidity and post-operative discomfort. RQ2a: Can extra short implants be used as abutments for the oral rehabilitation in the posterior area of the maxilla/mandibula in cases of severe bone resorption? RQ2b: Are implant survival rates similar to normal length implants placed in augmented bone? RQ2c: Are less invasive sinus augmentations (internal sinus lifting – ‘Summers technique’ & Intralift procedures) comparable and equally effective to augment severely resorbed posterior maxillary regions? Do these result in lesspost-operative pain for the patient? RQ2d: Do various surgical techniques for sinus augmentation have a different impact on the Schneiderian membrane? Does the impact on the Schneiderian membrane have a correlation with the reduction in graft volume during the healing phases? These research questions are addressed in: Chapter 2, page 65 Material & Methods: in vivo, clinical trials with split mouth design in 18 patients requiring bilateral sinus augmentation procedures. Volumetric changes of grafted volumes and the Schneiderian membrane after transcrestal and lateral sinus floor elevation procedures: a pilot clinical trial. Temmerman Andy, Vandessel Jeroen, Cortellini Simone, Jacobs Reinhilde, Wim Teughels Wim & Quirynen Marc. Journal of Clinical Periodontology, accepted.

Chapter 3, page 100 Material & Methods: in vivo, prospective cohort study The use of extra-short locking taper, plateau shaped oral implants in patients with extreme bony resorption: a 5-year follow up, prospective cohort study. Temmerman Andy, Teughels Wim, Duyck Joke & Quirynen Marc. In progress

3) The placement of oral implants in patients with very limited bucco-oral dimensions without pre/per-operative augmentation procedures is a treatment modality showing similar osseointegration rates & marginal bone level alterations as oral implants placed in sufficient amounts of bone. RQ3: Is there a difference in peri-implant marginal bone level alterations between implants placed in very narrow ridges (<4,5 mm) compared to wide ridges (>7 mm). These research questions are addressed in: Chapter 4, page 128 Material & Methods: in vivo, prospective clinical trial The outcome of oral implants placed in bone with limited bucco-oral dimensions: a 3-year follow-up study. Temmerman Andy, Keestra Hans, Coucke Wim, Teughels Wim, Quirynen Marc. (2015) Journal of Clinical Periodontology 42: 311-8.

PART 2: Impaired Bone Quality 4) Marginal bone level alterations following treatment with oral implants in the maxilla of post-menopausal women with or without osteoporosis/ penia are comparable. RQ 4: Is there a difference in osseointegration rates and peri-implant marginal bone level alterations between healthy and osteoporotic/osteopenic post-menopausal women, as evaluated radiologically? These research question is addressed in: Chapter 5, page154 Material & Methods: in vivo, multi-centric, controlled trial An open, prospective, non-randomized, controlled, multicentre study to evaluate the clinical outcome of implant treatment in women over 60 years of age with osteoporosis/osteopenia: 1-year results. Temmerman Andy, Rasmusson Lars, Kubler, Thor Andreas, Quirynen Marc. (2017) Clinical Oral Implants Research 28:95-102. 5) The use of L-PRF for ridge preservation is beneficial on bone quantity and quality. RQ5a: Is the use of L-PRF for ridge preservation beneficial in limiting the resorption which naturally occurs after extraction? RQ5b: Does the use of L-PRF to fill extraction sockets results in better bone quality? RQ5c: Does the use of L-PRF to fill extraction sockets results in less postoperative pain for the patient? These research questions are addressed in: Chapter 6, page 188 Material & Methods: in vivo, split-mouth RCT The use of Leucocyte & Platelet Rich Fibrin in socket management and ridge preservation: split-mouth, randomised, controlled, clinical trial.

Temmerman Andy, Van Dessel Jeroen, Castro Sarda Ana, Jacobs Reinhilde, Teughels Wim & Quirynen Marc. (2016) Journal of Clinical Periodontology 43: 990-999.

6) Remaining pathologies after extraction have an influence on the occurrence of retrograde peri-implantitis.

Chapter 7, page 221 Material & Methods: narrative review Etiology and treatment of periapical lesions around dental implants. Temmerman Andy, Lefever David, Teughels Wim, Balshi Thomas, Balshi Stefan & Quirynen Marc. (2014) Periodontology 2000 66: 247-54.

Chapter 3 was conducted with Bicon Short Implants™ (Bicon, Boston, USA). Chapter 5 was initiated on behalf of DentsplyImplants™ (Mölndal, Sweden). Implants were delivered free of charge for the patient. All studies were performed by Andy Temmerman. All Informed Consents, surgeries, follow-up appointments, data recording were performed by himself.

General Introduction

General Introduction Before predictable and successful oral implants became available, patients who lost more than a few natural teeth often found it impossible to regain full, comfortable masticatory function and facial esthetics. Dental prostheses, especially the removable designs, are far from ideal replacements for natural teeth. The introduction of oral implants, functioning as artificial tooth roots, widened the treatment options to restore a compromised dentition. In less than just a few decades, oral implants have moved from the fringes of dentistry to the mainstream and beyond the dental field. Indeed, implants are now utilized for purposes not foreseen even a decade ago (Tillander et al., 2010). The “fuse of titanium with bone”, is over 70 years old. It was already encountered in 1940 by Bothe, Baeton and Davenport (Bothe et al., 1940). They are thought to be the first researchers to have implanted titanium in animals and to observe the connection between titanium and bone. In 1951 the same connection between titanium and bone was described by Gottlieb and Leventhal (Leventhal & Gottlieb 1951). In the fifties, during an experiment a titanium chamber was inserted into the rabit fibula by Prof. P-I Brånemark and his coworkers (Brånemark et al., 1969), in order to observe the formation of blood cells in bone marrow and to study the blood flow. When, after a period, they wanted to remove these titanium chambers, they discovered that the titanium chamber had integrated completely within the bone. It became impossible to remove. The process was called “osseointegration” by Brånemark. And as his predecessors, Prof. Brånemark could already see the possibilities for clinical use in humans. Different definitions of the term “osseointegration” are used today, based on microscopic findings and a clinical perspective. Lekholm & Zarb proposed the definition of “osseointegration” as follows: “A process whereby a clinically asymptomatic rigid fixation of alloplastic materials is achieved and maintained in bone during functional loading” (Lekholm & Zarb 1985).

In 1965, Brånemark treated the first patient using this concept (Brånemark et al., 1977). Evidence of long term survival of oral implant supported prostheses, has since then emerged (Balshi et al., 2015; Jimbo and Albrektsson, 2015; Tenenbaum et al., 2016; Srinivasan et al., 2016). As years passed by, the standard osseointegration protocol was subjected to some minor and major changes. Some examples: the surface of the implants was liable to major changes. Turned implants, made from commercially pure titanium, had the disadvantage of requiring a fairly long osseointegration time, before functional loading. For patients this meant that they had a long edentulous period. By modifying the implant surface characteristics, an improved biocompatibility and faster osseointegration could be achieved (Cooper, 2000; Wennerberg and Albrektsson, 2010). Better bone response and histomorphometry have been shown on roughened surfaces as compared to minimally rough surfaces (Yeo et al., 2008). This faster osseointegration opened the door to alter the classical osseointegration protocol (of 6-8 months of osseointegration in the maxilla and 3-4 months in the mandible) in an attempt to decrease the treatment time. As such, oral implants were ‘early loaded’ (when the implants were loaded between 1 week and 2 months after placement) and ‘immediately loaded’ (when the implants were loaded within 1 week after implant placement). These treatments show high implant survival rate (Schwarz et al., 2016), although not all clinicians may achieve the desired results (Esposito et al., 2009). Nevertheless, high patient satisfaction seems to be the most important advantage of immediate loading, especially during early phases of healing (De Bruyn et al., 2014). Nowadays clinicians have to take several aspects into account when performing oral implant treatment. Due to ageing of the population, oral implant treatment is often and with great success used in elderly (Srinivasan et al., 2016). Nevertheless, one has to keep in mind that the bony tissues in elderly have a reduced vascular supply which is a critical factor for bone apposition. Furthermore, older patients seeking implant treatment may suffer from one or more general medical conditions and taking the necessary medication for these conditions. Also, their oral hygiene skills reduce with time.

Bone Quality: As the principle of osseointegration is based on an intimate contact between bone and implant surface, it seems logical that the alveolar bone quality of a patient is of utmost importance. The assessment of bone quality however, is not straightforward. First of all, some medical conditions and medications may interfere with the bone quality to a certain extent. Osteoporosis is a systemic skeletal disease affecting more than 75 million people in Europe, Japan and the USA. It is defined as a condition of decreased bone mineral density and changes in the micro-architecture of the bone tissue. This may lead to a decreased bone strength and an increased risk of fractures, primarily in the hip, spine and wrist. The most common form of osteoporosis is called primary osteoporosis and affects mainly elderly patients. It is 3 times more common in women than in men. This can be explained by the lower peak of bone mass in women as well as the hormonal changes that occur during the menopause (Kanis et al., 2013). Furthermore, women live longer than men and thus have larger reduction in bone mass. It has been estimated that 30% of all postmenopausal women have osteoporosis (Riggs, 1991). It is still unclear whether systemic osteoporosis also extrapolates in osteoporosis of the jaws and whether this can be of any clinical importance for oral implant treatment. The view that systemic osteoporosis is a contraindication for oral implant treatment has gradually changed over the years. Papers have shown that oral implant treatment can be successful in osteoporotic patients (Friberg et al., 2001; Dao et al., 1993; Becker et al., 2000). Nevertheless, a recent SR on the impact of osteoporosis on oral implant treatment concluded that based on the included studies osteoporotic patients presented with higher rates of implant failure. The authors specifically state that final conclusions regarding the effect of osteoporosis on oral implant treatment can not be made, due to the fact that there were no controlled clinical trials available (Giro et al., 2015). Furthermore, clinicians have to be aware of the growing number of patients taking bisphosphonate medication or other so-called anti-resorptive agents. BP are pyrophosphate analogues with a high affinity for bone hydroxyapatite and are considered to be effective drugs in the treatment of diseases affecting bone metabolism, such as osteoporosis but also bone metastasis of prostate, lung and breast carcinoma (Shabestari et al., 2010). One of the most serious complications of BP therapy is MRONJ, characterized by exposed bone or bone that can be probed through an intra-oral or extra-oral fistula.

However, no clear advices can be given at the moment due to an absolute lack on trials with longer follow-up periods. Recent evidence is alerting to be careful when it comes to oral implant planning in patients undergoing BP therapy (being intravenous or per-os)(Madrid and Sanz, 2009; de-Freitas et al., 2016). Other medical conditions that might have an influence on bone quality (but are no part of this thesis) are osteomalacia, poorly controlled diabetes mellitus (Naujokat et al., 2016; Annibali et al., 2016), Sjögren’s disease (Korfage et al., 2016),… Publications have shown that a good pre-operative diagnosis of a future implant site might decrease the development of peri-apical implant lesions and early implant loss. Peri-apical lesions seem to be provoked by remaining scar of granulomatous tissue at the recipient site: endodontic pathology of extracted teeth or possible endodontic pathology from neighboring teeth (Quirynen et al., 2005). Enhanced research on this topic, furthermore showed that when an endodontic pathology was present on an extracted tooth, it is significantly more likely that a per-apical lesion might develop around a future implant (Lefever et al., 2013). So clinicians have to be aware that the extraction of a tooth, already might have important impact on the bone quality of the future implant site. The question can be raised whether today we have surgical options to alter the bone quality when a tooth needs to be extracted. An interesting option would be to use patient derived surgical additives. The use of these additives in oral surgery and implantology is not new. However, the search for natural patient derived additives, which can be easily used during a surgical intervention, promote healing and regulate the inflammatory response, is still ongoing. This search started in the early seventies, with the introduction of fibrin glues. But it was only in the late nineties with the papers by Whitman (Whitman et al., 1997) and Marx (Marx et al., 1998), the first generation of platelet aggregates (‘Platelet Rich Plasma – PRP) gained more and more attention. PRPs became widely used in oral surgery and wound care. But with its success also came a downside: various preparation protocols, often complex in nature, started to develop in order to enhance its working mechanisms (e.g. Platelet Rich on Growth Factors –PRGF (Anitua, 1999)). Due to this and the lack of a clear classification of products the clinical benefit was difficult to evaluate. This resulted in a very controversial literature on the subject. Furthermore, PRPs

and their preparation, had several inherent disadvantages, such as several centrifugations, the need of bovine thrombin and calciumchloride and the cost for the patient. The introduction of the second generation of platelet aggregates (Platelet Rich Fibrin – PRF) by Choukroun (Choukroun et al., 2001), overcame most of these disadvantages. The simplified preparation protocol, without the need for biochemical blood handling, micro-pipetting, etc. made it easier to use in everyday practice. The obtained fibrin network has many similarities with the one formed during natural healing. Platelets are incorporated and lead to cell migration and proliferation. Furthermore, the activation of platelets will result in their degranulation and cytokine release. Growth factors (such as TFGβ-1, TGFβ2, VEGF, PDGF-AB,…), matrix glycoproteins (such as trombospodin, fibronectin and vitronectin) and cytokines (such as IL-4, VEGF) are released for more than 7 days, whereas the first generation only guaranteed a release of 20 minutes. Also the properties of PRF itself made every day clinical use more easy. It can be used as a membrane, it is suturable, it is shape cutable and it is inexpensive. Already some evidence exist on the fact that PRF has the power to influence the bone quality. In vitro it has been shown that the exudate of PRF membranes supports the metabolic activity and proliferation of human osteoblasts (Gassling et al., 2013). When used in adjunction with titanium barriers for bone augmentation procedures, PRF can increase the newly formed bone due to concentration of growth factors (Ozdemir et al., 2013). Hauser and co-workers (Hauser et al., 2013) used PRF as a socket filling material and could thereby achieve a significant positive effect on the intrinsic bone tissue quality. Bone Quantity: Conventional 2D radiographs intra-oral, peri-apical radiographs, panoramic radiographs are widely used radiological modalities to assess the bone quantity (and quality) prior to implant placement. However, these 2D radiographs frequently lead to undetected residual pathologies in the bone (Van Assche et al., 2009). Especially panoramic radiographs seem to be unreliable in planning implant surgeries (de Brito et al., 2016). 3D CBCT images seem to give significantly more surgically relevant information for implant surgery planning and diagnosis of the maxillary sinus (de Brito et al., 2016; Tadinada et al., 2016).

Surprisingly, panoramic imaging is still frequently advocated as a reliable tool in planning oral implant placement in different sites of the oral cavity (KĂźtĂźk et al., 2014; Dagassan-Berndt et al., 2016). The alveolar process is a tooth depended anatomical structure. Inherently, the extraction of natural teeth will result in resorption of bone. This occurs both on the vestibular and lingual sides. However, studies have shown that the buccal/ vestibular side is affected predominantly. The resorption may hamper future implant placement in a prosthetically driven ideal position, which increases the need for bone augmentation procedures. Clinicians consider a 1 to 2 mm buccal and lingual bone width mandatory around an implant at placement. However this is only partially supported by studies (Merheb et al., 2014; Teughels et al., 2009). In a recent study by Merheb and co-workers (Merheb et al., 2016) the buccal bone thickness was measured at implant placement at several distances from the implant shoulder. These measurements were repeated after 12 months of loading. It was concluded that implants with a very shallow initial bone thickness (<1 mm) did not loose significantly more bone than those with an initial thickness of >1 mm. After extraction of molar and premolar teeth in the posterior region of the maxilla, the maxillary sinus enlarges due to a pneumatisation process (Sharan and Madjar, 2008). This sinus expansion seems to be larger when several adjacent posterior teeth are extracted. Furthermore, the expansion is more extensive with the extraction of second molars compared to first molars. Sinus floor elevation procedures are widely used, and thoroughly investigated treatment modality to overcome this problem. Survival rates of oral implants placed in augmented sinuses are equal to those placed in pristine maxillary bone (Del Fabbro et al., 2013; Wallace and Froum, 2003). All these factors contribute to the fact that at the time a patient desires implant treatment, the amount of bone necessary to place an oral implant sometimes is insufficient. For these patients this means that he/she has to undergo bone augmentation procedures. These procedures may evoke a higher morbidity and post-operative pain and discomfort, when comparing this with standard implant treatment. These procedures will also lead to higher financial costs. As implants have become

a widespread treatment modality, thoughtful approaches to decrease treatment time, patient costs and especially patient morbidity and post-operative pain and discomfort get more and more attention. In an attempt to minimize the per- and post-operative discomfort various techniques for SFE have been described in literature (Crespi et al., 2012; Pjetursson and Lang, 2014; Troedhan et al., 2010; Velázquez-Cayón et al., 2012). However, well-performed RCTs comparing their outcome including patient related outcome measures are scarce. A possibility to overcome augmentation procedures, the higher patient morbidity and the higher costs, would be to use less invasive treatment options. Already in 1998, Ten Bruggenkate and co-workers published a paper on the use of 6 mm long oral implants. In a 6 year period 253 short implants were placed in 126 patients and were followed for 1 to 7 years. They could conclude that the survival rates for these short implants was comparable with the clinical results of longer implants (ten Bruggenkate et al., 1998). With improvement in the implant surface geometry and surface texture, short oral implants gain more and more attention. In recent years, well-performed RCTs have been published on the use of short implants as an alternative treatment option in patients requiring augmentation procedures (Calvo-Guirado et al., 2015; Esposito et al., 2015; Felice et al., 2015; Fan et al., 2016) As can be concluded from the introduction above, not all patients seeking oral implant treatment have ideal ‘host’ bone conditions. The aim of this thesis was to evaluate treatment strategies: • by which clinicians can, to some extent, interfere with bone quality prior to implant placement. • in patients with impaired bone quality (eg. osteoporotic patients) • by which clinicians can, to some extent, interfere with the per- and postoperative morbidity when augmentation procedures are necessary.

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Part 1 Impaired Bone Quantity

Assessment of the reliability of panoramic images in the planning of sinus augmentation procedures.

Are panoramic images reliable in planning sinus augmentation procedures? Temmerman Andy, Hertelé Stijn, Teughels Wim, Dekeyser Christel, Jacobs Reinhilde & Quirynen Marc. (2011) Clinical Oral Implants Research 22:189-94.

Oral presentations on Chapter 1 were given at: • the Post-Graduate Meeting of the European Federation of Periodontology (EFP)(Istanbul, Turkey) • the symposium on “30 years Periodontology” at the KU Leuven (Leuven, Belgium) • the ‘Free Communications Day’ of the Belgian Society for Periodontology (BVP)(Brussels, Belgium)

Abstract Objective: The inherent deformation and 2D nature of PAN might jeopardize their interpretation and quantitative measurements. This study aims to estimate the degree of underestimation of available mesio-distal bone in the premolar area (comparing panoramic radiographs with MSCT/CBCT), to determine the prevalence, width, length and position of the bony canal (artery) in the lateral sinus wall and to explore the prevalence, width and length of another (newly detected) bony canal at the palatal aspect of the upper canine. Material and methods: The distance between the distal side of canine/1st premolar and the mesial side of the 1st molar or the anterior wall of the maxillary sinus was measured on PAN and corresponding MSCT/CBCT images (65 patients). Measurements were made apically, mid-radicular and crestally, parallel to the occlusal plane. The presence and dimensions of the 2 above mentioned intra-osseous canals were verified on MSCT scans (144 patients) using reformatted cross sectional images and/or axial slices. Results: For all 65 patients, PAN underscored the mesio-distal distance of available bone in the upper premolar region (mean 2.90 mm, range 0.10 - 7.50 mm). An intra-osseous canal in the lateral maxillary sinus wall was clearly visible in 49,5% of the cases (mean diameter 1.40 mm). In the canine region a bony canal was obvious in 32,9% of the cases, with a mean diameter of 1.23 mm. For both canals there was no correlation between diameter and patientâ&#x20AC;&#x2122;s age. Conclusions: Based on the present data, CBCT imaging can be recommended for visualising anatomical structures during planning of sinus augmentation procedures.

Introduction The introduction of panoramic radiography was a major improvement in dental/oral imaging (Numata et al., 1933, Paatero et al., 1949). Today panoramic radiography is still one of the most commonly used dental radiographic examinations, also for the exploration of the jaw bones prior to implant surgery. In 2002, the EAO Guidelines, recommended panoramic radiography for planning oral implant placement in the upper jaw (Harris et al., 2002). Vazquez and co-workers (2008) even considered a panoramic radiograph reliable to quantify the alveolar bone height prior to insertion of posterior mandibular implants, when a safety margin of at least 2 mm is respected. Others consider panoramic radiographs less reliable and clearly inferior to MSCT or CBCT. For example for the visualisation of the mental loop, especially in poor bone quality (Kaya et al., 2008), or to identify the mandibular canal (Angelopoulos et al., 2008, Peker et al., 2008). Nedbalski and co-workers (2008) considered a PAN not reliable to diagnose a sinus involvement following extraction of maxillary premolars and molars. Several aspects have a negative impact on the reliability of PAN. The correct positioning of the patientâ&#x20AC;&#x2122;s head while scanning is of utmost importance, since a malpositioning will automatically lead to discrepancies and distortion of shape (Mckee et al., 2001). Moreover a panoramic radiograph remains a 2D image of a 3D object, with superimposition of neighbouring anatomical structures, rendering a correct diagnosis more difficult (Yeo et al., 2002). PAN are further degraded, to a variable degree, by shadows of soft tissues and surrounding air. Ghost images of the spine and mandible further reduce its diagnostic quality. PAN have an inherent magnification ranging from 10 to 30%, with the horizontal magnification being more variable and thus less reliable. Inherent to the arch-wise image built-up, PAN show a variable degree of overlap in the upper premolar region. This overlap can probably be explained by the difference in curvature of the upper and lower jaws in this region, where the panoramic unit is programmed for the shape of the mandible (Gijbels et al., 2000, Rushton & Horner 1996, 2003). Such overlap could result in an underestimation of the available mesio-distal bone size in front of the maxillary sinus. Other drawbacks: limited resolution (â&#x2030;¤ 6 line pairs/mm as oppossed to 12-22 line pairs/mm

for intra-oral sensors) and an oblique projection geometry hampering a correct visualisation of the anatomical relationships. All the abovementioned factors may hamper pre-surgical planning. After tooth extraction, the maxillary sinus, because of pneumatisation, can extend towards the oral cavity (Sharan et al., 2008). The latter can cause inadequate bone volume for implant placement in the premolar-molar area. The resorbed bone can predictably be reconstructed by a SFE procedure (internal or lateral approach) with favourable outcome for the intervention as well as for the future implants (see recent review papers: Graziani et al., 2004, Del Fabbro et al., 2004, 2008, Emmerich et al., 2005). In general, the surgical procedure to augment the sinus shows little complications. A systematic review identified a perforation of the sinus membrane as the most common intra-operative complication and concluded that there is still controversy whether such complication influences the survival rate of the implants (Tan et al., 2008). Infection of the grafted sinus is found to be an important complication, although rare. Other rare complications are excessive bleeding from the bony window or the sinus membrane, haematoma, wound dehiscences, injury of the infra-orbital neurovascular bundle and implant migration into the sinus cavity. These complications can be disabilitating for the patient (Tan et al., 2008, Pjetursson et al., 2008). An excessive bleeding may occur as a result of an arterial injury (Marx et al., 2002). Indeed, during the surgical procedure, especially after a lateral approach, there is a chance to damage the small arteries that supply the maxillary sinuses. A good knowledge of the arterial blood supply of the maxillary sinus is thus crucial. An ex-vivo study (Traxler et al., 1999) as well as a study of dental MSCT images (Mardinger et al., 2007) confirmed the presence of 3 primary arteries: the PSAA, the infra-orbital artery, (both branches of the maxillary artery, which originates from the external carotid artery), and the posterior lateral nasal artery (a branch of the sphenopalatine artery). The PSAA and infraorbital artery anastomose into a vessel that runs into a bony canal within the lateral wall of the sinus. These arteries influence the vitality of the bone, the vascularisation of the graft material and the healing of the soft-tissues.

This study has a triple aim: (i) to estimate the degree of underestimation of available mesio-distal bone width in the premolar area on PAN (via comparison with MSCT/CBCT images), and (ii) to determine the prevalence, width, length and position of the bony canal (in lateral wall of sinus) containing the arterial anastomosis of the PSAA and infraorbital artery, (iii) as well as to explore the prevalence, width and length of a newly detected canal at the palatal aspect of the upper canine, probably containing an artery (clinical experience).

Materials & Methods Mesio-distal bone width. A series of patients visiting the Department op Periodontology (University Hospital, KU Leuven) seeking implant therapy in the maxillary premolar area received a PAN (Cranex Tome®, Soredex, Tuusula, Finland) for overall diagnosis and treatment planning, whereafter 3D imaging via MSCT (Somatom Plus S®, Siemens, Erlangen, Germany) /CBCT (Accuitomo®, Morita, Japan) was undertaken. All patients, who had visited the radiology department the University Hospital between 2005/1 and 2009/4 were scanned for the availablity of both a PAN and MSCT/CBCT. The time between both radiographic examinations varied from 0-12 months (to let the degree of sinus pneumatisation not interfere with the results). Only patients who were partially edentulous in the maxilla (left or right) from canine/1st premolar to the first molar, or patients with an edentulous area from the canine/1st premolar to the anterior maxillary sinus wall, were included. A total of 65 patients fulfilled these inclusion criteria (52% males, 48% female, mean age 57y, range: 42 - 79 y), signed informed consent, and were enrolled in the present study. Via both radiographic examinations the bony distance between canine/1st premolar and mesial side of the 1st molar or the anterior wall of the sinus was recorded with a calliper and software measuring tool or via the software tool to the nearest 0.1 mm (PACS lightbox, IMPAX pacs, Agfa). Measurements (Figure 1A, 1B) were made parallel with the occlusal plane at 3 specific locations: apically, mid-radicular and crestally (the latter was omitted if the sinus was considered). The values were corrected for the magnification factor in case of PAN (the Cranex Tome®, Soredex has a magnification factor of 1,3). Artery in lateral sinus wall. A consecutive series of patients who visited the radiology department of the University Hopsital between 2005/1 and 2009/4 were enrolled in this part. The single inclusion criterium was the availabilty of MSCT images (Somaton Plus S®, Siemens, Erlangen, Germany). A total of 144 patients

were obtained, after informed consent. The group consisted of 66 females and 78 males with a mean age of 58.2 years (range: 22 - 79y). 80 patients were partially and 64 fully edentulous. Left and right maxillary sinuses were analysed for the presence of an intraosseous canal using reformatted cross-sectional images (Figure 2). Only when the intra-osseous canal was visible on cross-sectional images, it was considered as present. The diameter of this canal was measured on these cross-sectional images with a calliper or the software measuring tool to the nearest 0.1 mm (PACS lightbox, IMPAX pacs, Agfa). The distance between the floor of the sinus and bony canal was estimated in the premolar and molar region. The diameter of the canal was further analysed in relation to the age of the patient. Bony canal canine area. The above mentioned set of MSCT images was also used to evaluate the presence of an intra-bony canal at the palatal aspect of the upper canines. For the latter both cross-sectional as well as axial images were considered (Figure 3). The course of the canal was followed to the point where it left the maxilla. The diameter of this intra-bony structure was measured on the axial slices and its length on the cross-sectional images, using the software measuring tool to the nearest 0.1 mm (PACS lightbox, IMPAX pacs, Agfa). Data Analysis This study presents primarily descriptive data. All measurements of the mesiodistal bone width (PAN vs. MSCT/CBCT) have been compared in a point plot with linear regression analysis, to visually identify bias effects. Further, a 95% confidence interval has been derived, after confirmation of normality in distribution of data, with the patient as statistical unit.

For the bony canal in the anterior sinus wall and the bony canal at the palatal aspect of the canine area all methods used were non-parametric. A nonparametric percentile and interquartile range was derived after rejection of the normality of distribution using Dâ&#x20AC;&#x2122;Agostino-Pearson test for normal distribution. A Mann-Whitney test for independent samples was used to statistically compare both age groups. The null-hypothesis was rejected at p<0.05. Statistical analyses were performed using the Medcalc Software program version 11.2.

Results Mesio-distal bone width. All PAN clearly underscored the available mesio-distal bone distance between the distal side of the canine/1st premolar and the mesial side of the 1st molar or the anterior wall of the maxillary sinus. Figure 4 shows a plot of all PAN measurements against their corresponding CBCT/MSCT values, along with linear regression lines for the 3 locations. The average difference between measurements made on CBCT/MSCT and PAN was 2.90 mm (SD: 1.80 mm, 95% confidence interval: 2.57 - 3.12 mm). In other words, if a PAN shows an available mesio-distal bone distance (width) of 6 mm, it probably will be around 8.9 mm on CBCT/MSCT. The linear regression lines of the measurements taken apically, mid-radicular and crestally show a high degree of agreement. Moreover, these regression lines walk parallel to the 1:1-line which represents a perfect agreement, and thus suggests a systematic error. Artery in lateral sinus wall. An intra-osseous canal in the lateral maxillary sinus wall was detectable in 49.5% of the examined sites. In the group 22-59y this incidence was 47.0%, in the older age group (60-76y) 52.1%. The difference between these two prevalences was not statistically significant (p=0.27) after deriving the standard error and comparison of percentages (categoric scale). The mean diameter (Table 1) of the bony canal was 1.40 mm (range: 0.60 - 3.80 mm). No statistically significant difference (p=0.81) was observed between the younger and older subgroups (1.41 vs. 1.40 mm). The mean distance from the bony canal to the sinus floor was 9.13 mm in the premolar region (range: 2.00 â&#x20AC;&#x201C; 21.20 mm, Table 3); and 9.15 mm in the molar regions (range: 2.10 â&#x20AC;&#x201C; 25.50 mm, Table 2). This parameter was similar (no statistically significant difference) for both age subgroups (9.02 mm vs. 9.24 mm in the premolar region (p=0,77), 9.46 mm vs. 8.85 mm in the molar region (p=0.53).

Bony canal canine area. A bony canal in the upper canine region was detected in 32.9% of the cases. The mean diameter (Table 4) of this canal was 1.23 mm (range: 0.50 â&#x20AC;&#x201C; 7,70 mm). The difference between the two age groups was negligible and not statistically different (1.26 and 1.19 mm), respectively (p=0.54). The mean length (Table 5) of this bony canal was 6.71 mm (range: 2,60 â&#x20AC;&#x201C; 22.30 mm). Again, no statistically significant differences (p=0.34) were seen between both age groups (6.63 mm vs. 6.80 mm, respectively). This canal always started palatally, to run in a latero-cranial direction.

Discussion According to this study, PAN systematically underestimate the available mesiodistal bone distance. To the knowledge of the authors this is the first report on this issue. This observation has a significant impact when evaluating the need of a sinus augmentation procedure. The inferiority of PAN, when compared to MSCT/CBCT, was highlighted in other indications. Estrela and co-workers (2008) evaluated the accuracy of CBCT, PAN and periapical radiographs for the detection of apical periodontitis and concluded that CBCT images were more reliable. Also in the diagnosis of periodontal disease, PAN was considered unreliable (Ainamo et al., 1973), although some studies were less negative (Kaimenyi et al., 1988, Akesson et al., 1989). There is sufficient evidence that cross-sectional imaging (MSCT/CBCT) can be considered as the gold standard in implant planning (Jacobs & van Steenberghe 1998, Guerrero et al., 2006, Van Assche et al., 2007, Veyre-Goulet et al., 2008, Lofthag-Hansen et al., 2009). The impossibility to make accurate measurements in mesio-distal directions, as concluded in this study, can be added as a reason why CBCT/MSCT, remains the preference for pre-surgical implant assessment. Whereas the mesio-distal bone in a diastema between 2 adjacent teeth is intra-oral and per-operatory controllable, the result of this study has its main consequences in evaluating the mesio-distal bone width between the most mesial tooth and the anterior sinus wall. Our results indicate that a panoramic radiograph overestimates the need for sinus augmentation procedures. One should however realise that each panoramic radiography machine has its own degree of overlap in the premolar regions, and thus probably different correction factors. Sinus lifting has become a common surgical intervention for increasing alveolar bone height prior to the placement of oral implants in the posterior maxilla. A haemorrhage during or after such intervention can occur, but might be better anticipated during planning. Damaging the vascular structure can lead to bleeding, obscuring of vision and even perforation of the Schneiderian membrane (Solar et al., 1999). Moreover, this bony vessel is responsible for the vascularisation of the graft and the Schneiderian membrane (Solar et al., 1999,

Traxler et al., 1999). A pre-surgical CT evaluation of the course of the bony vessel and other anatomic important structures is recommended when performing a SFE procedure. Traxler and co-workers (1999), in a cadaver study, reported that the dental branch of the PSAA forms an anastomosis with the infra-orbital artery in almost all subjects. This anastomosis is always endosseously, in the lateral wall of the maxillary sinus. In our study an intra-osseous canal in the lateral sinus wall was clearly visible in 50% of the analysed CT images. This is in accordance with previous papers (Elian et al., 2005, Mardinger et al., 2007), which suggested that in the remaining cases the bony canal was too small to enable radiographic detection. Mardinger and co-workers (2007) found a negative correlation between age and diameter of the bony canal but this could not be confirmed in this study. In the present study the course of the vascular structure was most caudal in the 2nd premolar/1st molar region, to run higher-up more distally. Mardinger and co-workers correlated the location of the bony canal to the residual alveolar ridge height and found that the lower the residual alveolar ridge height the higher the probability of damaging the vascular structure, when preparing a lateral window needed for sinus augmentation (Mardinger et al., 2007). Although the present study identified a bony canal, at the palatal aspect of the canine region, in 32.9% of all analysed MSCT images, we were not able to find any anatomic nor radiographic study confirming its existence. The mean diameter of this bony canal was 1.23 mm. This bony canal could be visualised on all cross-sectional images as well as on axial slices. On the latter, the course of the canal could be followed from its bony entry point at the most apical position to the bony exit point in the most coronal position. It was possible to follow this bony canal over a mean distance of 6,71 mm. At present we have no evidence that damaging this bony vessel can cause any adverse effect. Anyhow, intense bleeding when damaging this vessel during osteotomy seems likely and has been encountered several times during our interventions. Further investigations are mandatory.

Conclusions Based on the present data, cross-sectional imaging can be recommended (because of lower radiation dosage, preferably CBCT) to visualise anatomical structures during surgical planning of SFE procedures and to estimate the available bone in the upper premolar region.

Figures Figure 1

Evaluation of mesio-distal distance canine to 1st/2nd molar / anterior wall of the maxillary sinus. A: Horizontal linear measurements on a PAN at 3 specific locations (apical, mid-radicular, crestal) parallel to the occlusal plane. B: Horizontal linear measurements on CBCT at 3 specific locations (apical, mid-radicular, crestal) parallel to the occlusal plane. Figure 2

On cross-sectional images (premolar and molar region) of MSCT the bony canal in the lateral wall of the maxillary sinus was examined (diameter, distance to floor sinus).

Figure 3

MSCT were evaluated for the presence of a bony canal at the palatal aspect of the canine region. On the axial slices, this canal can be followed from the point where it enters to the point where it leaves the bone. Measurements were made on the diameter of this canal and its length (reformatted cross-sectional images). A: Axial slice. B: Reformatted cross-sectional images (arrows indicate course of this newly detected canal). Figure 4

Point plot of all PAN measurements against their corresponding CBCT/MSCT measurements, along with linear regression lines for the 3 measurement locations (apically, mid-radicular and crestal) and the 1:1-line representing a perfect agreement.

Tables Table 1 Diameter of the intra-bony canal in the lateral wall of sinus as measured on MSCT. Visible in 143 of the 289 sites (49.5%); age group 22-59y, 47.0%; age group 60-79y, 52.1%. In every test there was no statistically significant difference between the two age groups, using a Mann-Whitney test for independent samples (p=0.81). Mean

95%CI

Standard

(mm)

(mean)

Deviation

Range

D’Agostino-

Interquartile

Pearson test

Range

Diameter (overall)

5/7

4/8

6/6

4/8

8/4

Diameter (22-59y)

38-78

31-72

46-74

43-65

39-72

40-75

Diameter (60-79y)

6/6

3/9

5/7

6/6

9/3

4/8

Table 2 Distance to the bottom of the sinus in the molar area of the intra-bony canal in the lateral wall of sinus as measured on MSCT. Visible in 143 of the 289 sites (49.5%); age group 22-59y, 47.0%; age group 60-79y, 52.1%. In every test there was no statistically significant difference between the two age groups, using a Mann-Whitney test for independent samples (p=0.53). Mean

95%CI

Standard

(mm)

(mean)

Deviation

Distance to sinus (overall – molar area)

9,15

[8,52; 9,79]

3,82

[2,10; 25,50]

Distance to sinus (22-59y – molar area)

9,46

[8,54; 10,37]

3,84

[2,10; 20,00]

[6,70; 10,90]

Distance to sinus (60-79y – molar area)

8,85

[7,95; 9,76]

3,81

[2,60; 25,50]

[7,10; 10,85]

Range

D’Agostino-

Interquartile

Pearson test

Range

Rejected normality (p<0,0001)

Table 3 Distance to the bottom of the sinus in the premolar area of the intra-bony canal in the lateral wall of sinus as measured on MSCT. Visible in 143 of the 289 sites (49.5%); age group 22-59y, 47.0%; age group 60-79y, 52.1%. In every test there was no statistically significant difference between the two age groups, using a Mann-Whitney test for independent samples (p=0.77). Mean

95%CI

Standard

(mm)

(mean)

Deviation

Range

D’Agostino-

Interquartile

Pearson test

Range

Distance to sinus (overall – premolar area)

9,13

[8,44; 9,82]

4,13

[2,00; 21,20]

Distance to sinus (22-59y – premolar area)

9,02

[8,07; 9,97]

3,95

[2,0; 18,90]

[6,27; 11,30]

Distance to sinus (60-79y – premolar area)

9,24

[8,21; 10,27]

4,33

[2,20; 21,20]

[5,60; 12,70]

Rejected normality (p<0,0001)

Table 4 Diameter of the bony canal apical and palatally to the upper canine as measured on MSCT (visible in 96 of the 289 sites)(32.9%); age group 22-59y, 32.4%; age group 60-79y, 33.6%. In every test there was no statistically significant difference between the two age groups, using a Mann-Whitney test for independent samples (p=0.54). Mean

95%CI

Standard

(mm)

(mean)

Deviation

Range

D’Agostino-

Interquartile

Pearson test

Range

Diameter – overall

1,23

[1,13; 1,32]

0,46

[0,50;7,70]

Diameter (22-59y)

1,26

[1,11; 1,41]

0,52

[0,50; 3,30]

[0,90; 1,40]

Diameter (60-79y)

1,19

[1,08; 1,31]

0,39

[0,50; 7,70]

[0,90; 1,42]

Rejected normality (p<0,0001)

Table 5 Length of the bony canal apical and palatally to the upper canine as measured on MSCT (visible in 96 of the 289 sites)(32.9%); age group 22-59y, 32.4%; age group 60-79y, 33.6%. In every test there was no statistically significant difference between the two age groups, using a Mann-Whitney test for independent samples (p=0.34). Mean

95%CI

Standard

(mm)

(mean)

Deviation

Length â&#x20AC;&#x201C; overall

6,71

[5,93; 7,50]

3,88

[2,60; 22,30]

Length (22-59y)

6,63

[5,45; 7,81]

4,11

[2,60; 21,90]

[4,15; 6,90]

Length (60-79y)

6,80

[5,73; 7,88]

3,66

[2,60; 22,30]

[4,57; 7,47]

Range

Dâ&#x20AC;&#x2122;Agostino-

Interquartile

Pearson test

Range

Rejected normality (p<0,0001)

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The influence of various surgical techniques for sinus augmentation procedures on the amount of augmented bone & on the Schneiderian membrane.

The impact of different sinus floor augmentation procedures on the amount of augmented bone volume & Schneiderian membrane: a pilot split-mouth, randomized trial. Temmerman Andy, Vandessel Jeroen, Cortellini Simone, Jacobs Reinhilde, Teuhgels Wim & Quirnen Marc. (2016) Journal of Clinical Periodontology (accepted).

Oral presentations on Chapter 2 were given at: • Spring Symposium of the ‘Together for Implantology’ Society (2015, Adana, Turkey) • Winter Symposium of the ‘Together for Implantology’ Society (2015, Istanbul, Turkey) • Najaarscongres Dutch Society for Periodontology (NVvP) (2016, Utrecht, The Netherlands)

Abstract: Background & Objective: To investigate the influence of various surgical techniques for sinus augmentation on the volumetric changes of graft, membrane and the post-operative discomfort. Materials and Methods: Eighteen patients in need of bilateral sinus floor elevation (SFE) were assigned to lateral SFE, transcrestal SFE and Intralift procedures. CBCT images taken at baseline, 1week and 6 weeks were analysed for volumetric changes in graft and Schneiderian membrane. Questionnaires were used to analyse post-op discomfort. Results: The overall average graft volume obtained after 1 week was 1,87 cm3 (range 0,12-4,72 cm3). Volumes decreased after 6 weeks to an overall mean volume of 1,33 cm3 (range 0,10-4,29 cm3 - average decrease of 27,6%). After 6 weeks the amount of graft volume decreased in every treatment option, ranging from -23,13% for the tSFE, over -24,55% for the lSFE, to -33,71% for the IL. Although all treatment options correspond in an increase in Schneiderian membrane volume, no statistically significant correlation between this increase and loss of graft volume could be obtained for all treatments (p=0,97). Conclusion: All SFE techniques provided sufficient graft volume for implant treatment. All techniques provoke a partially transient swelling of the Schneiderian membrane. All techniques resulted in a decrease in graft volume after 6 weeks, however no significant differences were obtained between treatments. Furthermore, no statistical significant correlation between the post-operative swelling of the Schneiderian membrane and reduction of graft volume at 6 weeks could be obtained.

Introduction Vertical bone deficits in the posterior maxilla are very common in the field of implant dentistry. Therefore, a maxillary sinus floor elevation (SFE) procedure has become a popular and thoroughly investigated surgical procedure to compensate for inadequate vertical residual bone height (RBH). Nowadays, the lateral window SFE (lSFE) procedure is widely used and considered reliable, with implant survival rates comparable with implants placed in pristine bone (Del Fabbro M. et al., 2013;Del et al., 2013;Wallace & Froum 2003;Del Fabbro et al., 2013;Jensen et al., 2012;Nkenke & Stelzle 2009; Esposito et al., 2010). In the eighties a less invasive, one-stage technique was introduced (Boyne & James, 1980) and thereafter modified by Summers (Summers 1994). Only a few modifications have been proposed since then (Chen et al., 2009;Rosen et al., 1999;Trombelli et al., 2014). Within this technique, osteotomes are applied via a transcrestal approach, to elevate the floor of the sinus and to advance bone substitutes beyond the level of the original sinus floor, and as such elevate the mucosal lining. Also for this approach, high implant survival rates have been reported. (Esposito et al., 2010;Jensen et al., 2012; Nkenke & Stelzle 2009;Tan et al., 2008). In literature the transcrestal SFE technique (tSFE) has been recommended in sites where the alveolar crest is of sufficient width and where an RBH of 5mm or more is available (Wang & Katranji 2008). Furthermore, the anatomy of the sinus floor should not be too oblique, as the osteotomes enter the sinus cavity at the lower level first while still have resistance in the higher parts. The main disadvantage of this technique are the risks of perforating the sinus membrane and the limited intra-operative visibilty (Al-Almaie et al., 2013;Jo et al., 2012;von et al., 2014;Nkenke & Stelzle 2009;Schwartz-Arad et al., 2004). In order to deal with these disadvantages, various alternative SFE procedures have been proposed (Kfir et al., 2011;Matern et al., 2015;Rao & Reddy 2014). One of them is the transcrestal hydrodynamic, ultrasonic, cavitational technique (IntraliftTM â&#x20AC;&#x201C; IL) (Troedhan et al., 2012; Troedhan et al., 2014). This technique was developed based on the atraumatic capacities of ultrasonic surgery and bone regeneration mechanisms under the sinus membrane. Indeed, the maxillary sinus is lined internally with a thin mucosa of respiratory ciliated epithelium. It has a transport function for fluids and mucus towards the internal ostium. The mucosa of the maxillary sinus has been given differ-

ent names: antral mucosa, maxillary sinus lining or Schneiderian membrane. The thickness of this Schneiderian membrane, which seems to have positive correlation with the gingival biotype (Aimetti et al., 2008), shows a wide range when measured on CBCT images, ranging from 0,2mm to 35.0mm. A mucosal thickening of >2mm is usually considered as a pathological change (Janner et al., 2011). However, a thickened Schneiderian membrane is a very common lesion which occurs in 61% of the patients (Shanbhag et al., 2014). From a surgical point of view, the thickness of the Schneiderian membrane shows a positive correlation with the perforation rates during tSFE. Membranes â&#x2030;Ľ1mm and <2mm showed less perforations than those less thick or thicker (Wen et al., 2014). It seems logical that different SFE procedures will result in different volumes of grafted sites. However, the question remains whether tSFE procedures and lSFE procedures can result in comparable volumes in grafted sites This could eventually lead to the use of less invasive surgical procedures on a more regular basis. Furthermore, the volumetric graft changes after SFE procedures are important in order to avoid the possibility of not achieving the amount of bone necessary for implant placement. Although these changes have been described in literature, they remain unclear (Wanschitz et al., 2006; Browaeys et al., 2007; Zijderveld et al., 2009). To assess the augmented bone volume, different techniques have been proposed in literature (Szabo et al., 2005). Two-dimensional (2D) peri-apical radiographs or panoramic radiographs are helpful in the analysis of the vertical dimension of the graft. On the other hand, they do not provide any important additional information on the three-dimensional (3D) volume of the graft. Furthermore, panoramic radiographs are prone to a not to be underestimated amount of images distortion (Temmerman et al., 2011). Recently, 3D Cone-Beam Computed Tomography (CBCT) analysis has been described as a fast, simple, relatively accurate and promising approach to quantify long-term changes in the grafted area (Ohe et al., 2016; UmanjecKorac et al., 2016).

The aim of this pilot, clinical trial was to provide information on the volumetric changes of the grafted area with different SFE techniques (primary outcome measure). Furthermore, the influence of the thickness of the Schneiderian membrane, pre-operatively and post-operatively, on the volume of the grafted site was assessed (secondary outcome measure). The impact of the different treatment modalities on the per- and post-operative pain and sensation was also recorded (tertiary outcome measures).

Material & Methods The study was designed as a pilot, prospective clinical trial. The study was approved by the Ethical Committee of the KU Leuven, UZ Leuven University Hospitals (S55459). This study was conducted in accordance with the requirements of the Helsinki Declaration of 1975 and revised in 2008. Patient population: Patients had to fulfill the following inclusion criteria: no history of systemic diseases, non-smoking and no history of sinus pathology as assessed on a pre-operative CBCT. Furthermore, they were in need of bilateral SFE procedures in order to obtain an implant supported rehabilitation. All patients were given oral and written information on the study protocol and its procedures and were asked to sign the Informed Consent form. From 2012 to 2015, 18 patients were enrolled in this study (Table1). Of these patients, 7 were male, 11 were female (mean age: 57,8y (range (29 -79y). Patients presented with a RBH ranging from 0,7 mm to 6,1mm (mean 3,1mm) as measured on the respective CBCT cross-sectional slices. Patient allocation: Based on the RBH of the left and right maxillary sinus of each patient the following treatments were allocated: lateral window sinus floor elevation technique (lSFE), transcrestal sinus floor elevation technique (tSFE) and Intralift technique (IL). Whenever the RBH was >4mm, one of the treatment options was randomly assigned. However, whenever the RBH was <4mm, IL or lSFE were randomly assigned. Surgical procedures: All SFE procedures were performed under local anesthesia and strictly sterile conditions.Prior to surgery, a venipuncture was performed (median basilica vein, median cubital vein, median cephalic vein). Venous blood was drawn into 8 sterile, plastic 10 mL tubes without anticoagulant. Leukocyte and Platelet Rich Fibrin (L-PRF) clots and membranes were prepared as described by Choukroun and co-workers (Choukroun et al., 2001). The tubes

were immediately centrifuged at 2700 rpm for 12 minutes using a table centrifuge (IntraSpin™, IntraLock®, Florida, USA). Hereby, platelets were activated and the coagulation cascade was triggered. After centrifugation, each L-PRF clot was removed from the tube and separated from the red element phase at the base with pliers. Four L-PRF clots were gently squeezed between a sterile glass plate and a metal box. All surgical procedures were performed by the same surgeon (AT). The lSFE procedures were performed as follows: after crestal incision a mucoperiosteal flap was raised to visualize the lateral wall of the maxillary sinus. Piezosurgery (Acteon, Satelec, Piezotome II, France) was used to prepare the lateral window. Via a ‘trapped door technique’ the wall was pushed inward, after detachment of the Scheiderian membrane from the inner maxillary sinus walls with hand instruments. Deproteinized bovine bone matrix (DBBM, BioOss, Geistlich, Wolhusen, Switserland) mixed with L-PRF (in a 60-40 percentage) was used to fill the antrum (Bolukbasi et al., 2015; Ali et al., 2015). L-PRF membranes were used to cover the grafted site and the laterals osteotomy (Gassling et al., 2013). tSFE procedures were performed as follows: crestal incision with limited mucoperiosteal flap elevation. When reaching the inferior maxillary sinus wall, a L-PRF membrane was inserted into the osteotomy and osteotomes were used in order to enter the maxillary sinus by gently tapping the osteotome with a mallet. A mixture of DBBM and L-PRF (in a 60-40 percentage) was used to fill the antrum. The IL procedures were performed as follows: crestal incision with limited flap elevation. The maxillary sinus was entered using piezosurgery and the Intralift inserts. The Scheiderian membrane was elevated using the hydrodynamic, cavitational effect after inserting collagenous sponge. A mixture of L-PRF and DBBM was used to fill the antrum. Osteotomy site preparation was performed using conventional rotatory instrumentarium according to the implant manufacturer guidelines (AstraTech TX Osseospeed, DentsplyImplants, Mölndal, Sweden). The possibility of placing of implants at the same time of the SFE procedure, was left to the opinion of the surgeon in charge, and was based on the amount of RBH and bone quality,

as assessed during surgery. The amount of graft material inserted varied according to the size of defect to be filled. Suturing (Prolene 4.0 or 5.0, Ethicon™, Johnsson & Johnsson®) was performed in 2 layers using horizontal matrass sutures and individual double-O sutures. All patients received antiobiotics (amoxicilline + clavulanic acid 500/125mg for 7 days) and were asked to take NSAIDs, 3 times a day (Ibuprofen 600 mg) for 5 days and to use an antiseptic spray twice a day for 1 week (PerioAid™ Spray 0,12%, Dentaid®, Spain). Furthermore they received a nasal spray containing corticosteroids (Nasonex 50µg, Mometasonfuroate) to be used once a day, for 7days. Patients were asked to answer some questions regarding the surgical techniques in order to evaluate a patient’s preference. Sutures were removed after 7-10 days. Pain scales: To assess post-operative pain, the Dutch version of the McGill Pain Questionnaire (MPQ-DLV) was used (Melzack, 2005) The reliability and the validity of the MPQ-DLV has been confirmed in various publications (van der Kloot et al., 1995; Vercruyssen et al., 2014). The questionnaire was handed out as a diary and patients were asked to fill in the questions every day, from day 1 until day 7. This questionnaire used 100 mm VAS-scales to evaluate the amount of pain, ranging from 0 (no pain) to 100 (worst pain imaginable) and the amount of swelling. The patients were asked to fill in the VAS-scales at the day of surgery every 4 h and afterwards daily till day 7. Patients were asked to score their pain three times; the pain they felt at the moment of questioning, and the minimum and maximum amount of pain they felt during the past 4 or 24 h. The patients were also asked to document the number and the sort of analgesics taken each day. Furthermore, patients were asked to fill in VAS scales at the time of surgery and at the evaluation meeting after 7 days. They were asked to score the following questions; mean amount of pain during the past 24 h, during surgery, if they would repeat the procedure in the future and if the duration of each procedure was tolerable. Questionnaires were collected at the 1 week follow-up visit.

Data acquisition & quantitative visualization High-resolution CBCT images (3D Accuitomo™ 170, Morita®, Kyoto, Japan) were obtained based on clinical justification by the treating implant surgeon as part of the treatment protocol (preoperatively (T0), one (T1) and six (T2) week follow-up) to allow an accurate surgical planning and a reliable post-operative evaluation of the bone healing at the level of the maxillary sinus floor (Department OMFS-Impath). A 100 x 100 mm field of view was chosen to include a view of both maxillary sinuses. Scanning parameters were fixed at 90 kV, 5 mA, 17.5 exposure time and standard 180° rotation. All datasets were exported in DICOM format with an isotropic voxel size of 250 µm³. The postoperative scans were spatially matched to the preoperative CBCT by a rigid image registration using maximization of mutual information (Maes et al.,, 1997). The aligned scans were imported into MeVisLab (MeVis Medical Solutions AG, Bremen, Germany) and an experienced implant surgeon, blinded for SFE technique, applied the semi-interactive livewire boundary extraction tool (Barret et al.,, 1997) to extract the sinus cavity and membrane. The livewire technique helps the operator to objectively select the most desirable path around edges by using the lowest cost pat algorithm. After extraction, a 3D surface of the sinus and membrane were reconstructed without being smoothed to preserve its raw volume measurement. Statistical Analysis Post-operative questionnaires Comparisons between treatments were performed for each time separately by means of a Wilcoxon signed rank test. Comparisons between measurements performed at distinct times were made by means of a paired Wilcoxon signed rank test with the patient as the pairing factor. For both types of comparisons, a correction for simultaneous hypothesis testing was applied according to Sidak. All analyses were performed using S-Plus 8.0 for Linux (Tibco, Palo Alto, CA, USA).

Graft volumes, membranes volumes and comparisons between treatments. Membrane volumes at 1 week were compared between treatments by means of a linear mixed model with patient as a random factor and treatment as random factor. Comparisons between treatments were corrected for simultaneous hypothesis testing according to Tukey. The same analysis was repeated for the differences between membrane volume at 1 week and the volume recorded prior to surgery, once for the absolute differences and once for the percentage differences. Normal quantile plots of the residuals showed that the data could be analyzed without transformation, except for the percentage differences, where a log-transformation was applied. Analysis was performed for the total of all treatments and for the treatments with and without simultaneous implant placement.

Results In total 36 SFE treatments were performed (13 lSFE, 10 tSFE & 13 IL). In total 59 implants were placed. In the lSFE group 2 ruptures of the Scheiderian membrane occurred during elevation. Both of them could be treated using a L-PRF membrane to cover the rupture. Graft Volume and Schneiderian membrane volume (Figure 1&2 +Table 2&3) The average pre-operative volume of the Schneiderian membrane (SMV) of all surgical sites was 4,53cm3 (range: 0,59-21,12cm3). There was no statistical difference between initial SMV of the 3 treatments (see table 2&3). One week after surgery the volume of the Schneiderian membrane rose to 11,27cm3 (+148,43%) on average over all surgical sites (range 2,57-40,39cm3). Overall no statistical significant differences could be seen between all treatment options in regards to the swelling of the Schneiderian membrane. The placement of implants simultaneously with the SFE did not have any significant influence on the swelling of the Schneiderian membrane (p>0,05). However, when the change in SMV was calculated, the lSFE provoked more swelling than the tSFE (p=0,02). Between all other treatment options no statistically significant differences could be seen (p>0,05). After 6 weeks the overall SMV was 6,85cm3 (range 1,10- 43,19 cm3), about 39,19% less than the volume at 1 week. The decrease in SMV was not statistically significant between all treatments, nor treatments with or without simultaneous implant placement (p>0,05). The overall average graft volume obtained after 1 week was 1,87 cm3 (range 0,12-4,72 cm3). This volume decreased after 6 weeks to an overall mean volume of 1,33 cm3 (range 0,10-4,29 cm3), which counts for an average decrease of 27,6%. When considering obtainable graft volumes with the different treatment modalities, we could see average graft volumes ranging from 0,64cm3 for the tSFA treatment, over 1,77cm3 for the IL treatment to 2,83mm3 for the lSFE treatment. After 6 weeks the amount of graft volume decreased in every treatment option, ranging from -23,13% for the tSFE, over -24,55% for the lSFE,

to -33,71% for the IL. No statistical significant difference could be obtained between tSFE and lSFE. Simultaneous implant placement didnâ&#x20AC;&#x2122;t interfere significantly with the volumetric changes after 6 weeks (p>0,05). Influence of the swelling of the Schneiderian membrane on the graft volume after 6 weeks. The difference between graft volumes after 6 weeks and 1 week were graphically explored. Afterwards a Spearman rank correlation was used to detect any possible correlation. Although all treatment options correspond in an increase in SMV, no statistically significant correlation between this increase and loss of graft volume could be obtained for all treatments (p=0,97). When treatments with and without implant placement were analyzed separately, no differences could be found (p=0,58 and p=0,38 respectively). Post-operative questionnaires Post-operative questionnaires revealed no statistical differences in subjective surgery times (lSFE vs. tSFE (p=0,59); lSFE vs. IL (p=0,62); tSFE vs. IL (p=0,9)) or subjective feeling toward the 3 procedures (p>0,05). Overall no significant differences could be seen between the subjective swelling sensation provoked by each treatment on day 1 & day 2 (p>0,05). From day 3 on tSFE and IL scored significantly less in subjective swelling when compared to lSFE (p<0,05). For tSFE vs. IL no significant differences could be detected (p>0,05) (Table 4 and figure 3). Concerning the post-operative pain sensation there is a trend that the tSFE evokes more pain during some timepoints of the very early stages of healing (at 8h compared to lSFE and at 8h, 12h, day 2 compared to IL). From day 3 on, no significant differences could be seen between tSFE and IL. Overall, the IL procedures scored significantly better than the lSFE during day 4,5,6 and 7.

Discussion The results of this pilot, clinical trial show that the surgical act of sinus augmentation, being lSFA, tSFE or IL, results in a transient clinical reaction (swelling) of the Schneiderian membrane. Furthermore, there seems to be no statistical significant correlation between the swelling of the Schneiderian membrane and the amount of graft reduction after 6 weeks. The transient swelling of the Schneiderian membrane has already been described by Quirynen and coworkers (Quirynen et al., 2014). In this study 2D measurements were made on CBCT images and the authors concluded that an tSFA technique results in transient swelling of the membrane, 5-10 times its original thickness. After a healing period of 6 months the thickness of the membrane normalized to its original thickness, leaving no post-operative complication for the patients. These results are in accordance with the present study, however 3D measurements seem to be more reliable in quantifying the swelling of the Schneiderian membrane. Recent studies indicate no significant changes in membrane thickness after a healing period of 7-9 months (Guo et al., 2016; Anduze-Acher et al., 2013). This observation conďŹ rms that the mucociliary function could recover from SFE without no impact on the natural sinus physiology (Timmenga et al., 2003). The swelling of the membrane probably can be explained by the surgical trauma induced when elevating the sinus mucosa from the sinus walls, resulting in a per- and post-operative bleeding. On the other hand, the intimate contact between the sinus mucosa and the sharp-edged biomaterial particles (as can be seen on scanning electron microscope (Vivan et al., 2016)), may cause â&#x20AC;&#x2DC;microrupturesâ&#x20AC;&#x2122; in the sinus mucosa. The present study shows that the swelling of the Schneiderian membrane is depended on the types of surgical procedure. The present study shows that the swelling of the Schneiderian membrane is depended on the type of surgical procedure. The lSFE seems to provoke a more intense swelling as compared to the tSFE. This may be explained by the more intense surgical manipulation during surgery. However this is just speculative and needs to be confirmed by studies. This failed to prove a possible association between the transient swelling of the Scheiderian membrane and the amount of graft volume reduction after 6 weeks, which could have been a co-factor.

Lots of attention in recent years has gone to different types of grafting materials. Stability of graft volume is considered as an important in factor in the success of a SFE procedure. Evidence clearly shows that autogenous particulated bone (APB) is prone to severe graft reduction over time. Sbordone and co-workers (Sbordone et al., 2013) showed a decrease of the APB graft volume with 23% at 6 months after lSFE and with 39,2% after 6 years. Results seemed to be better when using autogenous bone blocks (-21,5% after 6years). Other studies showed an even bigger graft volume reduction (-42,30% to -49,5%) at 6 months (Cosso et al., 2014; Johansson et al., 2001). However, when the APB was mixed with hydroxyapatite in a 20/80 scale, the GVR could be reduced to -25,8%. Therefore, it seems logical that different biomaterials may influence the graft volume stability before implant placement, but eventually also the stability of implants themselves (Browaeys et al., 2007). There is some evidence to support that deproteinized bovine bone materials (DBBM) seems to offer a more stable graft volume than mineralized and composite allografts. DBBM is a material with a very slow resorption rate and offering a good scaffold for natural bone growth during healing and integration period of the graft. This slow resorption rate probably explains the volumetric stability after SFE procedures, even during longer healing periods (Chiapasco et al., 2009; Boyne & James, 1980). In the present study a mixture (60/40) of DBBM and L-PRF was used which showed a 1,4 times higher new bone formation (Zhang et al., 2012). It could be argued whether the 40% of L-PRF used as a grafting material might have some influence on the volumetric changes over time. However, this is difficult to detect and to our best knowledge literature is lacking information on this topic. When evaluating the papers published by Thor and coworkers (Thor et al., 2007; Stefanski et al., 2016) regarding the immediate placement of implants without the use of bone grafts or other bone substitute materials, it was demonstrated that this a successful approach for new bone formation around implants in the posterior part of the maxilla, when the preoperative height of the subantral bone is moderate and enough to achieve primary stability. It is suggested that the use of this technique can reduce the risk for morbidity related to harvesting of bone grafts and eliminate costs for grafting materials. However, whenever the simultaneous placement of implants is not possible, the use of a bone substitute is of utmost importance to achieve graft stability. The question remains how much biomaterials is needed for such a purpose.

To our best knowledge, this is the first study to assess the influence of various surgical SFE techniques on volumetric changes. Graft volumes after lSFE seem to be around 2,5cm3 when assessed volumetrically. However, a study by Mazzocco ad co-workers was only able to obtain an mean graft volume of 1,43cm3 when performing a lSFE (Mazzocco et al., 2014). To our best knowledge, no information can be found in literature on the obtainable graft volumes after a tSFE or IL. In the present study, the amount of graft volume obtainable with the IL treatment was less than those what could obtained with the lSFE. Nevertheless, this results should be considered with caution, as the hydrodynamic pressure and cavitational effect is able to fully elevate the Schneiderian membrane which gives the surgeon the opportunity to graft in various sizeable volumes (Troedhan et al., 2014, 2012). The graft volume obtained with tSFE was significant less than the other treatments options. A tSFE is mostly applied when an augmentation for a single implant is necessary. Probably this can explain this significant difference obtained in this study. Various volumetric graft reduction rates have been reported in different studies, even when the same biomaterial was used (Mazzocco et al., 2014; Kirmeier et al., 2008; Gultekin et al., 2016; Umanjec-Korac et al., 2016; Kim et al., 2013; Cosso et al., 2014; Sbordone et al., 2014). The present study can agree on this, as the same composition of biomaterials was used for every treatment option. In comparison to the aforementioned studies, the present study has a shorter observation period, as we wanted to examine a possible influence of the transient swelling of the Scheiderian membrane on the attainable graft volumes. The differences in volumetric reduction rates may be explained by some patient depended factors: number of missing teeth, anatomy of the maxillary sinus, repneumatisation capacity of the patient, contact osteogenesis capacity of the residual wall surface area connected to the graft material and remaining alveolar height (Shanbhag et al., 2014; Kirmeier et al., 2008). Nevertheless, the surgeon himself can influence this by choosing the graft material (Gultekin et al., 2016; Sbordone et al., 2014; Cosso et al., 2014), influencing the compression force during insertion of the graft and the surgical technique, as shown by the present study. Furthermore, different measuring techniques and software variations will lead to differences reduction rates. However, quite some studies come to the conclusion that 3D analysis is a very promising and accurate tool in quantifying the long-term changes in the grafted area (Ohe et al., 2016;

Cosso et al., 2014; Gultekin et al., 2016). Studies have shown that 3D techniques are more accurate than 2D techniques when assessing the resorption of the grafted bone (Kim et al., 2013). In order to perform accurate measurements, the use of high resolution CBCT scans seems justifiable when taking into account the average thickness of the Schneiderian membrane (0,79Âą052mm; Insua et al., 2016) and the thickness of the inferior and lateral maxillary sinus wall (1-2mm; Monje et al., 2014). High resolution CBCT images, like the ones used in the present study, seem to show the least measurement errors in cortical and trabecular bone (Van Dessel et al., 2016). Based on the results of the present study, a post-operative CBCT scan, 6 weeks after the surgery, seems to be of clinical importance in order to visualize the graft volume and increased thickness of the Schneiderian membrane. Inherently, every surgical procedure has advantages and shortcomings. So do the various SFE techniques. The lSFE, can be seen as the gold standard in SFE techniques (Del Fabbro et al., 2013). Its inherent advantages are the per-operative visibility and complication management (as could be achieved in the 2 out of 13 lSFE (15%) performed in this study) and the possibility to augment large volumes. However, one has to be aware that a good pre-operative planning on CBCT is a prerequisite when performing a lSFE (Temmerman et al., 2011; Tadinada et al., 2016). Due to the fact that a lateral osteotomy has to be made, the anatomical structures have to be visualized as good as possible in order not to cause vascular damage. Indeed, the posterior superior alveolar artery, a branch of the infraorbital artery (Traxler et al., 1999) is running in the bony lateral sinus wall, providing vascularization for this wall. Its diameter can be up to 4mm (Temmerman et al., 2011). Damaging this vascular structure will not only provoke a per-operative arterial bleeding, but may possibly lead to necrosis of the bony lateral sinus wall, loss of the graft material and/or implants (Khojastehpour et al., 2016; GĂźncĂź et al., 2011; Danesh-Sani et al., 2016). The tSFE (Summers, 1994) is a less invasive technique and possibly this technique reduces the treatment time. The drawbacks of this technique are the limited intra-operative complication management, although rare complication, of bening paroxysmal positional vertigo (BPPV). It includes the displacement of otoliths by vibratory forces transmitted by osteotomes and mallet along with the hyperextension of the head during the operation, causing them to float around in the endolymph (Akcay et al., 2016; Giannini et al., 2015;

Pjetursson & Lang, 2014). Unexpectedly, the data of this study shows that this technique causes the most post-operative pain during the first 2 post-operative days. The tapping of the osteotome with a mallet seems to have a bigger impact for the patient than it was thought to have in the past. Further research should be done on how to replace this tapping procedure. In literature, tSFE procedures are predominantly used when the RBH is >5mm, as a lesser remaining bone height may not allow a primary implant stability (Pjetursson & Lang, 2014). However, recently tSFE have been successfully used in patients with less RBH (Si et al., 2013; Nedir et al., 2013) and extreme cases (Nedir et al., 2014). For now, a critical threshold in RBH can not be indicated due to the lack on data (Chao et al., 2010). In the present study, 4mm was used as a threshold for the tSFE procedures. Whenever the RBH was less, lSFE and IL where randomly allocated. It can be seen that the tSFE technique is able to generate lesser amounts of bone. Nevertheless this can be argued because this technique is predominantly used in 1-2 teeth diastema. The IL procedure is based on a minimal invasive hydrodynamic elevation technique to lift the sinus mucosa from a crestal approach, using specially developed inserts and ultrasound in order to be as atraumatic as possible and deminisch the post-operative discomfort (Troedhan et al., 2012; Wainwright et al., 2016). The limited intra-operative visibility and impossibility of any complication managment remain the main shortcomings of this technique. However, the main advantage is the augmentation quantities of large scales, due to a enhanced detachment of the Schneiderian membrane (Troedhan et al., 2014) and the inherent small post-operative burden for the patient. In the 15 IL surgeries performed in this study no complications were encountered. Nevertheless, when performing this technique, surgeons have to be aware that ruptures of the Schneiderian membrane are very difficult to detect. Noteworthy is the fact that an enhanced detachment of the Schneiderian membrane can also be seen as a shortcoming, as surgeons (who are less experienced with this technique) will have difficulties in acquiring a subjective feeling of the augmented volumes. One could argue that whenever an increased membrane release is obtained the osteogenic potential (exposure to the bony walls) would increase. However, this could not be verified in this study. Furthermore, it remains difficult to subjective feel the detachment of the Schneiderian membrane, when using this technique.

The simultanuous placement of implants didnâ&#x20AC;&#x2122;t seem to interfere with the volumetric changes of the graft after 6 weeks. However, there is a good chance that this can be explained by the rather short evaluation period (6 weeks). No longterm analysis of the graft volume, after implant loading was performed. Although it seems reasonable that when performing long term analysis, the placement of implants simultanuous with the SFE might become more important. This shortterm analysis therefore, can be seen as the main shortcoming of this study. Studies have shown that even after functional loading of oral implants placed in the augmented maxillary sinus, an ongoing volumetric resorption takes place (Berberi et al., 2015; Zijderveld et al., 2009). A further shortcoming might be the rather small sample sizes of each group of treatments.

Conclusion Within the limitations of the present prospective, pilot clinical trial, it can be concluded that all 3 surgical SFE techniques were able to provide sufficient graft volume for further implant treatment. All techniques provoked a partially transient swelling of the Schneiderian membrane, which is significantly bigger when using a lSFE technique. All surgical techniques resulted in a decrease in graft volume after 6 weeks, however no significant differences were obtained between treatments. Furthermore, no statistical significant correlation between the post-operative swelling of the Schneiderian membrane and reduction of graft volume at 6 weeks could be obtained. The IL technique caused the least post-operative discomfort to the patient, definitely during the early phases of healing. This technique has to be handled with care, as the surgeonsâ&#x20AC;&#x2122; subjective feeling on augmented volumes can be hampered. The surgical act of tapping the osteotome during a tSFE should not be underestimated as the tSFE causes more post-operative discomfort during the first days of healing. Acknowledgments The authors would like to aknowledge Dr. Wim Coucke for his support in the statistical analysis.

Figures figure 1 3D visualization of a study patient. Right side was treated with a lSFE and the left side was treated with IL SFE. (a) Pre-operative 3D visualization of both maxillary sinuses (blue: total sinus volume; red: volume of the Schneiderian membrane) (b) Pre-operative 3D visualization of both maxillary sinuses (red: total sinus volume; grey: bony surrounding structures). (c) 1 week post-op 3D visualization of both maxillary sinuses and grafted volume (red: remaining sinus volume; yellow: grafted volume). (d) 6 weeks post-op 3D visualization of both maxillary sinuses and grafted volume (red: remaining sinus volume; yellow: grafted volume).

figure 2 Semi-automatic LiveWire boundary extraction on panoramic slices of CBCT. (1a.) panoramic slice pre-operatively (1b.) panoramic slice pre-operatively, after extraction and color coding (red: volume sinus; blue: volume Schneiderian membrane; yellow:

volume graft). (2a.) panoramic slice 1 week post-operatively (2b.) panoramic slice 1 week post-operatively, after extraction and color coding (red: volume sinus; blue: volume Schneiderian membrane; yellow: volume graft). (3a.) panoramic slice 6 weeks post-operatively

(3b.) panoramic slice 6 weeks post-operatively, after extraction and color coding (red:

volume sinus; blue: volume Schneiderian membrane; yellow: volume graft).

figure 2 Graphical presentation of VAS-scales. In the Y-axis; the pain sensation and in the X-axis the time.

Tables Table 1 Patient demographics and overview between treatments with simultaneous and delayed implant placement. Overall

lSFE

tSFE

Mean 56,6y (28-78y)

Mean 57,2y (43-78)

Mean 53,9y (28-68)

Mean 57,5y (28-78)

7/11

5/8

4/4

5/10

21/38

7/20

9/1

5/17

Changes in Graft Volume (T2-T1) Simultaneous vs. Delayed

p=0,97

p=0,49

p=0,97

Membrane Volume changes (T1) with Simultaneous vs. Delayed

p=0,73

p=0,39

p=0,24

Membrane Volume changes (T2T1) Simultaneous vs. Delayed

p=0,29

p=0,28

p=0,03

Age Gender (male/female) Implants placed simultaneous/ delayed

Table 2 Overview of graft and membrane volumes & volumetric changes. Surgical

Lateral Sinus

Transcrestal Sinus

Intralift Sinus

Technique

Floor Elevation (lSFE)

Floor Elevation (tSFE)

Floor Elevation (IL)

Time points

Graft Volume (cm3)

2,84 SD: 1,22 (0,8-4,72)

2,14 SD: 1,20 (0,62-4,29)

Graft Volume Reduction

-24,55% (T2-T1)

p-values (overall) (simultaneous) (delayed)

0,63 SD: 0,33 (0,17-1,28)

0,49 SD: 0,29 (0,09-1,14)

-23,13% (T2-T1)

1,77 SD: 1,49 (0,12-3,91)

1,17 SD: 0,98 (0,09-3,45)

-33,7% (T2-T1)

lSFE vs. tSFE (p=0,62)overall, (p=0,98)simultaneous, (p=0,39)delayed tSFE vs. IL (p=0,98)overall, (p=0,99) simultaneous, (p=0,87)delayed lSFE vs. IL (p=0,45)overall, (p=0,97) simultaneous, (p=0,51)delayed

Table 3 Overview of Schneiderian membrane volumes & volumetric changes. Surgical

Lateral Sinus Floor

TranscrestalSinus

Intralift Sinus

Technique

Elevation (lSFE)

Floor Elevation (tSFE)

Floor Elevation (IL)

Time points Membrane volume (in cm3)

4,88 SD: 5,62 (0,5921,13)*

14,01 SD: 9,35 (4,7340,39)

7,54 SD: 11,11 (0,9943,19)

4,10 SD: 2,85 (0,658,32)*

9,21 SD: 4,68 (2,5717,29)

8,21 SD: 10,95 (1,2337,17)

4,04 SD: 4,09 (0,0313,64)*

10,13 SD: 5,01 (2,8720,24)

5,14 SD: 3,41 (1,708,95)

T0+ 187,14%

T146,1% (T0+ 54,57%)

T0+ 124,83%

T110,97% (T0+ 100,15%)

T0+ 172,05%

T153,21% (T0+ 27,27%)

Membrane volume changes p-value (overall) (simultaneous) (delayed) at T1 & T2

lSFE vs. tSFE (p=0,16)T1overall, (p=0,25)T1simultaneous, (p=0,49)T1delayed (p=0,04)T2overall, (p=0,70)T2simultaneous, (p=0,01)T2delayed tSFE vs. IL (p=0,79)T1overall, (p=0,38)T1simultaneous, (p=0,97)T1delayed (p=0,38)T2overall, (p=0,51)T2simultaneous, (p=0,21)T2delayed lSFE vs. IL (p=0,31)T1overall, (p=0,88)T1simultaneous, (p=0,37)T1delayed (p=0,26)T2overall, (p=0,80)T2simultaneous, (p=0,18)T2delayed

* No statistical significant difference were found for the pre-operative Schneiderian membrane volume between the 3 groups (p=0,72)

Table 4 Post-operative subjective swelling and pain differences as scored on VASscales, between 3 treatment options (lSFE, tSFE & IL) with respective p-values. Timepoint

lSFE vs.

p-value

lSFE vs. IL

p-value

tSFE vs. IL

p-value

tSFE Surgery + 4 hours

lSFE = tSFE

0,44

lSFE = IL

0,53

tSFE = IL

0,58

Surgery + 8 hours

lSFE = tSFE

0,84

lSFE = IL

0,10

tSFE = IL

0,16

Surgery + 12 hours

lSFE = tSFE

0,69

lSFE = IL

0,11

tSFE = IL

0,50

Surgery + 2 days

lSFE = tSFE

0,39

lSFE = IL

0,09

tSFE = IL

0,62

Surgery + 3 days

lSFE>tSFE

0,04

lSFE > IL

0,02

tSFE = IL

0,98

Surgery + 4 days

lSFE>tSFE

0,01

lSFE > IL

0,02

tSFE = IL

0,87

Surgery + 5 days

lSFE>tSFE

0,01

lSFE > IL

0,02

tSFE = IL

0,77

Surgery + 6 days

lSFE = tSFE

0,09

lSFE > IL

0,04

tSFE = IL

0,63

Surgery + 7 days

lSFE = tSFE

0,14

lSFE > IL

0,02

tSFE = IL

0,50

MAX Pain Sensation MIN Pain Sensation AVG Pain Sensation

Timepoint

lSFE vs. tSFE

p-value

lSFE vs. IL

p-value

tSFE vs. IL

p-value

Surgery + 4 hours

lSFE = tSFE

0,09

lSFE = IL

0,94

tSFE = IL

0,06

Surgery + 8 hours

lSFE < tSFE

0,02

lSFE = IL

0,98

tSFE > IL

0,03

Surgery +12 hours

lSFE = tSFE

0,12

lSFE = IL

0,50

tSFE > IL

0,04

Surgery + 2 days

lSFE = tSFE

0,41

lSFE = IL

0,16

tSFE > IL

0,03

Surgery + 3 days

lSFE = tSFE

0,76

lSFE = IL

0,06

tSFE = IL

0,12

Surgery + 4 days

lSFE = tSFE

0,56

lSFE > IL

0,03

tSFE = IL

0,19

Surgery + 5 days

lSFE = tSFE

0,15

lSFE > IL

0,02

tSFE = IL

0,43

Surgery + 6 days

lSFE = tSFE

0,08

lSFE > IL

0,02

tSFE = IL

0,89

Surgery + 7 days

lSFE = tSFE

0,15

lSFE > IL

0,01

tSFE = IL

0,43

Surgery + 4 hours

lSFE = tSFE

0,44

lSFE = IL

0,94

tSFE = IL

0,19

Surgery + 8 hours

lSFE = tSFE

0,25

lSFE = IL

0,62

tSFE = IL

0,22

Surgery +12 hours

lSFE = tSFE

lSFE = IL

0,30

tSFE = IL

0,48

Surgery + 2 days

lSFE = tSFE

0,92

lSFE = IL

0,15

tSFE = IL

0,40

Surgery + 3 days

lSFE = tSFE

0,64

lSFE > IL

0,03

tSFE = IL

0,60

Surgery + 4 days

lSFE = tSFE

0,38

lSFE = IL

0,07

tSFE = IL

0,61

Surgery + 5 days

lSFE = tSFE

0,17

lSFE > IL

0,03

tSFE = IL

0,78

Surgery + 6 days

lSFE = tSFE

0,40

lSFE = IL

0,06

tSFE = IL

0,55

Surgery + 7 days

lSFE = tSFE

0,50

lSFE = IL

0,06

tSFE = IL

0,23

Surgery + 4 hours

lSFE = tSFE

0,06

lSFE = IL

0,78

tSFE > IL

0,04

Surgery + 8 hours

lSFE = tSFE

0,07

lSFE = IL

0,80

tSFE > IL

0,04

Surgery +12 hours

lSFE < tSFE

0,04

lSFE = IL

0,40

tSFE > IL

0,03

Surgery + 2 days

lSFE = tSFE

0,38

lSFE = IL

0,18

tSFE = IL

0,06

Surgery + 3 days

lSFE = tSFE

0,75

lSFE = IL

0,07

tSFE = IL

0,32

Surgery + 4 days

lSFE = tSFE

0,45

lSFE > IL

0,01

tSFE = IL

0,23

Surgery + 5 days

lSFE = tSFE

0,18

lSFE > IL

0,01

tSFE = IL

0,51

Surgery + 6 days

lSFE = tSFE

0,29

lSFE > IL

0,02

tSFE = IL

0,45

Surgery + 7 days

lSFE = tSFE

0,34

lSFE = IL

0,06

tSFE = IL

0,41

Table 5 Overview of patient ID and treatments. Patient ID

Treatment Right - Left

1001

tSFE – lSFE

1002

tSFE – IL

1003

IL – tSFE

1004

tSFE – IL

1005

lSFE – IL

1006

IL - tSFE

1007

lSFE – IL

1008

IL – lSFE

1009

lSFE – IL

1010

tSFE – lSFE

1011

tSFE – lSFE

1012

IL – lSFE

1013

tSFA – IL

1014

lSFE – IL

1015

IL - lSFE

1016

ISFE – IL

1017

IL- lSFE

1018

lSFE – IL

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• Zhang, Y., Tangl, S., Huber, C.D., Lin, Y., Qiu, L. & Rausch-Fan, X. (2012) Effects of Choukroun’s platelet-rich fibrin on bone regeneration in combination with deproteinized bovine bone mineral in maxillary sinus augmentation: a histological and histomorphometric study.

Journal of Cranio-Maxillo-Facial Surgery: Official Publication of the European Association for Cranio-Maxillo-Facial Surgery 40, 321–328.

• Zijderveld, S.A., Schulten, E.A.J.M., Aartman, I.H.A. & ten Bruggenkate, C.M. (2009) Long-term changes in graft height after maxillary sinus floor elevation with different grafting materials: radiographic evaluation with a minimum follow-up of 4.5 years.

Clinical Oral Implants Research 20, 691–700.

The use of extra-short oral implants in patients with extreme bone resorption.

The use of extra-short locking taper, plateau shaped oral implants in patients with extreme bony resorption: a 10 year follow up, prospective cohort study. Temmerman Andy, Teughels Wim, Duyck Joke & Quirynen Marc. Preliminary results (ongoing long-term follow-up).

Abstract Background & objective: Short implants might by a interesting alternative treatment option for patients suffering from limited RBH, reducing the morbidity, treatment time and inherent costs of vertical bone augmentation procedures. The aim of this prospective cohort study was to provide information on • the long-term clinical succes of extra short implant (≤6 mm) when used in patients with severe atrophy (survival rate – primary outcome measure) • the long-term alterations in MBL (secondary outcome measure) • long-term influence of in an increased C/I ratio on MBL alterations and technical complications (tertiary outcome measure). Materials & Methods: A total of 44 patients were enrolled in this study. Of these patients, 21 were male, 23 were female (mean age: 59,3y (range (49-81y)). A total of 144 implants were placed, all of them in the posterior regions of the maxilla or mandible, via a 2-stage protocol. All implants were 5 or 6 mm in length and 4, 4,5 or 5 mm in width. None of the implants were placed in extraction sockets, nor were they treated with a GBR procedure. Results: The mean submerged healing period was 3.1± 1,2 months. Six implants (in 3 patients) were lost due to non-integration (4,2%) and 2 implants were lost before the 1 year recall visit. This resulted in a CSR of 94,45%. The implants were primarily placed subcrestally (mesially: 1,12 mm ± 0.6,7, and distally: 1,36 mm ± 0.57 below bone level). Six months after LD an average loss of marginal bone of -0,12 mm (range: 0,68 to -0,97 mm). After 12 months of LD the average loss of marginal bone was +0,09 mm. All restored implants were divided into 3 groups, according to their respective C/I ratio: group A (<1,75), group B (1,75-2,4) & group C (≥2,4). At 1-year no differences between groups on MBL alterations could be found. Conclusions: These preliminary data suggest that short implants might be a valuable treatment option for patients suffering from impaired RBH. C/I ratio seems not to interfere with the MBL alterations. Long-term follow-up is mandatory to give decisive conclusions.

Introduction The use of tissue integrated implants has improved the quality of life for innumerable patients. Long-term data from clinical studies, mostly report succesfull treatment outcomes (Hultin et al., 2000; Astrand et al., 2008). Bone quality and quantity seems to be of utmost importance in order to achieve succesfull osseointegration. Unfavourable conditions of the alveolar bone (eg. periodontitis, extractions, trauma, infections) might provoke a decrease in alveolar ridge height due to bone atrophy. This atrophy might cause a challenging interarch relationship in vertical, horizontal and sagittal planes (Chiapasco et al., 2009). In order to overcome the problem of impaired bone quantity, the clinician has 3 options. The first option is to enhance the bone quantity via different, surgical techniques. Various techniques are described in literature: SFE procedures (Del Fabbro et al., 2013), distraction osteogenesis (Rossini et al., 2016; Yun et al., 2016), inlay and onlay grafting via bone blocks (Nkenke and Neukam, 2014) and GBR procudures (Benic and HĂ¤mmerle, 2014; Urban et al., 2014). For these purposes different materials can be used (eg. autologous bone (Chiapasco et al., 2009), allografts (Milinkovic and Cordaro, 2014), xenografts, alloplastic materials (Wheeler, 1997) & osteoinductive materials (Faour et al., 2011)) Other techniques that intervine with anatomical structures (eg. Alveolar nerve transpositioning and lateralisation) have also been described. Frequently associated with (sometimes transient) neurosensory alterations (Abayev and Juodzbalys, 2015a; Abayev and Juodzbalys, 2015b; Vetromilla et al., 2014). Besides the high costs, these techniques frequently cause higher morbidity to patients. Furthermore, they might not always be as predictable, especially when bone augmentation in a vertical direction is desired (Esposito et al., 2009). In addition, these augmentation techniques go hand in hand with prolonged treatment times (Lai et al., 2013). A second option to overcome the problem of impaired bone quality is to choose for oral implants that differ from the standard dimensions. In patients with a very narrow alveolar bone width, small diameter implants could be an alternative (Temmerman et al., 2015). In patients with limited alveolar height on the other hand, short implants might be the alternative.

A third option might be to tilt oral implants to avoid damage to anatomical stuctures (Barnea et al., 2016; Maló et al., 2003; Lopes et al., 2016). Depending on the definition used for short implants these might include implants ≤10 mm (Sun et al., 2011; Menchero-Cantalejo et al., 2011). However, the most used definition for short oral implants only includes implants ≤8 mm (Neldam and Pinholt, 2012; Nisand and Renouard, 2014; Lee et al., 2014). Initial resuls with short implants were not encouraging (Jemt, 1991; Naert et al., 1992). However, it should be kept in mind that these papers were focussing on turned implants. Nowadays, the results with short implants are definitly much more encouraging due to enhanced implant surfaces and designs (Table 1). When using short implants this can be in patients with a sufficient bone quantity and with an impaired bone quantity. When used in the last group of patients this will inherently result in an increase in C/I ratio (Morand and Irinakis, 2007; Tawil et al., 2006). Initially the recommendations, for C/I ratio were copied from C/I ratios for tooth supported fixed prothodontics (Tawil et al., 2006). An increased C/I ratio risks to lead to higher stress peaks, which in turn may provoke higher MBL alternations, implant failure and mechanical failures (Bayraktar et al., 2013; Urdaneta et al., 2010; Mertens et al., 2012; Sun et al., 2015).Such explicit stress related peri-implant bone changes are, however, nor observed nor reported. The aim of this prospective cohort study was to provide information on • the long-term clinical succes of extra short implant (≤6 mm) when used in patients with severe atrophy (survival rate – primary outcome measure) • the long-term alterations in MBL (secondary outcome measure) • long-term influence of in an increased C/I ratio on MBL alterations and technical complications (tertiary outcome measure).

Material &Methods The study was designed as an open, prospective, cohort study trial. The study was approved by the Ethical Committee of the KU Leuven, UZ Leuven University Hospitals (S54248) and was conducted in accordance with the requirements of the Helsinki Declaration of 1975 and revised in 2008. Patient population: Patients had to fulfill all of the inclusion and non of the exclusion criteria (Table 2). All patients were given oral and written information on the study protocol and its procedures and were asked to sign the Informed Consent form. From 2012 to 2015, 44 patients were enrolled in this study. Surgical Procedures: All surgical procedures was performed under local anaesthesia and strict sterile conditions. After a crestal incision, a mucopersioteal flap was raised. Osteotomies were performed according to the guidelines of the company: a pilot drill was used, at 1200 rpm, over a length 1-2 mm longer than the length of the implant to be placed. Afterwards reamers of different sizes were used to widen the osteotomy to the desired width. In contrast to the osteotomies for screw type implants, the osteotomy for a plateau shaped locking taper implant is not undersized. During osteotomy site preparation, bone chips were collected from the reamers. Afterwards, 1-6 Bicon Integra-CP (Bicon LLC, Boston, MA, USA) were inserted in the prepared osteotomies, using an implant seating tip on an osteotome and a hand mallet. All implants were placed 1-3 mm subcrestally in order to prevent soft tissue penetration during the healing phase (Van Assche et al., 2008). PEAK plugs were cut down to the height of the implant and inserted into the implant connection. The collected autologous bone chips were used above the implant and to cover possible small implant dehiscencies. Primary implant stability was assessed manually as for this type of implant no other techniques (eg. RFA) are available. Mucoperiostal flaps were sutured back to secure a tight seal in order to achieve a submerged healing. All subjects were given a prescription for a chlorhexidine rinse. Postoperative antibiotics and anti-inflammatory drugs could be prescribed according to the assessment of the surgeon in charge. One week after implant surgery,

sutures were removed and the existing prostheses were relined with a temporary soft lining. Twelve weeks after implant surgery, healing abutments were connected. Via a crestal incision, implant were retrieved and the possible excess of bone was removed in order to get access to the covering plugs. After removal of the covering plugs and whenever necessary, an especially designed reamer was used to widen the entrance to the inside of the implant and secure a good fit of the healing abutment. Implant stability was evaluated manually. Healing abutments were inserted using a seating tip on an osteotome and a hand mallet. The mucoperiosteal flaps were sutured back to ensure a tight seal. After 1 week, sutures were removed. Prosthetic Procedures: After a short period of healing, the healing abutment is removed by the restorative dentist with a forceps by gripping the healing abutment and making slight rotational movements. Once removed, the implant well is dried with a cotton roll and an impression post is placed into the implant well by using only finger pressure. On top of this impression post, a transfer sleeve is seated. After performing a closed tray impression, the transfer sleeve is picked up by the impression material where the impression post â&#x20AC;&#x2DC;has to stayâ&#x20AC;&#x2122; seated in the implant after removal of the impression tray. If the impression post comes out with the transfer sleeve inside the impression, there is a high chance the impression is inaccurate. After removal of the impression tray, the impression post is removed from the implant well with a forceps and seated in the transfer sleeve. An implant analogue is then placed in position. This allows for the design of one-piece abutment and crown restoration called the Integrated Abutment Crown or IAC. These IAC crowns are seated in the implant well and pushed only slightly into position.The cold weld is installed by having the patient bite down firmly on a cotton roll, and by tapping it with a special mallet and seating jig. A tug-back test on the crown after final seating was used in order to assess the stability.

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Radiological Follow-up: The digital intra-oral radiographs (follow-up) were obtained using the parallel technique, with position holders and a long-cone radiographic unit (Digora® photostimulable phosphor plates and the MinRay® intra-oral radiographic system, Soredex, Tuusula, Finland).The University Hospitals Leuven use a standardized protocol in which the setting of the radiographic system is depended on the region of the mouth where the photo is taken. Radiographs were taken at different time points: immediately after surgery and abutment connection, LD, LD+6 months, LD+1-10y. Marginal Bone Levels: The distances, in millimetres, between the shoulder of the implant and the first clear bone-to-implant contact were recorded both mesially and distally.The thread pitch distance and the full length of the implant were also recorded and were used for conversion.These measurements (accuracy of 0.01 mm) were performed with a software program (Image J®, NIH, Bethesda, Maryland, USA).The measurements were initially made in a pixel format.Linear distance measurement (mm) could be retrieved after calibration of the images according to the respective thread pitch distance, provided by the manufacturer. The full length of the implant was used for the conversion. The analysis of peri-implant bone level alterations was performed by 2 calibrated, independent periodontologists.Results were re-evaluated when there was a ≥1 mm inter-examiner difference. The marginal bone level at the time of final restoration delivery, and thus functional loading, was regarded as baseline. Clinical Examination: Oral examinations evaluating the presence of plaque, PPD, CAL, and BoP was performed at all stages of follow-up. Furthermore the presence of keratinized tissues around the implant were evaluated in mm.

C/I ratio: C/I ratio was determined on the periapical radiographs taken at final crown delivery and thus functional loading. The functional C/I ratio was used, being the length of the crown, measured from the top of the crown to the first visible BIC. Due to the fact that this functional C/I will vary according to the MBL alterations following loading, these measurements are only performed on the initial radiographs. Statistical Analysis: Data are represented by their mean, standard deviation and median, and were calculated for each implant.Empirical cumulative distribution functions are going to be used to represent them graphically. All statistical analysis was performed using a statistical software package SPSS Statistics version 21 (IBM Corp, Chicago, IL, USA).

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Results Patient & Implant data: A total of 44 patients were enrolled in this study. Of these patients, 21 were male, 23 were female (mean age: 59,3y (range (49-81y)). Patients presented with a residual bone height ranging from 5,7 mm to 7,3 mm (mean 6,2 mm) as measured on the respective CBCT cross-sectional slices.All implant sites were analysed on CBCT (Scanora 3D®, Soredex, Tuusula, Finland). A total of 144 implants were placed, all of them in the posterior regions of the maxilla or mandible, via a 2-stage protocol. All implants were 5 or 6 mm of length and 4, 4,5 or 5 mm in width. None of the implants were placed in extraction sockets, nor were they treated with GBR procedure. The mean submerged healing period was 3.1± 1,2 months.Six implants (in 3 patients) were lost due to non-integration (4,2%) and 2 implants were lost before the 1 year recall visit. This resulted in a CSR of 94,45%. Marginal Bone Level Alterations and C/I ratio relationships: The implants were primarily placed subcrestally (mesially: 1,12 mm ± 0.6,7, and distally: 1,36 mm ± 0.57 below bone level). Nevertheless, from LD on, all positive measurements were changed to “0”, in order to receive information on the exact amount of MBL alterations. Six months after LD an average loss of marginal bone of -0,12 mm (range: 0,68 to -0,97 mm). After 12 months of LD the average loss of marginal bone was +0,09 mm. The cumulative percentage distribution of the implants according to their marginal bone level at 1, 5 and 10 years are planned for the final results. All restored implants were divided into 3 groups, according to their respective C/I ratio: group A (<1,75), group B (1,75-2,4) & group C (≥2,4). A C/I ratio of 2,4 has been used as a critical value in other studies (Anitua et al., 2014). MBL alterations were thereafter calculated for every group (Table 3). Clinical Parameter: For the clinical parameters no analysis has been done so far.

Discussion The preliminary results of this open, prospective trial show that the CSR for extra-short implant is comparable of the results described in other studies (see Table 1). Although short implants have drawn quite some attention in recent years, we are still in need of clinical trials with a long-term follow up. This is the main reason why, for this study, a final paper will be written after 10 years of follow up. Recently some interesting studies have been published that used a split-mouth RCT design, to test the clinical outcomes of short implants as compared to standard length implants placed in augmented sites. Esposito and co-workers (Esposito et al., 2014) included 15 patients with bilateral atrophic mandibles (5-7 mm above the mandibular canal) and 15 patients with bilateral atrophic maxillae (4-6 mm height below the maxillary sinus). One side was vertically augmented using, interpositional bone bone blocks (mandible) or lSFE procedures and particulated bone (maxilla). After a healing period of 4 months 10 mm implants were placed. The contralateral side was treated with short oral implants (5 mm). However, 5 out of 15 augmented mandibles could not be treated with 10 mm long implants (and shorter ones were used). Implants were loaded after 4 months of osseointegration. Patients were followed for 3 years. After 3 years, 1 implant was lost in the augmentation group and 2 implants were lost in the short implants group. There were no statistical significant differences in MBL alterations between the treatment groups. A recent SR was published with the focused question: â&#x20AC;&#x153;Are short implants superior to longer implants in the augmented sinus in terms of survival and complication rates of implants and reconstructions, patient-reported outcome measures and costs?â&#x20AC;?. It was concluded that complications mainly occurred during SFE procedures and were about 3 times as high compared to short implants. Survival rates were comparable. Patient-reported outcomes, morbidity, surgical time and costs were in favour of short implants (Thoma et al., 2015). When placing and restoring short implants some biomechanical considerations have to be taken into account. It has been shown that the implant length is not the most critical factor for the transfer of occlusal loads to the bone-implant interface. An increase in implant diameter is able to decrease the maximum of stress around the neck of implant more than an increase in implant length, due to a more favourable distribution of masticatory forces (HimmlovĂĄ et al., 2004).

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This seems logical as the bone crest will receive most of the stress and less stress is transferred to the apical portion. An increase in implant width therefore, allows and improved distribution of occlusal forces. The impact of the C/I ratio, on implant failure, MBL alterations and mechanical failures, remains a topic of discussion. An increased C/I ratio might act as a vertical cantilever leading to crestal bone loss and implant failure. However, most studies do not seem to support this statement. Nunes and co-workers evaluated 118 implants with a mean C/I ratio of 2,53. They concluded that an increased C/I ratio does not seem to be correlate with increased MBL alterations (Nunes et al., 2016). The results were confirmed by other studies (Urdaneta et al., 2010; Guljé et al., 2016; Mangano et al., 2016; Quaranta et al., 2014). In the present study, there was a small difference in MBL alterations in favour of the groups A and B. However, long-term follow-up of the study population and implants needs to confirm these preliminary results. Although implant supported FDPs with cantilevers might look like a biomechanical challenge, most studies do not seem to support this. Hälg and co-workers (Hälg et al., 2008) examined 27 implant support FDPs with cantilevers and compared them with 27 FDP without cantilevers. They could conclude that cantilever FDPs did not lead to higher implant failure rates nor increased MBL alterations. However, they could observe more technical complications in the cantilever group. A SR by Aglietta and co-workers focussed on cantilever FDPs with an observation period of at least 5 years. They could conclude that cantilever FDPs are a valid treatment modality with no detrimental effects on the bone levels (Aglietta et al., 2009). These conclusions were confirmed in another, more recent SR. Furthermore, some minor technical complications were found (Torrecillas-Martínez et al., 2014). In our study no cantilevers were used. All implants were restored with single IAC. Due to this concept the number of implants was increased and thereby also the functional area to withstand the loading forces. An interesting subject for further research is whether splinting of implants may be beneficial. Splinting might increase the functional area and thereby transmits less force to the prosthesis, abutments screws and bone-to-implant interface. A recent study Slotte and co-workers used 4 mm short, splinted oral implants in the posterior mandible with a 5 year follow-up. In 28 patients, 86 implants were placed to support a 3- or 4 unit FDP, with the use of pontics nor cantilevers. After 5 years the CSR was 92,2% (Slotte

et al., 2015). In a photo-elastic model study, it was concluded that splinting of the crowns and increasing length of the first implant was the beneficial for the transmission of stress (Pellizzer et al., 2015). Implant designs might be of importance when discussing short implants. The implant surface can be increased by (1) increasing the number of threads, (2) altering the depth of the threads, (3) altering the design of the threads and (4) the implant surface (Misch, 2005). The implants used in the present study are plateau-shaped. Unlike screw type implants and due to the specific protocol for preparing the osteotomy, this implant will achieve a very poor primary stability. Indeed, the osteotomy is prepared as wide as the future implant.This also explains why these types of implants are mainly placed using a two-stage protocol.An interesting study in dogs evaluated the early bone healing around different implants and surgical techniques. In this study screw-type implants with a small or large pitch were compared to plateau-shaped implants with there respective surgical technique for osteotomy site preparation and therefore specific healing chamber configuration. Different implant designs and surgical protocols resulted in different bone healing pattern. After 2 to 4 weeks the bone morphology evolution, however was comparable (Coelho et al., 2010). Healing chamber configuration seems to significantly affect the measurable parameters of osseointegration (eg. BIC)(Marin et al., 2010). Furthermore, the implant – abutment connections need to be considered. Implants with a Morse Cone tapered connection seem to have a positive impact on the crestal bone remodelling when placed subcrestally (Castro et al., 2014), promoting bone growth over the implant shoulder. All implants in the present study, were placed subcrestally following this guideline. Within Morse taper connections the conical abutment and implant entrance show an identical convergence. When these 2 components merge together a strong connection is build (called ‘locking taper’). The smaller the convergence, the higher the friction between the 2 components will be. Morse taper connections are known for a complete stability between the two component, with no micro-movements during occlusal forces. Another ‘finite element analysis’ study concludes that in implants with Morse taper connection the stresses are deducted to the apex of the implant. Possibly this may be beneficial on crestal bone levels (Hanaoka et

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al., 2014). Some studies could find Morse taper connections to be beneficial in situations with a high C/I ratio and non-axial loading (Sotto-Maior et al., 2015; Rossi et al., 2011; Pieri et al., 2011).

Conclusions: The preliminary results of this prospective, cohort clinical trial showed that extra short plateau-shaped, locking taper implants are an alternative for vertical bone augmentation procedures. Marginal bone level alterations are minimal. There seems to be no significant influence of a high C/I ratio on the crestal bone. Long-term follow up is needed to make these preliminary results conclusive. Various biomechanical challenges play a role in the clinical performance of short implants. When addressing these challenges, various studies use ‘finite element analysis’ or ‘photoelastic modelling’. Although these papers have and inherent value, they have to interpreted with care. After all, bone is a living tissue, constantly rejuvenating itself, through a fine equilibrium of bone resorption and new bone formation. The implant design itself and the surgical technique have to be chosen with care, as they seem to influence the clinical performance of short implants as well.

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Figures figure 1 Radiological follow-up of a study patient.

(a) peri-apical radiograph taken at implant placement. (b) peri-apical radiograph taken at abutment connection. (c) peri-apical radiograph taken at delivery of the final crown and functional loading. (d) peri-apical radiograph taken at the 1 year follow-up visit. figure 2 Radiological follow-up of a study patient.

Tables Table 1 SR and meta-analyses on short oral implants (≤8 mm). Implant lenght

Follow-up

Implant Survival

Lee et al., 2014

5-8 mm >8 mm

1-5 y

98,7% 98%

Srinivasan et al., 2014

<6 mm

1-8 y

93,7%

Neldam & Pinholt 2012

6 mm 7 mm 8 mm

1-14 y

85,5-100% 62,5-100% 77,1-100%

Srinivasan et al., 2012

<8 mm

3 months – 9 y

92,2-100%

Romeo et al.,

8 mm

3-14 y

97,9%

Das Neves et al., 2006

7 mm

90,3%

Renouard & Nisand 2006

≤8 mm

88-100%

Friberg et al., 2000

6-7 mm

5-10 y

95,5% (5 y) 92,3% (10 y)

6 mm

1-7 y

88%

Ten bruggenkate et al., 1998

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Table 2 Inclusion and exclusion criteria. Inclusion criteria 1.

Provision of Informed Consent

advanced atrophy of the alveolar process, which made standard implant placement (without augmentation procedures) impossible.

In need of 1-6 implants I the posterior zones of the maxilla or mandible

A history of edentulism in the area of oral implant therapy of at least 3 months

Exclusion criteria 1.

Unlikely to be able to comply with the study procedures, as judged by the investigator

Untreated or uncontrolled caries/periodontal disease

Known or suspected current malignancy

History of chemotherapy, 5 years prior to implant surgery

History of radiation in the head and neck region

History of other metabolic bone diseases, e.g. Pagetâ&#x20AC;&#x2122;s disease, hyperparathyroidism, fibrous dysplasia or osteomalacia

A medical history that makes implant insertion unfavourable

Need for systemic corticosteroids

Current or previous use of intravenous bisphosphonates

10.

Current or previous use of oral bisphosphonates

11.

History of bone grafting and/or sinus lift in the planned implant area

12.

Current need for bone grafting and/or sinus lift in the planned implant area

13.

Present alcohol and/or drug abuse

14.

Participation in a clinical study during the last 6 months.

Table 3 C/I ratio groups and the respective average MBL alterations after 6 months and 1 year of LD. C/I ratio

MBL alteration – 6 months

MBL alteration – 1y

Group A (<1,75)

-0,87 (± 0,60)

-0,11 (±0,34)

Group B (1,75-2,4)

0,07 (±0,52)

0,09 (±0,52)

Group C (≥ 2,4)

-0,32 (±0,32)

-0,31 (±0,24)

C/I ratio

MBL alterations – 6 months

MBL alterations – 1y

Group A + B (<2,4)

-0,14 (±0,66)

-0,13±(0,53)

Group C (≥2,4)

-0,32 (±0,32)

0,31 (±0,24)

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The use of oral implants in patients with very limited bony dimensions of the alveolar process in a bucco-oral direction.

The outcome of oral implants placed in bone with limited bucco-oral dimensions: a 3-year follow-up study. Temmerman Andy, Keestra Hans, Coucke Wim, Teughels Wim, Quirynen Marc. Journal of Clinical Periodontology (2015) 42: 311-318.

This paper received the ‘DentsplyImplants Best Research Award” in 2015 Oral presentations on Chapter 4 were given at: • the symposium on “30 years of Osseointegration” at the KU Leuven (Leuven, Belgium) Poster presentations on Chapter 4 were presented at: • European Association for Osseointegration (EAO) Annual Symposium 2102 (Athens, Greece) – 1 year results • European Association for Osseointegration (EAO) Annual Symposium 2014 (Rome, Italy) – 3 year results • European Association for Osseointegration (EAO) Annual Symposium 2016 (Paris, France) – 5 year results

Abstract Objective: The dimension of the alveolar bone reduces significantly after tooth loss. Clinicians consider a 1 to 2 mm buccal and lingual bone width mandatory around the implant at placement. This prospective study analysed the outcome of implants inserted in jaws with narrow (≤ 4.5 mm) bucco-oral bony dimensions. Material and methods: 28 patients (mean age 63; 89% female) with a narrow alveolar crest (≤ 4.5 mm in width on CBCT) received 100 implants (Astra Tech®, Dentsply Implants, Mölndal, Sweden) via a two-stage procedure. Intra-oral radiographs were taken at placement, functional loading and after 1, 2, and 3-years of follow-up. Peri-implant bone level alterations were recorded by 2 calibrated, independent periodontologists. Results: All implants integrated and the CSR after 3-years was 100%. The implants were inserted 0.81 mm ± 0.83 subcrestal. At functional loading the bone was located 0.65 mm ± 0.6 apical of the implant shoulder (baseline). During the first 3 years of loading the amount of annual marginal bone loss was 0.17 ± 0.4, 0.05 ± 0.4, and - 0.06 ± 0.1 mm, respectively. Conclusions: Based on the present data and within the limitations of this study it became clear that implants, placed in sites with limited dimensions (≤ 4,5 mm width), showed minimal amounts of marginal bone loss during the first 3 years of functional loading.

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Introduction Whenever bone of sufficient quantity and quality is available, oral implants are considered to be a valuable treatment option to replace missing teeth. Consequently implants became part of mainstream dentistry (Adell et al., 1981, Albrektsson et al., 1981). Survival rates of over 95% in non-compromised patients have been reported (den Hartog et al., 2008). Unfortunately, an oral implant does not always osseointegrate. The clinical success of an implant partially depends on several external factors such as primary implant stability, bone quality, time of loading, infection control, surgical technique and height and width of the alveolar bone. Primary implant stability is determined by the properties of the bone that contribute to its strength. Implant micro-movements within a range of 50-150 Âľm seem to be acceptable for optimal bone healing (Szmukler-Moncler et al., 1998). The defining factors for bone quality are Tb.Th, BMD and micro-architecture (Ribeiro-Rotta et al., 2007). In relation to time of loading, a recent review showed no differences in MBL changes between different loading protocols (Suarez et al., 2013). However, the length of the implant seems of interest for the survival rate of most implant systems. Since implant survival decreases when the implant is shorter than 7 mm (Pommer et al., 2011). To determine the health of the peri-implant tissues a radiological assessment of the MBL around the shoulder of an implant is a reliable option (Grusovin et al., 2010). Several factors might influence the MBL. These factors include trauma during implant placement (Sakka et al., 2012), trauma during abutment surgery (Vela-Nebot et al., 2006), the loading protocol (Kim et al., 2005), abutment type (Annibali et al., 2012a) and establishment of the biological width (Hermann et al., 2001). However these factors are still not proven and the debate is still going on. To consider an implant as successful, it has to meet criteria with respect to tissue physiology (osseointegration), function (chewing), absence of pain and patient satisfaction (Tonetti et al., 2012). In 1986, Albrektsson and co-workers stated that a mean marginal bone loss of 1.5 mm after the first year of loading is acceptable (Albrektsson et al., 1986). More recent studies show a mean marginal bone loss of 1.0 mm after the first year of loading and in the following years an annual 0.1 mm additional bone loss (Cecchinato et al., 2008). More recently the criteria for success have become more stringent with three domains that are

important for identifying success. These domains are: patient-reported outcome measures (health-related quality of live and general satisfaction), peri-implant health (MBL, BoP and PD) and implant-supported restorations (longevity of the restoration, function/occlusion related outcomes and technical complications)(Tonetti et al., 2012). Periodontal disease, tooth extraction or trauma can lead to alveolar ridge atrophy. This eventually results in a ridge with deficient width and height for optimal implant therapy (Schropp et al., 2003). To provide adequate bone volume and to assure an adequate aesthetic result bone augmentation procedures are often required. Some papers indicate that the bone thickness around an implant should be at least 1 or 2 mm to assure long-term success and bone coverage (Grunder et al., 2005, Esposito et al., 2007). A recent systematic review on this issue, however, failed to confirm this hypothesis (Teughels et al., 2009). To increase bone volume, different techniques can be used such as guided bone regeneration (GBR), block grafts, ridge splitting, distraction osteogenesis, osteotomy of the ridge or combinations of the above (Milinkovic and Cordaro, 2014, Aghaloo and Moy, 2007). In addition, there are a lot of different materials such as autografts, allografts, xenografts, alloplasts, barrier membranes, osteosynthesis materials or combinations of the above that can be used (Jensen and Terheyden, 2009). The results of these treatments are however not always predictable. For large onlay grafts a survival rate of 87% was reported (Jensen and Terheyden, 2009, Chiapasco and Zaniboni, 2009, Aghaloo and Moy, 2007). For the less invasive grafting techniques the survival rate was 95.5% (Aghaloo and Moy, 2007, Chiapasco and Zaniboni, 2009, Jensen and Terheyden, 2009). Complications occurred in 3.8 to 29.8% of the patients (Chiapasco and Zaniboni, 2009, Aghaloo and Moy, 2007, Jensen and Terheyden, 2009). To date, there is insufficient evidence to set a threshold for the minimal amount of bone necessary in bucco-oral dimensions at implant placement (Teughels et al., 2009, Merheb et al., 2014). This prospective follow-up study aims to evaluate radiologically the interproximal bone changes of oral implants placed in sites with â&#x2030;¤ 4,5 mm of bucco-oral bone width.

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Materials & Methods This prospective, single centre study was carried out at the Department of Periodontology of the University Hospitals Leuven. All oral implants (Astra Tech®, DentsplyImplants, Mölndal, Sweden) were placed in the period between 2009 and 2010. The following inclusion criteria had to be fulfilled: • Implant sites with ≤ 4.5 mm bone in bucco-oral dimensions. • Patients expectations were pure functional, without any severe aesthetical demand. This study was approved by the ethical committee of the University Hospitals of Leuven. All patients included fulfilled all of the inclusion criteria. After oral and written information, all patients signed the Informed Consent Form. All implant sites were analysed on a MSCT (Somatom Plus S®, Siemens, Erlangen, Germany) or CBCT (Scanora 3D®, Soredex, Tuusula, Finland). The implants were placed according to the surgical protocol provided by the implant company (Instruction manual, Astra Tech®, DentsplyImplants, Mölndal, Sweden). However, in most cases, bone condensators were used as an extra tool to widen the osteotomy without the need of rotatory burs. The digital intra-oral radiographs (follow-up) were obtained using the parallel technique, with position holders and a long-cone radiographic unit (Digora® photostimulable phosphor plates and the MinRay® intra-oral radiographic system, Soredex®, Tuusula, Finland). The University Hospitals Leuven uses a standardized protocol in which the setting of the radiographic system is depended on the region of the mouth where the photo is taken. Marginal bone level changes The intra-oral, long-cone radiographs were taken at: implant placement, functional loading, 1, 2, and 3-year follow-up (Figure 1). The distances, in mm, between the shoulder of the implant and the first clear BIC were recorded both mesially and distally. The thread pitch distance and the full length of the implant were also recorded and were, if needed, used for conversion. These measurements (accuracy of 0.01 mm) were performed with a software

program (Image JÂŽ, NIH, Bethesda, Maryland, USA). The measurements were initially made in a pixel format. Linear distance measurements (mm) could be retrieved after calibration of the images according to the respective thread pitch distance, provided by the manufacturer. The full length of the implant was used for the conversion. The analysis of peri-implant bone level alterations was performed by 2 calibrated, independent periodontologists (JK and AT). Results were re-evaluated when there was a â&#x2030;Ľ1 mm inter-examiner difference. The following parameters were also recorded: age, medical history, implant length, timing of placement and position in the mouth. Statistics Data are represented by their mean, SD and median, and were calculated for each implant. Empirical cumulative distribution functions were used to represent them graphically. All the statistical analysis was performed using a statistical software package SPSS Statistics version 21 (IBM CorpÂŽ, Chicago, IL, USA).

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Results Patient and implant data (Table 1-4) A total of 28 patients (3 males and 25 females) were included. All patients belonged to the Caucasian race with an average age of 63.4y. (range 42 to 76y, SD 9.1y). A total of 100 implants were placed (13 in males, 87 in females). Two in one patient with diabetes and 7 in 2 patients with a history of chemo / radiotherapy outside the head and neck region. Eighty eight percent of the implants were placed in the upper jaw and 12 % in the lower jaw, primarily in the region between the 2nd incisor and 2nd premolar. All implants had a diameter of 3.5 mm and their length ranged from 8 mm to 15 mm. The majority of the implants had a length of 13 mm (45 %) or 11 mm (33 %). The mean insertion torque was 35 N/cm, with a mean ISQ of 68.9 ± 8.3 at insertion, and of 67.7 ± 9.8 at the time of placement of the final abutment (Osstell AB®, Göteborg, Sweden). None of the implants were placed in extraction sockets. The mean submerged healing period was 3.6 ± 0.9 months. Only for 7 implants a simultaneous grafting, according to the GBR principle, was required. The implants were loaded with single crowns, partial or full fixed bridges and mostly with overdentures (Department of Prosthetic dentistry). One hundred implants were followed during the first year. Over the time course of the study, 2 patients did not show up for the follow-up appointments so that the number of followed implants dropped to 98 during the second year and to 95 during the third year. None of the implants failed, resulting in an overall implant survival rate of 100% after 3 years. Marginal bone level changes The implants were primarily placed subcrestally (mesially: 0.94 mm ± 0.87, and distally: 0.68 mm ± 0.97 below bone level). At abutment connection the marginal bone was located 0.65 mm ± 0.6 apically of the implant shoulder (mesially 0.63 mm ± 0.7, distally 0.67 mm ± 0.6). One, 2 and 3 years after final abutment connection, this “bone level” was slightly more apically (0.80, 0.84 and 0.79 mm apically to the implant shoulder, respectively).

The overall mean MBL during first year of functional loading was 0.17 mm ± 0.40, between the first and second year 0.05 mm ± 0.37. Between the second and third year there was a slight bone gain of 0.06 mm ± 0.14. The cumulative percentage distribution of the implants according to their marginal bone level at 1, 2 and 3 years is presented in Figure 2. After one year, 80% of the implants had a MBL between 0.25 mm and 1.12 mm apically to the shoulder After the 2nd year this was between 0.20 mm and 1.19 mm, and after the third year this was between 0.18 mm and 1.03 mm (Table 5).

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Discussion The results of this prospective clinical trial demonstrated that the interproximal bone changes for implants placed in sites with ≤ 4.5 mm of bucco-oral bone width were stable during 3 years of functional loading. Furthermore, the implant survival rate was 100%. The MBL changes around implants are most common, between abutment connection and the first year of functional loading. The present study showed a mean marginal bone loss of 0.17 mm ± 0.40 in the first year of functional loading. After the first year the marginal bone loss varied. After 2 years a marginal bone loss increase with another 0.05 mm ± 0.37 and after 3 years a marginal bone loss decrease with 0.06 mm ± 0.14 was observed. In 2012 the success criteria for implants were adjusted and divided into three domains (Tonetti et al., 2012). The domains, patient-reported outcome measures and implant-supported restorations were not evaluated in this study. Only for the domain peri-implant health, the marginal bone level was measured. These data for the marginal bone level are in agreement with the present success criteria that allow a marginal bone loss during the first year of 1-1.5 mm and further annual loss of 0.1 mm (Albrektsson et al., 1986, Cecchinato et al., 2008). Wennström and co-workers reported for the same implant system a mean marginal bone loss, between implant insertion and functional loading, of 0.02 mm ± 0.65 during the first year, 0.08 mm ± 1.02 in the second year, 0.03 mm ± 0.81 in the third year (Wennstrom et al., 2005). Another study showed a mean marginal bone loss after 5 years of 0.39 mm ± 0.28 for the upper jaw and 0.12 mm ± 0.16 for the lower jaw (Astrand et al., 2004). After 12 years the mean marginal bone loss was 0.32 mm ± 0.78 for the upper jaw and 0.29 mm ± 0.77 for the lower jaw (Ravald et al., 2013). The latest meta-analysis for AstraTech® implants showed that the weighted mean marginal bone loss over a period of 5 years was 0.27 mm. All these implants were placed in sites were the bucco-oral bone width was 5 mm or more, and for all studies functional loading was taken as baseline. These observations are similar to our findings, however, in sites with ≤ 4.5 mm of bucco-oral bone width. These favourable outcomes might be explained by the presence of the microthreads in the marginal part of the implant. Bratu and co-workers (2009) compared implants with a 1 mm polished neck to implants with a roughened

surface with micro-threads (Bratu et al., 2009). The results after 1 year showed that the implants with a polished neck had a marginal bone loss of 1.47 mm ± 0.40 while the implants with a roughened surface with micro-threads had a loss of 0.69 mm ± 0.25. These micro-threads and the combination of the roughened surface in the marginal part of the implant might be of importance for the maintenance of the marginal bone level. The bucco-oral bone width is considered to be crucial for osseointegration and even more important for an aesthetic outcome. In the literature there are some guidelines available which suggested a zone of 1.5-2 mm of bone around the implant (Grunder et al., 2005, Esposito et al., 2007). In the current study implants with a diameter of 3.5 mm were placed in sites with ≤ 4.5 mm bucco-oral bone width. This means that less then 1 mm of bone is surrounding the most coronal part of the implant (Table 6). The marginal bone loss observed around these implants was however comparable to the latest long-term results of Astra Tech® implants (Wennstrom et al., 2005, Astrand et al., 2004, Ravald et al., 2013). Factors that can interfere with preserving the marginal bone thickness around an implant, besides bacteria, may probably be bone compression and blood supply. Bone compression can be reduced to the minimum by using a pretap or cortical drill. In the current study a minimal undersized drilling sequence was used. The discrepancy between the osteotomy and the implant was only 0.3 mm. Moreover, the manufacturer recommends a cortical drill for sites where more cortical bone is present. This cortical drill reduces the stress forces exhibited on the cortical bony walls while inserting the implant. This might give less surgical trauma and finally it may lead to a less pronounced remodelling of the cortical bone around the shoulder of the implant. Lowering the stress forces on the bony wall could jeopardize the primary stability but at the end it might lead to the preservation of the MBL. In the literature different invasive surgical procedures are reported to obtain an ideal three-dimensional bony structure to place an implant in the prosthetic most ideal position. The drawbacks of these procedures are more complications, longer treatment time, more costs, higher morbidity en post-operative discomfort for the patient (Milinkovic and Cordaro, 2014). The question could rise whether in cases without aesthetic demands these invasive treatments

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are justified when less invasive options are available such as tilted implants (Menini et al., 2012), short implants (Annibali et al., 2012b), cantilever extensions on implants (Aglietta et al., 2009) and the rarely used cantilever extensions on natural teeth (Pjetursson et al., 2004, Tan et al., 2004). The present study indicates that bone grafting procedures can be avoided when sites with â&#x2030;¤ 4.5 mm of bucco-oral bone width are available. Of course, it has to be taken into account that all included cases were cases without aesthetical demands. Today, the aesthetic outcome of an implant positioned in the anterior area is of high priority for the patient. Factors that could influence the aesthetical outcome are: optimal 3D implant planning, adequate bone volume around an implant, ideal soft-tissue dimensions and a stable bone level (Belser et al., 2004) In the literature several different clinical guidelines are available for the implant positioning in bucco-oral dimension. The idea for a perfect aesthetical outcome is a need of 1 or 2 mm of bone thickness around an implant (Grunder et al., 2005, Esposito et al., 2007). Most of the patients in this study have been treated with an overdenture. Here, the aesthetics are not very relevant because most of the time it can be compensated with the dental prosthesis. Therefore the implants were often placed bone driven instead of prosthetically driven. In this study the aesthetical outcome of the implants were not reported, but so far no gingival recession nor exposure of the implant has been encountered. All patients included in the study, were following a very strict maintenance protocol and as a result had a high level of oral hygiene. This might not be the best reflection of an average patient in the daily practice. Further studies are necessary to analyse the long-term stability of the bone level, the aesthetic outcome and the bucco-oral bone changes around the implant.

Conclusions Within the limits of this study, it can be concluded that implants placed in sites with limited dimensions (â&#x2030;¤ 4,5 mm bucco-oral) can be successful for a period of 3 years, comparable to implants placed in wider alveolar crests. This effect could be explained by the micro-threads in the conical and marginal part of the implant system used as well as by the special drilling sequence avoiding bone compression. These results showed that if patients are not ready for bone grafting procedures this treatment option could be a good alternative.

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Figures figure 1 Radiological follow-up of a study patient.

figure 2 Cumulative distribution curves.

Tables Table 1 Demographic characteristics of subjects (n, mean ± SD, %). Variable

Male

Female

Number of patients

3 (10,7%)

25 (89,3%)

Number of implants

13 (13%)

87 (87%)

Mean Age / SD

63,4 ± 9,1

Range of age

42 – 76

Presence systemic disease

Yes

Smokers (<20 cigarettes / day)

4 (14,3%)

Diabetes

1 (3,6%)

History of chemo / radiotherapy

3 (10,7%)

Table 2 Implant characteristics (n, mean ± SD). Osseointegration time

3,55 ± 0,94

Implant stability quotient by placement

68,9 ± 8,3

Implant stability quotient by abutment

67,7 ± 9,8

Implant failure

Smoking (<20 cigarettes / day)

Diabetes

History of chemo / radiotherapy

3 (10,7%)

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Table 3 Intra-oral distribution of implants (n, %). Quadrant

1st

2nd

3rd

4th

Table 4 Distribution of implants according to jaw and length (n, %). Length (Ă&#x2DC;3.5 mm)

Upper Jaw (n)

Lower Jaw (n)

Percentage (%)

139

0.22±1.01 0.40

0.16±1.10 0.38

0.27±1.01 0.51

Placement

-0.81±0.83 -0.77

-0.94±0.87 -0.96

-0.68±0.97 -0.78

Overall

Mesial

Distal

0.77±0.77 0.87

0.54±0.82 0.72

0.68±0.74 0.75

1 year

0.75±1.01 0.75

0.61±0.87 0.53

0.67±0.91 0.53

3 year

-1.03±0.84 -1.01

-1.13±0.87 -0.89

-1.08±0.74 -0.99

MB loss difference (abutment – placement)

-1.45±0.85 -1.32

-1.51±0.66 -1.56

-1.49±0.69 -1.46

MB difference (1 year – placement)

0.08±0.59 0.03

0.05±0.38 0.10

0.07±0.45 0.11

MB difference (2 year – 1 year)

-0.04±0.34 -0.06

-0.05±0.38 -0.07

-0.04±0.30 -0.05

MB difference (3 year – 2 year)

None of the implants failed up to the 3-year follow-up (overall cumulative survival rate after 3 year of loading = 100% on implant level). The implants were placed subcrestal with a mean 0.81 mm (SD = 0.83). The mean marginal bone loss difference during the months of submucosal healing and integration period after subcrestal placement was -1.08 mm (SD = 0.74). The loss of marginal bone at the implants during the first year of functional loading (including the remodeling phase) was 0.68 mm (SD = 0.74) and after 3 years 0.67 mm (SD = 0.91).

0.69±0.98 0.73

0.56±0.86 0.67

0.62±0.90 0.70

2 year

Analysis of mean (SD) and median marginal bone (MB) loss (mm).

Table 5

Table 6 Width of the future implant site, measured on specific heights (mean, SD and range in mm). Crest Width

Mean

Range

TOP

2,8

0,8

[1,1; 4,4]

TOP -2 mm

3,5

0,6

[1,2; 4,7]

TOP -4 mm

3,9

0,7

[2,5; 6,7]

TOP -6 mm

4,5

1,2

[2,9; 9,6]

TOP -8 mm

5,5

1,4

[3,7; 11,2]

TOP -10 mm

6,6

1,6

[3,7; 12,4]

TOP -12 mm

8,1

1,7

[5,4; 13,2]

141

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• Jensen, S. S. & Terheyden, H. (2009) Bone augmentation procedures in localized defects in the alveolar ridge: clinical results with different bone grafts and bone-substitute materials.

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• Kim, Y., Oh, T. J., Misch, C. E. & Wang, H. L. (2005) Occlusal considerations in implant therapy: clinical guidelines with biomechanical rationale.

Clinical Oral Implants Research 16: 26-35.

• Menini, M., Signori, A., Tealdo, T., Bevilacqua, M., Pera, F., Ravera, G. & Pera, P. (2012) Tilted implants in the immediate loading rehabilitation of the maxilla: a systematic review.

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• Ravald, N., Dahlgren, S., Teiwik, A. & Grondahl, K. (2013) Long-term evaluation of Astra Tech and Branemark implants in patients treated with full-arch bridges. Results after 12-15 years.

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• Ribeiro-Rotta, R. F., Lindh, C. & Rohlin, M. (2007) Efficacy of clinical methods to assess jawbone tissue prior to and during endosseous dental implant placement: a systematic literature review.

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• Suarez, F., Chan, H. L., Monje, A., Galindo-Moreno, P. & Wang, H. L. (2013) Effect of the timing of restoration on implant marginal bone loss: a systematic review.

Journal of Periodontology 84: 159-169.

• Szmukler-Moncler, S., Salama, H., Reingewirtz, Y. & Dubruille, J. H. (1998) Timing of loading and effect of micromotion on bone-dental implant interface: review of experimental literature.

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• Tan, K., Pjetursson, B. E., Lang, N. P. & Chan, E. S. (2004) A systematic review of the survival and complication rates of fixed partial dentures (FPDs) after an observation period of at least 5 years.

Clinical Oral Implants Research 15: 654-666.

• Teughels, W., Merheb, J. & Quirynen, M. (2009) Critical horizontal dimensions of interproximal and buccal bone around implants for optimal aesthetic outcomes: a systematic review.

Clinical Oral Implants Research 20: 134-145.

• Tonetti, M., Palmer, R. & Working Group 2 of the VIII European Workshop on Periodontology. (2012)

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• Vela-Nebot, X., Rodriguez-Ciurana, X., Rodado-Alonso, C. & Segala-Torres, M. (2006) Benefits of an implant platform modification technique to reduce crestal bone resorption.

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• Wennstrom, J. L., Ekestubbe, A., Grondahl, K., Karlsson, S. & Lindhe, J. (2005) Implant-supported single-tooth restorations: a 5-year prospective study.

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Part 2 Impaired Bone Quality

The use of oral implants in post-menopausal women over 60 years of age suffering from osteoporosis/osteopenia.

An open, prospective, non-randomized, controlled, multicentre study to evaluate the clinical outcome of implant treatment in women over 60 years of age with osteoporosis/osteopenia: 1-year results. Temmerman Andy, Rasmusson Lars, Kubler, Thor Andreas, Quirynen Marc. Clinical Oral Implants Research (2017) 28: 95-102.

This paper and oral presentation received the EAO Award for best surgically related research and presentation 2015 (Stockholm, Sweden) Oral presentations on Chapter 5 were given at: â&#x20AC;˘ European Association for Osseointegration (EAO) Annual Symposium 2015 (Stockholm, Sweden)

Abstract Background & Objective: Osteoporosis has been called a potential risk factor for bone healing around oral implants. The aim of this multicentre study was to verify the clinical performance of fluoridated implants in the maxilla of subjects with diagnosed systemic primary osteoporosis/osteopenia. Material and methods: Postmenopausal women in need of 2-8 splinted implants in maxilla, underwent BMD measurements in the hip and spine, using DXA-scans. Based on their T-scores, they were divided into three groups: Group O (osteoporosis/osteopenia group) subjects had a T-score ≤ -2; Group C (control group) had a T-score of ≥ -1; subjects with a T-score <-1 but >-2, were excluded. Implants were placed via a 2-stage procedure and loaded 4-8 weeks after abutment surgery. Six months and 1 year after functional loading clinical parameters (including peri-apical radiographs) were assessed. Results: One hundred and forty-eight implants were placed in 48 subjects (mean age: 67y (range [59-83]). Sixty-three implants were placed in 20 osteoporosis subjects (Group O, mean age: 69y; range [59-83]) and 85 were placed in control subjects (Group C, mean age: 65y; range [60-74]). The CSR, on an implant level, was 99.3% (Group O: 98,4%; Group C: 100,0%). The CSR, on a subject level was 97,9% (Group O: 94,7%; Group C: 100,0%). MBL alterations from functional loading to the 1-year follow up visit were measured on an implant level and a subject level. The overall MBL alterations on an implant level was -0,01±0,51 mm (Group O: -0,11±0,49 mm; Group C: 0,05±0,52 mm). The overall MBL alterations on a subject level was -0,04±0,27 mm (Group O: -0,17±0,30 mm; Group C: 0,04±0,23 mm). Conclusions: Within the limitations of this prospective, non-randomized, controlled, multicentre study it can be concluded that oral implant therapy in patients suffering from osteoporosis/osteopenia is a reliable treatment option with comparable integration rates as compared to healthy patients.

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Introduction Throughout life bone is continuously rejuvenating itself through a fine balance of bone resorption and new bone formation. Unfortunately, in case of unbalance (such as osteoporosis) this can eventually lead to bone fragility, resulting in a reduced bone strength (loss of bone mass) and alteration of the trabecular bone characteristics (deterioration of the micro-architecture)(Raisz 2005). Osteoporosis is one of the most common systemic diseases as it is estimated that over 300 million people worldwide suffer from osteoporosis (Kanis et al., 2002). Despite the advances in diagnosis and management, osteoporosis remains a global health problem, with an important economic burden on the health care systems (Harvey et al., 2010). Osteoporosis causes more than 8.9 million fractures annually worldwide and its prevalence is expected to further increase due to ageing of the population (Cooper et al., 1992; Melton et al., 1992; Randell et al., 1995; Johnell et al., 2006; Schuler et al., 2012). Furthermore it is an important cause of morbidity and mortality in the elderly population, particularly postmenopausal women (Bliuc et al., 2009, 2015). As bone belongs to the oestrogen-dependent tissues, the deficit of the protective influence of oestrogens compromises the dynamic balance of the bone transformation process towards resorption, thus reducing bone mass and quality, while increasing the risk of fractures (Horst-Sikorska et al., 2011). Thirty percent of all menopausal women will develop osteoporosis in the United States and Europe. These patients will experience one or more fragility fractures in their life (primarily in the hip, spine & wrist)(Park et al., 2011). The diagnosis of osteoporosis is mainly based on DXA, which is still considered as the â&#x20AC;&#x2DC;gold standardâ&#x20AC;&#x2122; for the measurement of BMD, due to its speed, precision and relatively low radiation exposure (Blake & Fogelman 2007; Miller 2006; Gordon et al., 2008). By these scans a T-score can be defined. This score will compare the BMD with the mean peak mineral density for an individual of the same gender. It is expressed in the number of SD below that average. Other medical imaging modalities, such as ultrasound and quantitative/qualitative CT can also be used (Kazakia & Majumdar 2006). Oral implant therapy is currently an established part of mainstream dentistry. In recent years it has become a popular, well accepted and widespread treatment modality to replace missing teeth (Amet 2010; Waasdorp et al., 2010). Due to an imbalance between the activity of osteoblasts and osteoclasts, osteoporosis

contributes to impaired bone regeneration and bone remodelling and therefore it has been considered as a potential risk factor for the bone healing around implants (Fini et al., 2004). Osteoporosis acts in the peri-implant bone due to a decreased cancellous bone volume and therefore on the rate of BIC, leading to a reduced bony tissue support (Keller et al., 2004). As such, systemic osteoporosis has been considered a contraindication for treatment with oral implants. This view has gradually changed over the years, due to several reports showing that oral implant treatment can also be successful in osteoporotic patients (Friberg et al., 2001; von Wovern & Gotfredsen 2001) and that there are no differences in treatment outcome between osteoporotic and non-osteoporotic patients (Amorim et al., 2007; Becker et al., 2000). The aim of this multicentre study was to provide information on the clinical performance of surface modified and fluoridated screw-type implants when used in the maxilla of patients with diagnosed systemic primary osteoporosis/osteopenia versus healthy patients.

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Material & Methods Postmenopausal women in need of 2-8 splinted implants in the maxilla were screened for possible inclusion into this multicentre study (Centres: Leuven (Belgium), Gothenburg (Sweden), Würzburg (Germany) & Uppsala (Sweden)). Subjects were informed orally and in writing about the study and its perspectives. Afterwards, they were asked to sign an Informed Consent form, prior to any further examination. The study was approved by the Ethical Committee of the University Hospitals Leuven and the investigation was conducted according to the principles of the Helsinki Declaration for biomedical research involving human subjects. The first part of the screening procedure included the collection of demographic data as well as clinical and radiographic assessment. Subjects fulfilling all inclusion and none of the exclusion criteria (Table 1) after this first part of screening were scheduled for a second screening. This included BMD measurements in the hip and spine, using DXA (Discovery A™, Hologic®, Hologic Inc., Bedford, USA). All DXA-scans were read centrally (Uppsala, Sweden) and T-scores were calculated. Based on each patient’s lowest T-score (i.e. either the hip T-score or the spinal T-score), subjects were divided into three groups. • Group O (osteoporosis/osteopenia group) subjects had a T-score ≤ -2; • Group C (control group) had a T-score of ≥ -1; • Subjects with a T-score <-1 but >-2, were not fulfilling all inclusion criteria for treatment in the study and were therefore excluded. All subjects were personally informed about their BMD results by telephone or regular mail. In case of osteoporosis/osteopenia the subject was referred to a general practitioner for consultation on treatment. All subjects underwent a dental multi-slice Computed Tomography (MSCT, Somatom Plus Ss℠®, Siemens, Erlangen, Germany) examination, in order to determine the BMD at the future implant sites and pre-operative planning. The surgical procedure was performed under local anaesthesia or sedation & local anaesthesia. After crestal incision, 2-8 implants (OsseoSpeed™ implant, AstraTech, DentsplyImplants, Mölndal, Sweden) were inserted in the maxilla. All implants were placed slightly subcrestally in order to prevent soft tissue penetration during the healing phase

(Van Assche et al., 2008). In only 2 cases a mandatory small ‘Guided Bone Regeneration’ (GBR) with autologous bone chips was performed. In 1 case (1 implant) a simultaneous internal sinus lift was performed. Primary implant stability was assessed both manually and by the use of RFA measured by ISQ (Osstell AB®, Gothenburg, Sweden). Mucoperiostal flaps were sutured back to secure a tight seal in order to achieve a submerged healing. Intra-oral periapical radiographs were taken immediately after surgery, according to the long-cone principle. All subjects were given a prescription for a chlorhexidine rinse. Postoperative antibiotics and anti-inflammatory drugs could be prescribed according to the assessment of the surgeon in charge. One week after implant surgery, sutures were removed and the existing prostheses were relined with a temporary soft lining. Twelve weeks after implant surgery, healing abutments were connected. Via a small crestal incision, cover screws were removed and implant stability was evaluated both manually (reverse torque) and by RFA. Whenever necessary, sutures were used. Intra-oral periapical radiographs were taken. After 1 week of soft tissue healing, impressions were taken at abutment level for fabrication of the screw-retained permanent restoration(s) or bar-attached overdenture. This permanent restoration was delivered between 4 to 8 weeks after impression. At this stage an oral examination evaluating the presence of plaque and the condition of the peri-implant mucosa PPD and BoP was performed. Intra-oral radiographs were taken. All subjects returned for follow-up visits at 6 and 12 months after functional loading. During these follow up visits, the same oral examination as described before, was performed. MBL were measured from a reference point, defined as the junction of the roughened and machined bevelled surface, to the most coronal point of BIC, both mesially and distally. The mean value for each implant was calculated from these 2 measurements and used for further analyses. The MBL at the time of final restoration delivery, and thus functional loading, was regarded as baseline. MBL alteration was defined as the difference between the MBL at baseline and each follow-up appointment. The analysis of the peri-implant bone levels was performed by a radiologist, independent from the research groups and DentsplyImplants®. Both analogue and digital radiographs were used in the study. For the analogue radiographs, measurements were made to the nearest 0,1 mm under 7× magnification. The digital radiographs were displayed in software (Illustrator® CS, Adobe Systems Inc., San Jose, CA, USA) on a 24-inch LCD screen (iMac Apple Inc, Cupertino, CA, USA). The screen resolution was 1,920 × 1,200

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pixels. The measuring tool of the software was used to make the measurement, taking the magnification into account. The radiographs were calibrated individually using the implant length and thread pitch to correct for dimensional errors. Statistical Analysis The study hypothesis was that the alteration in MBL from prosthetic restoration to the 1-year follow-up visit is equal (i.e. a two-sided hypothesis) in patients in group O and in group C. The hypothesis was tested by means of the Wilcoxon rank sum test. (NPAR test Mann-Whitney Wilcoxon Rank Sum equivalent). A two-sided p-value <0,05 at the 1-year follow up visit was considered statistically significant. Wilcoxon rank sum test was also used for analyzing ISQ results. Fisherâ&#x20AC;&#x2122;s exact test was used for comparing implant survival between Group O and C.

Results Population sample: In total, 148 implants were placed in 48 subjects, with a mean age of 67y (range [59-83]). Sixty-three implants were placed in 20 osteoporosis subjects (Group O, mean age 69y; range [59-83]) and 85 were placed in 28 control subjects (Group C, mean age 65y; range [60-74]). In Group O, 25% of the subjects were ex-smokers, 5% were habitual smokers, 10% were occasional smokers and 60% were non-smokers. In Group C, 36% were ex-smokers, 7% were habitual smokers and 57% were non-smokers. Concerning periodontal health, 3 subjects were diagnosed with a chronic, moderate, adult periodontitis, which was treated before starting any oral implant related therapy. All subjects were treated under local anaesthesia and 6 subjects (12%) also received sedation. As antibiotics were not mandatory for post-surgical management, this was left to the opinion of the surgeon. Overall, 71% of the subjects received postoperative antibiotics. Implant survival: Up to the 1-year follow-up visit after final prosthesis delivery and functional loading, 136 out of the initial 148 implants were examined. One subject (Group O) with 2 implants died from unknown reason before abutment surgery and 1 subject with 3 implants (Group O) died after the 6-months follow up visit also from unknown reason. One subject (group O) lost 1 implant at abutment surgery due to non-integration. In this same subject a new implant was placed and a final prosthesis was delivered after a prolonged healing period. Twenty-six months after functional loading, all implants (5) were explanted, fulfilling the patientâ&#x20AC;&#x2122;s wish (although there was no medical reason for it). Before explantation, ISQ values were measured (>80). The peri-implant tissues were healthy and were not showing any signs of inflammation. The CSR, on an implant level was 99,3% (Group O: 98,4%; Group C: 100,0%). The CSR, on a subject level was 97,9% (Group O: 94,7%; Group C: 100,0%). One year after functional loading (LD), there was no significant difference in implant survival between Group O and Group C, neither on implant level (p=0.430) nor on subject level (p=0.417).

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Resonance Frequency Analysis: The mean ISQ value at implant placement and abutment connection in Group O was 65,8 (SD: 10,2; range [30,0-81,0]) and 70,6 (SD: 8,8; range [48,5-85]), respectively. The corresponding mean ISQ value in Group C were 69,2 (SD: 7,7; range [48,0-81,5]) and 73,8 (SD: 6,5; range [52,5-84,0]), respectively. Changes in ISQ values between implant and abutment connection are shown in Table 2. The ISQ values increased significantly from implant placement to abutment connection in both Group O and Group C. At abutment connection, the absolute ISQ values were significantly higher in Group C than in Group O (p=0.049) but there was no significant difference in ISQ changes from implant surgery to abutment connection between the groups (p>0.05). Marginal bone level alterations: MBL alterations from LD to the LD + 1 year were analysed on an implant level and a subject level. The overall MBL alteration on an implant level was -0,01±0,51 mm (Group O: -0,11±0,49 mm; Group C: 0,05±0,52 mm). The overall MBL alteration on a subject level was -0,04±0,27 mm (Group O: -0,17 ±0,30 mm; Group C: 0,04±0,23 mm). Changes in MBL are shown in Table 3. The MBL changes between LD and LD+1 year differed significantly between Group O and C, both on implant level (p=0.013) and on subject level (p=0.019) with Group O losing slightly more bone than Group C. There were no significant differences in MBL changes from LD to LD+6 months between the groups (p >0.05 both on implant and subject level). On implant level, absolute values differed significantly (p <0.05) between Group O and C at abutment surgery, LD and LD+6 months, where Group C showed higher values than Group O. On subject level, this was registered only at LD. At LD+1 year there was no significant difference in absolute values between Group O and C (p=0.179). Nor was there any difference in MBL changes from implant placement to LD+1 year. Thus, from implant placement to LD+1 year, Group O and C lost almost comparable levels of bone but for Group O, most of the bone loss took place after loading and for Group C before loading. Cumulative plots of MBL changes from LD to LD+1year on an implant level and subject level are shown in Figure 1 & 2.

Clinical parameters: PPD, BoP and plaque were measured at LD, LD+6 months and LD+1year. Descriptive methods are used in order to display the results (Table 4, 5, 6 & 7).

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Discussion Historically, due to the principle of osseointegration, oral implants were predominantly placed in generally healthy, fully edentulous patients (Adell et al., 1981; Adell et al., 1990; Branemark et al., 1977; Branemark et al., 1983). Due to the ageing of the population and the fact that patients are maintaining their natural teeth longer (Muller et al., 2007), dentists are getting confronted more often with older patients, suffering from one or more systemic diseases, searching for oral implant treatment in order to regain comfortable masticatory function and quality of life (Kuoppala et al., 2013; Zembic & Wismeijer 2014). Osteoporosis/osteopenia is a systemic skeletal disease, which will increase bone fragility and susceptibility for fractures (Eastell 1998). To date, there is limited evidence to predict the BMD in the maxilla or mandible by using DXA-scans. Merheb and co-workers compared DXAâ&#x20AC;&#x201C;scans with MSCT scans of patients suffering from osteoporosis. They concluded that the maxillary bone density of patients suffering from osteoporosis was significantly lower than that of healthy patients. They furthermore found a direct correlation between the density of the skeleton and the density of some sites of the maxilla, concluding that maxillary bone density measurements could be helpful in the screening of osteoporosis (Merheb et al., 2014). Jacobs and co-workers investigated, on a long-term basis, the bone mass at the mandible and the lumbar spine, in patients receiving hormonal replacement therapy. They concluded that the bone mass of the mandible and the lumbar spine only showed limited relationship (Jacobs et al., 1996). To date, there is still an assumption that osteoporosis can interfere with successful integration of oral implants. However, a recent study concluded that successful implant therapy can be expected in osteoporosis patients (Otomo-Corgel 2012). In 2 reviews, Mombelli and co-workers and Bornstein and co-workers concluded that association of osteoporosis and implant failure was low (Bornstein et al., 2009; Mombelli & Cionca 2006). The present, controlled multicentre study can confirm these conclusions. No statistically significant difference was seen in implant integration and survival after 1 year of functional loading. Systemic osteoporosis is frequently treated with bisphosphonates. These drugs can be administered orally or intravenously and have been proven to increase the BMD at the hip and spine and therefore reduce the number of fractures

(Black et al., 1996; Lyles et al., 2007b; Lyles et al., 2007a). Several studies have reported on potential complications (e.g. MRONJ) when performing oral surgery, including the placement of oral implants, in patients under the treatment with bisphosphonates (Chadha et al., 2013; Fernandez et al., 2014; Holzinger et al., 2014; Kim & Kwon 2014; Rasmusson & Abtahi 2014). However, there is limited information about how long-term usage of oral bisphosphonates may pose a challenge to overall bone healing in particular for oral implant therapy and what the real risk of developing MRONJ is (Marx et al., 2005; Madrid & Sanz 2009). As for intravenously administered bisphosphonates it has become clear that it should be considered as a contraindication for oral implant treatment (Madrid & Sanz 2009). The present study had no intention on investigating the placement of oral implants in osteoporotic patients treated with bisphosphonates, as the current or previous use of bisphosphonates was considered an exclusion criterion. All subjects in this study were screened for osteoporosis/osteopenia using DXA-scans. They were informed on their BMD results by telephone or regular mail. All subjects of Group O were referred to their general practitioner for consultation on treatment. These subjects received a letter informing their general practitioner about the participation in the study together with a recommendation not to start with bisphosphonates until the healing period had been completed and the abutment surgery had been carried out. This recommendation, which is in accordance with several studies and position papers, saying that invasive dental procedures should be completed before starting medication with bisphosphonates to minimize the risks for inducing MRONJ, was considered at the discretion of the general practitioner. Subjects starting with bisphosphonate treatment during the study were carefully informed about the risk of developing MRONJ (Ata-Ali et al., 2014) and also on the importance of maintaining a good oral hygiene to minimize the risks. MBL changes around oral implants are most commonly seen between abutment connection and the first year of functional loading. This present study showed a mean marginal bone loss of 0,01 mm Âą 0,51 in the first year of functional loading for all subjects. When comparing Group O and C, there was no statistically significant difference between the groups in MBL after 1 year of functional loading. These data are in agreement with the present success criteria, allowing a marginal bone loss during the first year of 1-1.5 mm and

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further annual loss of 0.1 mm (Albrektsson et al., 1986; Cecchinato et al., 2008). For the same implant type, as used in this study, Wennström and co-workers reported a mean marginal bone loss of 0.02 mm ± 0.65 during the first year of functional loading (Wennstrom et al., 2005). Another study showed a mean marginal bone loss after 5 years of 0.39 ± 0.28 mm for the upper jaw (Astrand et al., 2004). These findings are comparable with the results in this study. In order to achieve a successful osseointegration of oral implants, primary stability is still considered a prerequisite, as elevated micromotions can initiate the formation of fibrous tissue at the bone-to-implant interface (Merheb et al., 2010). In order to measure the primary stability, RFA is a widely used technique (Meredith et al., 1996; Rasmusson et al., 2012). It assesses the BIC by attaching a transducer to the implant body. Implant stability is expressed in ISQ values. Some patient and implant depending factors might have an influence on ISQ values. In a study by Merheb and co-workers it was concluded that implant length, diameter or the presence of bony dehiscence did not have a significant effect on the mean RFA scores at implant insertion. However, they found significant linear relations between RFA values and HU and cortical bone thickness (Merheb et al., 2010). On the other hand, Sim and co-workers found that ISQ values are affected by the bone structure and implant length (Sim & Lang 2010). Bone quality is considered as an important parameter for future implant treatment outcome, by many specialists in the clinical field (Lindh et al., 2014). According to an interpretation of the MSCT slices, immediately before the surgery, the bone at the implant site (Rokn et al., 2014) was categorized in 4 types according to the Lekholm & Zarb classification (1985). Various studies concluded that it is possible to predict initial implant stability using MSCT and CBCT scans (Aranyarachkul et al., 2005; Hao et al., 2014; Salimov et al., 2014). In the present study, 42,8% and 0,12% (27 out of 63 vs. 1 out of 85) of the oral implants in Group O and Group C, respectively, were placed in type 4 bone (Table 8). Forty-seven percent (30 out of 63) in Group O and 60% (51 out of 85) in Group C, were placed in Type 3 bone (Table 8). Although, the mean RFA value for Group C was higher than Group O, both at implant placement and abutment connection, no statistically significant difference between RFA values of both groups could be observed.

Conclusions Within the limitations of this non-randomized, controlled multicentre study it can be concluded that oral implant therapy in patients suffering from osteoporosis/osteopenia is a reliable treatment option with comparable integration rates as healthy patients. When considering MBL changes, no difference could be observed between both groups from implant placement to 1 year after functional loading.

163

Figures figure 1 Cumulative plot of MBL change from Functional Loading (LD) to 1-year followup (LD+1y), implant level (Group O, Group C)

figure 2 Cumulative plot of MBL change from Visit 7 (LD) to Visit 9 (1-year follow-up), subject level (Group O, Group C)

165

figure 3 5-year follow-up of a study patient of group O: (a) occlusal view after implant placement. (b) peri-apical radiograph taken after implant insertion. (c) peri-apical radiograph taken at healing abutment connection. (d) peri-apical radiograph taken at delivery of the final crowns and functional loading (LD). (e-i) peri-apical radiographs taken at LD+1y, LD+2y, LD+3y, LD+4y and LD+5y.

figure 4 4-year follow-up of a study patient of group C: (a) occlusal view after implant placement. (b) peri-apical radiograph taken after implant insertion. (c1 and c2) peri-apical radiograph taken at healing abutment connection. (d1 and d2) peri-apical radiograph taken at delivery of the final crowns and functional loading (LD). (e-h) peri-apical radiographs taken at LD+1y, LD+2y, LD+3y, LD+4y.

Tables Table 1 Inclusion and exclusion criteria. Variable

Inclusion criteria

Provision of Informed Consent

Postmenopausal women aged 60 years and over

In need of 2-8 implant in the maxilla

A history of edentulism in the area of oral implant therapy of at least 3 months

A BMD suitable for Group O or C (A:T-score ≤ 2SD in g/cm² & B: T-score ≥-1 in g/cm²

Exclusion criteria 1.

Unlikely to be able to comply with the study procedures, as judged by the investigator

Untreated or uncontrolled caries/periodontal disease

Known or suspected current malignancy

History of chemotherapy, 5 years prior to implant surgery

History of radiation in the head and neck region

History of other metabolic bone diseases, e.g. Paget’s disease, hyperparathyroidism, fibrous dysplasia or osteomalacia

A medical history that makes implant insertion unfavourable

Need for systemic corticosteroids

Current or previous use of intravenous bisphosphonates

10.

Current or previous use of oral bisphosphonates

11.

History of bone grafting and/or sinus lift in the planned implant area

12.

Current need for bone grafting and/or sinus lift in the planned implant area

13.

Present alcohol and/or drug abuse

14.

Participation in a clinical study during the last 6 months.

167

Table 2 RFA- ISQ values at Implant Placement (IP) and Abutment Connection (AC) & Changes (Δ) in ISQ values from IP to AC. IP/AC criteria ISQ value*

Group O

Δ AC - IP

Group C

Change in ISQ**

Total

Group O

Total

54/61

73/81

127/142

121

Mean

65,8/70,6

69,2/73,8

67,7/72,5

Mean

5,2

4,8

5,0

Std

10,2/8,8

7,7/6,5

9,0/7,7

Std

6,93

7,58

7,28

Min

30,0/48,5

48,0/52,5

30,0/48,5

Min

-16

-29

Median

65,5/72,0

70,0/75,0

69,0/74,5

Median

4,25

Max

81,0/85,0

81,5/84,0

81,5/85,0

Max

25,5

* ISQ was measured both bucco-palatally and mesio-distally for each implant. The table is based on the average of these two measurements **A positive value denotes a higher ISQ value at Visit 5 than at Visit 3 (an increase in ISQ) and a negative value denotes a decrease in ISQ

Table 3 Marginal Bone Level Alterations – changes from Functional Loading (LD) to 6-months follow-up (LD+6 m) and 1-year follow up (LD+1y) on an implant level/ subject level. MBL

LD+6 m

LD+1y

MBL

LD+6 m

LD+1y

MBL

Changes

from LD

(mm)

Group

Group O

Group 0

LD+6 m

LD+1y

O+C N implants/ subjects

136/45

132/42

N implants/ subjects

54/18

51/16

N Implants/ subjects

82/27

79/26

Mean

0,00/-0,02

-0,01/-0,04

Mean

-0,03/-0,07

-0,11/-0,17

Mean

0,02/0,01

0,05/0,04

Std

0,41/0,26

0,51/0,27

Std

0,33/0,19

0,49/0,30

Std

0,46/0,29

0,52/0,23

Min

-2,00/-0,65

-3,00/-0,85

Min

-1,00/-0,48

-2,00/-0,85

Min

-2,25/-0,65

-2,50/-0,33

Median

0,00/-0,03

0,00/-0,04

Median

0,00/-0,06

0,00/-0,10

Median

0,00/0,03

0,05/-0,01

Max

1,00/0,60

1,55/0,51

Max

0,75/0,33

1,55/0,48

Max

1,00/0,60

1,30/0,51

*a negative value denotes a loss of bone from installation of Prosthetic Restoration

Table 4 PPD absolute values, at Functional Loading (LD), 6-month follow-up visit (LD+6 m) and 1-year follow up visit (LD+1y) on an Implant level. LD PPD (mm)

Group O

LD+6 m Group C

Group O

LD+1 y Group C

Group O

Group C

Mean

2,7

2,8

2,9

2,6

2,5

Std

1,3

0,9

0,7

1,0

0,8

Min

0,0

0,5

1,3

1,0

0,8

1,0

Median

2,5

2,8

2,5

Max

6,5

5,8

5,3

6,7

5,3

3,8

Table 5 Pocket Probing Depth (PPD) Alterations â&#x20AC;&#x201C; changes from Functional Loading (LD) to 6-months follow-up (LD+6 m) and 1-year follow up (LD+1y) on an implant level. PPD

LD+6 m

LD+1 y

PPD

LD+6 m

LD+1 y

PPD

Changes

from LD

(mm)

Group

Group O

Group C

LD+6 m

LD+1 y

O+C N implants/ subjects

136

N implants/ subjects

N Implants/ subjects

Mean

0,24

-0,02

Mean

0,26

0,09

Mean

0,23

-0,10

Std

1,46

1,36

Std

1,35

1,38

Std

1,53

1,35

Min

-3,00

-4,00

Min

-3,00

-4,00

Min

-2,00

-3,00

Median

0,00

Median

0,00

Median

0,00

Max

4,00

5,00

Max

4,0

5,0

Max

4,00

3,00

NB a negative value denotes an increase of pocket depth since Functional Loading

169

Table 6 Plaque: Functional Loading (LD) to 6-months follow-up (LD+6 m) and 1-year follow up (LD+1y) on a subject level. LD Any plaque? (Subject level)

Δ AC - IP

Total

LD+1Y Total

Grand Total Total

15 (79%) 23 (82%) 38 (81%) 16 (89%) 21 (78%) 37 (82%) 15 (94%) 20 (74%) 35 (81%)

110 (82%)

Yes

4 (21%)

5 (18%)

9 (19%)

2 (11%)

6 (22%)

8 (18%)

1 (6%)

7 (26%)

8 (19%)

25 (18%)

Grand Total

135

Table 7 Bleeding on Probing (BoP): Functional Loading (LD) to 6-months follow-up (LD+6 m) and 1-year follow up (LD+1y) on a subject level. LD

Δ AC - IP

LD+1Y

Any bleeding? (Subject level)

5 (26%)

Yes

14 (74%) 16 (57%) 30 (64%) 14 (78%) 17 (63%) 31 (69%) 12 (75%)

Grand Total

Total

12 (43%) 17 (36%)

4 (22%)

(78%)

Total

10 (37%) 14 (31%)

(63%)

4 (25%)

Grand Total Total

16 (59%) 20 (46%)

51 (38%)

11 (41%)

23 (54%)

84 (62%)

135

Table 8 Implant sites according to bone quality and quality (Lekholm & Zarb classification). Bone Quality Treatment Group

Bone Quantity

Grand Total

171

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179

The use of Leucocyte & Platelet Rich Fibrin (L-PRF) in ridge preservation techniques and socket management.

The use of Leucocyte & Platelet Rich Fibrin in socket management and ridge preservation: split-mouth, randomised, controlled, clinical trial. Temmerman Andy, Van Dessel Jeroen, Castro Sarda Ana, Jacobs Reinhilde, Teughels Wim & Quirynen Marc. Journal of Clinical Periodontology (2016) 43: 990-999.

Oral presentations on Chapter 6 were given at: • European Association for Osseointegration (EAO) Annual Symposium 2015 – main auditorium (Stockholm, Sweden) • European Association for Osseointegration (EAO) Annual Symposium 2016 (Paris, France) • 1st European Meeting on Enhanced Natural Healing in Dentistry (ENHD) 2016 (Leuven, Belgium)

Abstract: background and objecTive: Various surgical interventions for alveolar ridge preservation have been described in literature to, at least partially, reduce the dimensional changes after tooth extraction. There is no real consensus on which biomaterial or which surgical technique is preferentially used for this purpose. Additionally, current biomaterials come at a significant cost and some biomaterials are not replaced by biological tissues. A natural, patient derived surgical additive would therefore be very useful, as it would decrease the need for biomaterials and decrease the cost for patients. Leucocyte and Platelet Rich Fibrin (L-PRF) seems to have many important and beneficial characteristics. It has a very easy and cheap preparation protocol and furthermore it is accessible for surgical manipulation. The aim of this study was to investigate the influence of the use L-PRF as a socket filling material and its ridge preservation properties. maTerial and meThods: Twenty two patients in need of symmetric bilateral tooth extractions in the maxilla or mandible were recruited for a split-mouth RCT. Treatment modalities were randomly assigned after tooth extraction (L-PRF socket filling vs. natural healing). CBCT scans were obtained immediately after tooth extraction and after 3 months of healing. CBCT scans were evaluated by superimposition using the original DICOM data. To assess postoperative pain, the Dutch version of the McGill Pain Questionnaire was used. resulTs: Mean vertical height changes at the lingual aspect after the healing period were -0,7 mm (± 0,8) for control sites and -0,4 mm (± 1,1) for test sites. At the buccal aspect they were -1,5 mm (± 1,3) for control sites and 0,5 mm (± 2,3) for test sites (p<0.05). Mean ridge width differences between baseline and after 3 months of healing were measured at 3 levels below the crest (HW-1 mm, HW-3 mm & HW-5 mm) on both the buccal and lingual sides. lingual: For the control sites measured values at the lingual side were respectively, -2,1 (±2,5), -0,3 mm (±0,3) and -0,1 mm (±0,0). Values for the test sites at the lingual side were respectively -0,6 mm (±2,2) , -0,1 mm (±0,3) and 0,0 mm (±0,1). Statistical significance was reached at HW-1 mm level (p<0,05).

183

Buccal: For the control sites measured values at the buccal side were respectively, -2,9 (±2,7), -1,0 mm (±1,1) and -0,5 mm (±0,6). For the test sites at the buccal side these values were respectively -0,8 mm (±2,5), -0,2 mm (±1,5) and -0,2 mm (±1,7). Statistical significance was reached at HW-1 mm & HW -3 mm level (p<0,05). Statistically significant differences (p<0,005) were found for the amount of total width reduction (expressed in percentages) between test (-22,84% (± 24,28)) and control sites (-51,92% (± 40,31)). Statistically significant differences (p<0,05) were found for the percentage of socket fill between test (94,7% (± 26,9) and control sites (63,3% (± 31,9)). Significantly less post-operative pain could be analysed during day 2-3-4 after extraction. Conclusions: Within the limitations of this RCT with split mouth design, it can be concluded that the use of L-PRF as a socket filling material in order to achieve ridge preservation is beneficial. Furthermore, the use of L-PRF results in less post-operative discomfort and pain for the patients, especially during the early phases of healing.

Introduction The alveolar process is a tooth dependent structure and is prone to major resorption in a vertical and horizontal dimension after tooth extraction (Pietrokovski & Massler, 1967; Schropp et al., 2003), due to the loss of bundle bone. This loss of bundle bone and the resulting pronounced shrinkage of the buccal bony wall of the extraction socket have been investigated extensively (Araújo & Lindhe, 2005; Schropp et al., 2003). Subsequently, various surgical techniques have been proposed and described to compensate for this resorption process. Although immediate implantation has been praised in older studies (Chen et al., 2004; Denissen et al., 1993; Paolantonio et al., 2001; Sclar, 1999), more recent studies have shown that this technique is not preventing the bony resorption processes accompanying tooth extraction (Araújo et al., 2005; Discepoli et al., 2015; Vignoletti et al., 2012a, 2009; Vignoletti & Sanz, 2014). So called ‘socket preservation techniques’, are widely used treatment options to partially overcome the resorption process. The application of different grafting biomaterials into extraction sockets, with or without additional membranes, has been thoroughly investigated in both animal and clinical studies. A systematic review by Vignoletti and co-workors concluded that today there are no clear guidelines, fully supported by scientific evidence on which biomaterial to use for these purposes (Vignoletti et al., 2012b). A more recent systematic review concluded that xenografts performed better when compared to allografts and alloplastic materials and natural healing for ridge preservation purposes. However, sockets grafted with alloplastic materials provided the highest amount of vital bone and the least amount of remnant graft material and connective tissue (Jambhekar et al., 2015). This seems to be of utmost importance, when keeping in mind that these remnants may decrease the final BIC when an oral implant is inserted (Zitzmann et al., 2001). Flapless and careful tooth extraction, with non-detachment of the periosteum, preservation of the blood supply and thereby reducing the surgical trauma, can be seen as the cornerstone of all treatment modalities (Barone et al., 2015b; Fickl et al., 2008). A flapless extraction technique has currently the preference over a ‘flapped’ extraction technique since the latter reduces the amount of remaining keratinized tissue (Barone et al., 2015a). More specialized ‘proof of principle’ techniques, such as the ‘socket shield technique’, in which the vestibular part of the root is left in place, are starting to develop (Hürzeler et al., 2010). The physiologic healing process after tooth extraction starts with the formation of a blood clot within the socket.

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This clot will eventually mature into a connective tissue matrix and become mineralized, firstly into woven bone and subsequently into lamellar bone (Amler 1969; Cardaropoli et al., 2003; Trombelli et al., 2008). To enhance wound healing, the use of biological additives, preferably from the patient himself, that regulate inflammation, angiogenesis and increase healing postoperatively would be very beneficial. Platelet concentrates are considered to be a source of autologous growth factors. A first generation of platelet concentrates, the so called PRP, were introduced by Marx and co-workers in 1998 (Marx et al., 1998). Their clinical benefit was difficult to evaluate due to the large number of preparation protocols and the lack of a clear classification of products (Dohan Ehrenfest et al., 2012). This resulted in a very controversial amount of literature on the use PRP in oral surgery (Dohan Ehrenfest et al., 2009). Furthermore, the preparation of PRP was time consuming, expensive and therefore less easy to use in daily practice. The preparation demanded artificial additives to influence the coagulation cascade (eg. calciumchloride and bovine trombin). A second generation of platelet concentrates, L-PRF, was introduced by Chouckroun and co-workers in 2001 (Choukroun et al., 2001). The simplified preparation protocol, without the need for biochemical blood handling, made it easier to use in everyday practice. The coagulation leads to a fibrin clot, incorporating approximately 97% of circulating platelets and approximately 50% of the leucocytes (Dohan Ehrenfest et al., 2010). These incorporated platelets lead cell migration and proliferation. Furthermore, the activation of platelets will result in their degranulation and cytokine release (Choukroun et al., 2006). The fibrin network has many similarities with the one formed during natural healing. The clot itself is easy moldable in desired shapes, being membranes or plugs. Various medical disciplines have used L-PRF in various types of surgery, not in the least in periodontology, implant dentistry and maxillofacial surgery (Bielecki & Dohan Ehrenfest 2012; Sammartino et al., 2011; Simonpieri et al., 2012, 2011; Toffler et al., 2010; TunalÎš et al., 2015; Zumstein et al., 2014). Nevertheless, results remained contradictory (GĂźrbĂźzer et al., 2010; Simonpieri et al., 2009). The use of L-PRF in oral surgery seems to be associated with less post-operative pain and discomfort is reported (Jankovic et al., 2012; Kumar et al., 2015a) and in wound repair (Chignon-Sicard et al., 2012).

The aim of this study was to evaluate the benefits of L-PRF in ridge preservation procedures. More specifically, the question if the use of L-PRF as a socket filling material results in a reduced alveolar resorption process, better intrinsic bone quality and less post-operative discomfort for the patient compared to natural healing was addressed.

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Material & Methods Surgical Procedure & L-PRF Preparation Protocol All patients received bilateral extractions under local anesthesia and strictly sterile conditions. Teeth were extracted flapless and as atraumatically as possible using periotomes and elevators. However, sites with damage to one of the bone plates (dehiscencies or loss of the buccal or palatal bone plate <50% of the initial height) were not excluded. Infectious tissues in the sockets were carefully removed using curettes. Sockets were randomized as control or test site in a split mouth design, via a randomization table. The treatment codes (PRF – test / blood – control) were available in closed envelopes. These were sealed and opened after the curettage by a nurse not involved in the study. For Demographic data of included patients and sites, inclusion and exclusion criteria, see Table 1. Prior to tooth extraction, a standard venipuncture was performed (median basilica vein, median cubital vein, median cephalic vein). Blood was drawn into 8 sterile, plastic 10 mL tubes without anticoagulant. L-PRF clots and membranes were prepared as described by Choukroun and co-workers (Choukroun et al., 2001). The tubes were immediately centrifuged at 2700 rpm for 12 minutes using a table centrifuge (IntraSpin™, IntraLock®, Florida, USA). Hereby, platelets were activated and the coagulation cascade was triggered. After centrifugation, each L-PRF clot was removed from the tube and separated from the red element phase at the base with pliers. Four L-PRF clots were gently squeezed between a sterile glass plate and a metal box. At the test site 2 to 5 PRF clots, depending on the size of the socket, were inserted and compressed with a large plunger. The site was thereafter covered with 2-3 membranes. Suturing (Vicryl 4.0 or Vycril 5.0, Ethicon™, Johnsson & Johnsson®) was performed in order to stabilize the L-PRF in situ, using a crossed horizontal matrass suture followed by individual sutures whenever necessary for better stabilization of the material. There was no attempt to close the wound. At the control site, a normal suturing technique was performed in order to stabilize the coagulum without any attempt to close the wound (Figure 1). All patients were asked to take an NSAID, 3 times a day (Ibuprofen 600 mg) for 2 days and use an antiseptic spray twice a day for 1 week (PerioAid™ Spray 0,12%, Dentaid®, Spain).

After the extraction, a CBCT scan (Aquitomoâ&#x201E;˘, MoritaÂŽ, Japan) was taken with a resolution of 0,3 mm, scanning time of 8,5s and exposure time of 4s, 120 kV and 5 mA. Follow up One week after tooth extraction, patients were scheduled for a control visit in order to remove the sutures. Three months after tooth extraction, patients received a second CBCT, with the same settings as mentioned above. Post-operative questionnaires To assess post-operative pain, the Dutch version of the McGill Pain Questionnaire (MPQ-DLV) was used (Melzack, 2005). The reliability and the validity of the MPQ-DLV has been confirmed in various publications (van der Kloot et al., 1995; Vercruyssen et al., 2014). The questionnaire was handed out as a diary and patients were asked to fill in the questions every day, from day 1 until day 7. This questionnaire used 100 mm VAS-scales to evaluate the amount of pain, ranging from 0 (no pain) to 100 (worst pain imaginable) and the amount of swelling. The patients were asked to fill in the VAS-scales at the day of surgery every 4h and afterwards daily till day 7. Patients were asked to score their pain three times; the pain they felt at the moment of questioning, and the minimum and maximum amount of pain they felt during the past 4 or 24h. The patients were also asked to document the number and the sort of analgesics taken each day. Furthermore, patients were asked to fill in VAS scales at the time of surgery and at the evaluation meeting after 7 days. They were asked to score the following questions; mean amount of pain during the past 24h, during surgery, if they would repeat the procedure in the future and if the duration of each procedure was tolerable. Questionnaires were collected at the 1 week follow-up visit. CBCT analysis The analysis of the CBCTs was performed according to the analysis described by Jung and co-workers (Jung et al., 2013). In order to perform the radiographic measurements, CBCTs taken immediately after extraction (T1) and after 3 months of healing (T2) were superimposed using the original DICOM data. For the superimposition of the cross sectional slices, the fixed anatomical

189

landmarks were set to be the palatal vault in the maxilla, where no changes had occurred after extraction. Both data sets could be spatially aligned in order match perfectly. The apex of the extraction socket at T1 was marked and the vertical reference line passing the apex in the center of the socket was set. Perpendicularly to the vertical reference, a horizontal reference line passing the apex was established. Following measurements were performed in the center of the extraction socket (Figure 2). • at baseline (T1) the thickness of the buccal bone plate was measured at 1, 3 & 5 mm below the lingual bone crest (PBWidth) • horizontal ridge width at 3 levels (crest -1 mm (HW-1 mm), crest -3 mm(HW-3 mm) & crest -5 mm (HW-5 mm)) below the most coronal aspect of the crest, in mm and percentages • vertical resorption on both the buccal and palatal side, measured in mm. • socket fill as being the highest point of viewable mineralized bone. Percentages of socket fill were measured by comparing the initial depth of the socket and the depth after three months of healing. Primary outcome variables were defined as the changes in horizontal width at crest-1 mm levels. Secondary outcome variables were defined as the changes in horizontal width at crest -3 mm and -5 mm; vertical resorption at the lingual and buccal side; socket fill. Post-operative scores were defined as tertiary outcome variables. Biopsies and Intrinsic Bone Quality Measurements (Van Dessel et al., in preparation) In 10 patients in need of oral implants after extraction, cylindrical bone biopsies (using a 2,8 mm trephine bur) were collected prior to implant placement and scanned in a SkyScan 1172® high-resolution (9 µm) system. Subsequently,

dedicated phantoms were scanned for calibration of the bone mineral density. Morphometric parameters were calculated using CT-AnalyserÂŽ for 3 dominant factors characterizing bone: (1) quantity, (2) structure and (3) BMD. Sample size calculation Sample size calculation was performed using Van Assche et al., 2013 as a reference. A sample size of 12 patients was estimated to have an 80% power to detect a difference in horizontal ridge width of 15-20% between the treatment groups at a one-sided error level of 2.5%. The study enrolled more subjects to account for potential dropout patients. Statistical analysis For each different response variable, summary statistics were made per depth. A linear mixed model was fit with treatment (L-PRF/control group) as fixed factor and patient as random factor for each depth separately. Differences between the L-PRF and control control group were corrected for simultaneous hypothesis testing according to Sidak in order to obtain an overall confidence level for the different depths and response variables of 95%. In addition, the difference between the control and LPRF was assessed by considering the measurements at 1, 3 and 5 mm depth as dimensions of a multivariate space. As such, a Hotelling TÂ˛ statistic was applied to assess the difference between treatment and control for various distances together. Concerning the post-operative questionnaires, for each combination of question and time, VAS-scores were compared between treatments. Also here, a correction for simultaneous hypothesis testing was applied according to Sidak.

191

Results Patients In total 22 patients were included in this study, all of them in need of bilateral extractions. Four patients received extractions in the mandible (premolar region) and 18 received extractions on the upper jaw (5 in the premolar region, 2 in the canine region, 11 in the incisor region). Three dehiscencies of approximately 6 mm on the buccal side occurred in the test group (2 in the premolar region and 1 in the incisor region). One dehiscence of approximately 3 mm occurred in the control group (incisor region). All patients were treated according to the protocol mentioned in the materials and methods section. All but 2 sites healed uneventful. Both of them were control sites. Patients experienced pain and malodor. Both sites were retreated under local anesthesia by the use of curettes until bleeding was provoked. Both patients received systemic antibiotics (Amoxicilline 500 mg/3 times a day) for 1 week, where after both sites further healed without problems. All patients received 2 CBCT scans and completed the study protocol. Baseline CBCT analysis of the buccal plate. The thickness of the buccal bone plate was measured at 3 levels (BPWidth -1 mm, BPWidth-3 mm & BPW-5 mm). This thickness ranged from a minimum of 0,5 mm to a maximum of 2,6 mm in the test-group. In the control-group a minimum of 0,7 mm and a maximum of 5,7 mm could be found. Overall no statistically significant differences (p>0,05) could be observed in the width of the buccal bone plates between test and control sites (Table 2). CBCT analyses CBCT’s of test and control sites in 2 patients are represented in Figure 4. The dimensional changes after 3 months of healing are presented in Table 3. Vertical resorption: Mean vertical height changes at the lingual aspect after a 3-month healing period were -0,7 mm (±0,8) for control sites and -0,4 mm (±1,1) for test sites. After exclusion of all sites were a dehiscence

occurred after extraction, values changed to -0,7 mm (±0,8) for control sites and -0,3 mm (±1,2) for test sites. For the lingual aspect, no statistical differences were reached. Mean vertical height changes at the buccal aspect after a 3 month healing period were -1,5 mm (±1,3) for control sites and 0,5 mm (±2,3) for test sites. After exclusion of all sites were a dehiscence occurred after extraction, values changed to -1,6 mm (±1,2) for control sites and -0,1 mm (±1,6) for test sites. Statistically significant differences between test and control sites were reached for the vertical height changes at the buccal aspect (p<0,05). Horizontal resorption: The mean ridge width differences between baseline and after 3 months of healing were measured at 3 levels below the crest (HW-1 mm, HW-3 mm & HW-5 mm) on both the buccal and lingual sides. Lingual: For the control sites measured values at the lingual side were respectively, -2,1 mm (±2,5), -0,3 mm (±0,3) and -0,1 mm (±0,0). They changed to -2,0 mm (±2,6), -0,2 mm (±0,3) and -0,1 mm (±0,3) after exclusion of all sites with dehiscences after extraction. Values for the lingual test sites were respectively -0,6 mm (±2,2) , -0,1 mm (±0,3) and 0,0 mm (±0,1). These values changed to -0,3 mm (±1,9), -0,1 mm (±0,3) and 0,0 mm (±0,1) after exclusion of all sites with dehiscences after extraction. Statistically significant differences between test and control sites were reached at the HW-1 mm level (p<0,05). Buccal: For the control sites, measured values at the buccal side were respectively, -2,9 mm (±2,7), -1,0 mm (±1,1) and -0,5 mm (±0,6). They changed to -3,3 mm (±2,6), -1,0 mm (±1,1) and -0,5 mm (±0,7) after exclusion of all sites with dehiscences after extraction. For the buccal test sites these values were respectively -0,8 mm (±2,5), -0,2 mm (±1,5) and -0,2 mm (±1,7). These values changed to -1,2 mm (±2,6), -0,8 mm (±0,9) and -0,5 mm (±0,6) after exclusion of all sites with dehiscences after extraction. Statistically significant differences between test and control sites were reached at the HW-1 mm and HW-3 mm level (p<0,05). Changes in total horizontal width: The mean ridge width changes at the three levels below the crest (HW-1 mm, HW-3 mm and HW -5 mm) amounted to -5,4 mm (±4,4 mm), -1,2 mm (±1,1 mm), -0,5 mm (±0,5 mm) for the control sites. For the test sites following values were

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obtained at the same three levels below the crest: -2,4 mm (±2,3 mm), -0,6 mm (±0,7 mm) and -0,4 mm (±0,5 mm). At HW-1 mm level statistical significance was reached (p<0,05). At HW-3 mm levels, values were borderline not significant. Changes in total ridge width between 3 months and baseline based on CBCT measurements expressed in percentages are shown in Table 4 and Figure 3. Socket Fill: Statically significant differences (p<0,05) were found in the percentage of socket fill between test (94,7% (± 26,9) and control sites (63,3% (± 31,9))(p<0,05). Intrinsic Bone Quality Structural-related parameters showed a significantly (p<0.01) denser organized trabecular bone (↑ Tb.Pf; ↓ Tb.Sp; ↓ Po[tot]; ↓ Tb.N; ↓ SMI; ↓ Conn.Dn) in L-PRF as compared to natural healing. These findings were confirmed by a significantly (p<0.01) increased bone quantity (↑ BV/TV; ↑ Tb.Th; ↓ BS/TV). Finally, the trabecular bone displayed a significantly (P <0.01) higher BMD after L-PRF treatment (Table 6 & Figure 7) Post-operative pain sensation: Statistically significant differences in post-operative pain sensation (maximum amount of pain and average amount of pain) differences were observed at day 2, 3 and 4 days (p < 0.05)(Figure 5). For the minimum amount of pain, the difference was present but not statistically significant.

Discussion The present prospective, split mouth, randomised controlled clinical study confirms that the use of 2nd generation platelet concentrates, as a socket filling material after tooth extraction, is associated with a better preservation of the alveolar process following tooth extraction, compared to natural healing. Various studies observed that the major hard tissue alterations after tooth extraction occurred during the early phases (3-6 months)(Schropp et al., 2003), but that in later phases also various amounts of ridge shrinkage can be seen (Iasella et al., 2003; Schropp et al., 2003). There is an unanimous agreement on the fact that resorption is more prominent in the vestibular bone plates (Araújo et al., 2005), than it is in the lingual bone plates and that horizontal resorption is more pronounced than vertical resorption (Iasella et al., 2003; Tomasi et al., 2010). Partially this can be explained by the fact that the vestibular bone plates are generally thinner (Araújo et al., 2015, 2005). Resorption percentages in a horizontal vestibular direction have been shown to reach 56% (vs. 30% in lingual horizontal way). The overall reduction in width of the ridge has been reported to be ±50% (Schropp et al., 2003). These results are in accordance to the values obtained in this study. Due to these processes, the ridge is relocated to a more lingual position (Botticelli et al., 2004). Whenever the vestibular bone plates is partially or fully lost in due to uncarefull extraction or inflammatory processes, ridge remodelling is even more extensive (Iasella et al., 2003). Consequently the magnitude of these dimensional changes is particularly important for future comprehensive treatment planning, when oral implants are involved. The reduction in height and width of the alveolar process may hamper implant placement in a prosthetically ideal position and possibly have its consequences on the aesthetic outcome of an implant supported restoration. Surgical alveolar ridge preservation treatments are a widely used treatment modality in order to partially compensate for the resorption process following tooth extraction. Essentially, ridge preservation procedures aim to minimize external resorption of the ridge and to maximize bone formation within the socket. Various techniques have been described in literature, frequently varying greatly in difficulty and biomaterials used (Barone et al., 2015c; Canullo et al., 2015; Ikawa et al., 2015; Jung et al., 2013; Lee et al., 2015; Mendoza-Azpur et al., 2015; Sbordone et al., 2015). The use of autologous bone particles did not significantly alter the ridge resorptive process (Araújo & Lindhe, 2011).

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Biomaterials, such as auto-, allo- and xenografts have been used in humans with varying degree of success. These materials might either be resorbable or non-resorbable. In animal and clinical studies, the use of xenografts could counteract, to some extent, the ridge resorption in vestibule-oral dimension. On the other hand, their use in sockets has also been questioned as they possible may interfere with natural healing process (Buser et al., 1998). Very recent systematic reviews could conclude that alveolar ridge preservation techniques can not stop the ridge resorption process, but can only partially counteract. To date, there is limited evidence that alveolar ridge preservation techniques may minimise the overall changes in residual ridge height and width, 6 months after extraction. Furthermore there is no convincing evidence of any clinically significant difference between different grafting materials and barriers used for. However, it seems that the use alveolar ridge preservation techniques resulted in less implant sites that need additional augmentation, which can be beneficial for the patient (Atieh et al., 2015; Mardas et al., 2015; Vignoletti et al., 2012b; Willenbacher et al., 2015). Tan and co-workers reported in their systematic review, based on 20 studies exploring the dimensional changes in non-grafted sockets 6 months after tooth extraction, an average horizontal bone loss of 3.8 mm and an average vertical loss of 1.2 mm. This corresponded to a horizontal resorption of 32% at 3 months, and of 29% to 63% at 6 to 7 months, and a vertical resorption of 11 to 22%. These findings are in correspondence with the average horizontal and vertical resorption in the non-grafted sites, in the present study (respectively 3,6 mm and 1,5 mm). A recent systematic review (Jambhekar et al., 2015) examined 32 RCTs studying 1354 sockets, which addressed the clinical flapless extraction with socket grafting and provided dimensional information after 3 months of healing. From these RCTs, the mean loss of bucco-lingual width at the ridge crest was lowest for xenografts (1.3 mm), followed by allografts (1.63 mm), alloplasts (2.13 mm), and sockets without any socket grafting (2.79 mm). The mean loss of buccal wall height from the ridge crest was lowest for xenografts (0.57 mm) and allografts (0.58 mm), followed by alloplasts (0.77 mm) and sockets without any grafting (1.74 mm). Jung and co-workers used CBCT to examine the ridge preservation after the application of different bone substitutes (tri-calcium phosphate, demineralized bovine bone vs. natural healing) in combination with a soft tissue sealing (autogenous soft tissue graft) after

six months. This last group obtained the best result with a gain in height of the oral plate of 0.3 mm, of the buccal plate of 1.2 mm and loss of 1.4 mm of alveolar width. Based on the above findings this would bring L-PRF’s effectiveness at the same level as these osseous substitutes, but without having the disadvantages of graft particles remaining and a considerable cost (for comparison see Figure 6). All alveolar ridge preservation techniques have some things in common. Inherently, they include the use of wide variety of biomaterials, which will result in higher costs for the patient. Sometimes they include the use of autologous soft tissue grafts, which results in a donor site and subsequently higher patient morbidity and post-operative discomfort. The preparation of L-PRF is straightforward, easy and inexpensive for the patient and the clinician. Contrary to the first generation of platelet concentrates, the preparation does not include second centrifugations, pipetting or heating. Nor is there any need for bovine thrombin or calciumchloride as an coagulant (Dohan Ehrenfest et al., 2014). In this way, L-PRF can be used on a routine basis in everyday practice. Also from a surgical point of view the use of L-PRF as a socket filling materials looks promising. There is no need for difficult surgical procedures, as the material itself only needs to be stabilised. As L-PRF is an autograft of blood origin, it will not leave any residual particles in the preserved sites. From a ‘healing’ point of view this may be an important issue as this may increase the proportion of “vital” bone. In a recent systematic review it was concluded that grafting materials in general reduce the proportion of vital bone in comparison to naturally repaired sockets (Chan et al., 2013). Jambhekar and co-workers (Jambhekar et al., 2015), for example, reported following proportions of remaining graft particles: allograft (21.8%), xenografts (19.3%), and alloplastic materials (13.7%). One has to be aware of the fact that the BMD has a positive association with primary implant stability. (Marquezan et al., 2012). An interesting future topic is to investigate whether L-PRF as a surgical additive can enhance the surgical outcomes when combined with biomaterials. To our knowledge, to date there is only one study focussing on this topic. In a prospective cohort study by Barone and coworkers, extraction sockets with partial or full buccal bone dehiscencies were treated with L-PRF membranes on the buccal aspect to separate the gingival tissues from the xenograft in the socket. Furthermore, a trimmed collagen membrane

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was used to cover the socket. It was concluded that this treatment option can be effective in repairing buccal bony defects prior to oral implant placement (Barone et al., 2015b) This study clearly showed the influence of L-PRF on the post-operative discomfort and pain for the patients, definitely on the early phases of healing. Studies focussing on pain sensation and post-operative sequelae (eg. alveolar osteitis) after 3th molar extraction could conclude that L-PRF has a clear effectiveness (Kumar et al., 2015a, 2015b; Ozgul et al., 2015). A similar study as the present one, by Marenzi and coworkers (Marenzi et al., 2015) could conclude that L-PRF filling of in post-extraction sockets is an efficient and useful procedure in order to manage the post-operative pain and to enhance the alveolar soft tissue healing process, especially in the first days after the extractions, reducing the early adverse effects of the inflammation. L-PRF seems to have a huge potential to be used routinely to reduce post-operative discomfort (Kumar et al., 2015b). Possible explanations include a supportive effect on the immune system, due to stimulation of defence mechanisms (Gassling et al., 2009). Protection of growth factors from proteolysis due to the fibrin network and the release of high quantities of , TGF-Î˛1, PDGF-AB, VEGF and trombospondin-1 (and to lesser extent EGF, FGF, IL-1b, IL-6 and TNF-Îą) which stimulate biological functions, such as chemotaxis, angiogenesis, proliferation, differentiation, modulation (Choukroun et al., 2001; Kumar et al., 2015a; Singh et al., 2012). Platelets may also attract macrophages after delivering signalling peptides and thereby play a role in host defence mechanisms at the wound area. Possible shortcomings of this study are the rather low number of included patients and the lack histological confirmation of bone preservation. Further studies, should take these shortcomings into account.

Conclusions Within the limitations of this RCT with split mouth design, it can be concluded that the use of L-PRF as a socket filling material in order to achieve ridge preservation is beneficial with results comparable to those when biomaterials are used. Furthermore, the use of L-PRF results in less post-operative discomfort and pain for the patients, especially during the early phases of healing. L-PRF is an easy to prepare and surgically easy to use biological patient-derived additive, which can be used in daily practice on a routine basis. Furthermore the results of ÂľCT analysis are strongly supportive that L-PRF treatment enhances the bone quality.

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Figures figure 1 (a) 6 tubes in the centrifuge ready for centrifugation (b) Tube after centrifugation. Three parts are clearly visible (red blood cells, fibrin clot & acellular plasma). (c) fibrin clots are removed from the tubes using tweezers, and the red blood cell part is removed using a periosteal elevator. (d) fibrin clots are laid down on a perforated metal box and covered by a glass plate. (e) L-PRF membranes are formed after 5 minutes of compression by the glass plate. (f) Study patient: Test site (11) filled with L-PRF and covered with 2 membranes before suturing; control site (21) after suturing and stabilization of the coagulum.

figure 2 Cross-sectional slice of a test/control site at baseline (immediately after extraction). HW-1 mm, HW-3 mm, HW-5 mm are representing the measurements performed at 3 levels below the bone crest. The width of the buccal plate (BPwidth) was measured 1 mm below the crest. The depth of the socket was measured as the deepest point of the socket to the bone crest. Modified from Jung et al., 2013.

201

figure 3 Changes in ridge height and width between 3 months and baseline based on CBCT measurements expressed in %.

figure 4 Representative CBCT images of 2 study patients (1-2) at baseline and 3 months. (1.a & 2.a) test site immediate after extraction (1.b & 2.b) control site immediate after extraction. (1.c and 2.c) test site after 3 months of healing. (1.d & 2.d) control site after 3 months of healing.

figure 5 Graphical representation of the pain sensation as scored on VAS-scores. In the Y-axis the pain sensation and in the X-axis the time in days.

203

figure 6 Comparison between the results obtained in the present study using L-PRF for ridge preservation properties and the ‘socket seal technique’ (Jung et al.,2013). Comparisons can be made as identical measurements were made in both studies.

figure 7 Respective 3D volumes scanned with a µCT, of bone biopsies in 1 study patient. (a) scanned bone biopsy of L-PRF test-side (b) scanned bone biopsy of the control side.

Tables Table 1 Demographic data exclusion criteria.

included

patients

and

sites,

inclusion

and

Patients demographics Age (years) Mean ± SD

54 ± 11

Male/Female

15/7

Mandible/maxilla

4/18

Inclusion criteria

Exclusion criteria

>18 years of age

Smoking

+60% of bony support (radiographs)

Systemic diseases inferring with healing Bisphosphonate treatment – radiation of the jaws

Table 2 Baseline radiographic measurements of the width of the buccal bone plate using the CBCT images at T1. Radiographic measurements

TEST SITES Mean

CONTROL SITES

Range

Mean

Range

P-value

Buccal bone plate -1 mm

1,15

0,7

(0,5; 2,6)

1,58

1,4

(0,7; 5,7)

0,15

Buccal bone plate -3 mm

1,59

1,2

(0,5; 4,3)

1,92

1,7

(0,9; 6,2)

0,28

Buccal bone plate -5 mm

1,90

2,1

(0,5; 7,6)

2,40

2,3

(0,7; 8,6)

0,07

Buccal bone plate -1 mm to -5 mm (mean)

1,55

1,3

1,98

1,8

205

0,31

Table 3 The dimensional changes after 3 months of healing. (HW-1 mm (Horizontal width reduction 1 mm below the crest), HW-3 mm (Horizontal width reduction 1 mm below the crest), HW-5 mm (Horizontal width reduction 5 mm below the crest), BHplate (vertical dimension changes at buccal and lingual plate). CBCT

Horizontal Width Reduction Dehiscencies included Control (22 sites) Buccal

Test (22 sites)

Lingual

Buccal

Lingual

mean

P-value (buccal)

P-value (lingual)

HW-1 mm

-2,9

2,7

-2,1

2,5

-0,8

2,5

-0,6

2,2

0,003

0,004

HW-3 mm

-1,0

1,1

-0,3

0,3

-0,4

1,5

-0,1

0,3

0,04

0,06

HW-5 mm

-0,5

0,6

-0,1

0,0

-0,4

1,7

0,0

0,1

0,38

0,06

BHplate

-1,5

1,3

-0,7

0,8

0,5

2,3

-0,4

1,1

CBCT

Horizontal Width reduction Dehiscencies excluded Control (21 sites) Buccal

Test (19 sites)

Lingual

Buccal

Lingual

mean

HW-1 mm

-3,3

2,4

-2,0

2,6

-1,2

2,6

-0,3

1,9

HW-3 mm

-1,0

1,1

-0,2

0,3

-0,8

0,9

-0,1

0,3

HW-5 mm

-0,5

0,7

-0,1

0,3

-0,5

0,6

0,0

0,1

BHplate

-1,6

1,2

-0,7

0,8

-0,1

1,6

-0,3

1,2

CBCT

Total Width Reduction (% - dehiscencies included) Control (22 sites)

Test (22 sites)

Mean

p-value

HW-1 mm

-51,92

40,31

-22,84

24,28

0,0004

HW-3 mm

-14,51

19,6

-5,42

6,16

0,007

HW-5 mm

-4,47

4,89

-2,91

4,54

0,02

BHplate

CBCT

Socket Fill (mm and % - dehiscencies included Control (22 sites)

Test (22 sites)

Mean

p-value

HW-1 mm

6,2(mm)

3,9(mm)

8,1(mm)

3,1(mm)

0,005

HW-3 mm

63,3(%)

31,9(%)

94,7(%)

26,9(%)

0,0004

Table 4 Changes in ridge width between 3 months and baseline based on CBCT measurements expressed in %. CBCT

Control

Test

Mean

HW-1 mm

-51,92

40,31

-22,84

24,28

HW-3 mm

-14,51

19,6

-5,42

6,16

HW-5 mm

-4,47

4,89

-2,91

4,54

207

1,02

0,80

0,31

Median

1,16

DAY

Range

(0-2,94)

(0-1,87)

(0-2,77)

(0-2,14)

(0,18-2,85)

(0-4,1)

(0-5,71)

0,49

0,93

1,51

1,29

0,84

Median

(0-1,78)

(0-2,59)

(0-4,46)

(0,09-3,75)

(0-3,6)

(0-4,91)

Range

Control

0,87

0,98

0,56

0,16

0,77

0,12

P-value

0,09

0,71

0,89

1,65

2,05

1,69

Median

(0-2,68)

(0-2,67)

(0-3,21)

(0,18-2,58)

(0,09-3,12)

(0,45-4,19)

(0,27-5,53)

Range

Test

0,27

0,36

1,25

1,82

2,45

2,51

1,69

Median

(0-4,2)

(0-2,68)

(0-4,19)

(0-4,64)

(0,09-4,64)

(0,45-4,28)

(0,27-4,73)

Range

Control

Average amount of pain

0,07

0,56

0,03

0,02

0,87

P-value

0,09

0,62

1,25

2,81

3,66

2,85

Median

(0-5,79)

(0-4,2)

(0-3,65)

(0,09-3,75)

(0,09-4,20)

(0,45-5,17)

(0,36-5,44)

Range

Test

0,23

0,75

2,14

2,81

3,52

3,60

2,67

Median

(0-4,19)

(0-3,92)

(0-4,82)

(0,09-5,08)

(0,18-5,62)

(0,54-5,79)

(0,36-5,44)

Range

Control

Worst amount of pain

Numerical values for VAS-scores.

Test

Weakest amount of pain

VAS-scores (weakest, average and worst amount of pain)

0,11

0,19

0,03

0,92

0,99

p-value

Table 5

Table 6 Respective values of µCT evaluation of bone biopsies. Normal values for healed bone biopsies were obtained by paper from Bertl et al., 2015 and Blok et al.,2012. Parameter (n=10)

Normal

L-PRF

CONTROL

p-value

value

BMD (g/cm3)

0,90

mean

1,32

0,16

1,08

0,11

0,008

BV/TV (%)

24,2

43,6

7,6

34,5

5,5

0,01

Tb.Th (µm)

210,1

258,6

42,0

165,1

41,8

0,001

209

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The influence of remaining pathologies in the bone after extraction on oral implant outcome and retrograde periimplantitis: a literature review.

Etiology and treatment of peri-apical lesions around dental implants. Temmerman Andy, Lefever David, Balshi Thomas, Balshi Stefan, Teughels Wim & Quirynen Marc. (2014) Periodontology 2000 66: 247-254.

Aetiology, microbiology and therapy of peri-apical lesions around oral implants: a retrospective analysis. Lefever David, Van Assche Nele, Temmerman Andy, Teughels Wim & Quirynen Marc. (2013) Journal of Clinical Periodontology 40: 296-302.

Oral presentations on Chapter 7 were given at: • Annual Meeting of the Belgian Society of Periodontology (2014, Leuven, Belgium) • Spring Symposium of the ‘Together for Implantology’ Society (2015, Adana, Turkey) • Winter Symposium of the ‘Together for Implantology’ Society (2015, Istanbul, Turkey)

Abstract: The widespread use of oral implants in recent years has resulted in various types of complications. One of those complications is the peri-apical implant lesion. Different factors have been proposed to play a role in the development and emergence of a peri-apical implant lesion. To date, there is no consensus on the etiology and therefore peri-apical lesions around dental implants are considered to have a multifactorial etiology. The diagnosis of an implant peri-apical lesion should be based on both clinical and radiological findings. Additionally, in order to apply the best treatment strategy the evolution of the lesion should be taken into account. The treatment of this kind of lesion, however, is still empiric. Data, primarily from case reports, seem to indicate that the removal of all granulation tissue is a first step to arrest the progression of the bone destruction. The removal of the apical part of the implant seems a valuable treatment strategy.

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Introduction During the last 30 years the osseointegration principle has proven solid experimental and clinical data. This has led to an increase of the popularity of the use of endosseous implants for the replacement of missing teeth and a patient’s oral rehabilitation (Adell et al., 1981; Albrektsson et al., 1988; Adell et al., 1990). Their widespread use in recent years, however has produced different types of complications. Even with most stringent rules for sterility (van Steenberghe et al., 1997), an optimal surgical planning and a careful patient selection/ preparation, still some implants fail to integrate. One of these complications is the implant peri-apical lesion, and case-reports have suggested that this lesions are possible causes for the failure of an endosseous implant (Ayangco et al., 2001; Bretz et al., 1997; Flanagan 2002). The implant peri-apical lesion is also called ‘apical peri-implantitis’ and ‘retrograde peri-implantitis’ (Quirynen et al., 2003). It is defined as a clinically symptomatic peri-apical lesion (and therefore diagnosed as a radiolucency) that normally develops shortly after the placement of an oral endosseous implant. The coronal portion of the implant achieves a normal bone to implant interface (Quirynen et al., 2003; McAllister et al., 1992). The first cases where described by McAllister in 1992 (McAllsiter et al., 1992 and soon thereafter by Sussman and Moss in 1993 (Sussman & Moss 1993). The purpose of this review is to give a literature overview concerning the aetiology of these lesions, the prevalence and its diagnosis in order to understand the pathology and to suggest strategies for prevention and treatment.

AETIOLOGY Different aetiological factors have been proposed to play an important role in the development and emergence of a peri-apical implant lesion. To date however, there is no consensus about the aetiology and peri-apical lesions around dental implants are considered to have a multifactorial aetiology, combining different factors (Balshi et al., 2007). As a retrograde peri-implantitis is often accompanied by symptoms of pain, tenderness, swelling, and/or the presence of a fistulous tract, two type should be distinguished: the active periapical implant lesion and the inactive peri-implant lesion. Lesions are called â&#x20AC;&#x2DC;inactiveâ&#x20AC;&#x2122; when the radiological findings are not comparable with the clinical findings and/or the patients symptoms. A clinically a-symptomatic, peri-apical radiolucency which is usually caused by placing implants that are shorter than the prepared osteotomy is to be considered inactive (McAllister et al., 1992; Reiser et 1995). When an implant is placed next to an, already existing, detectable radiolucency, which is caused by scar tissue this also can evoque an inactive lesion (McAllister et al., 1992; Reiser et al., 1995). Furthermore an inactive lesion can also be caused by aseptic bone necrosis, frequently induced by overheating the bone during osteotomy preparation. Overheating is mentioned as a risk factor for bone necrosis. This can eventually compromise the dental implant primary stability. Uncontrolled thermal injury can result in a fibrous tissue, interpositioned at the implant-bone interface, compromising the long-term prognosis of the implant. An active peri-apical implant lesion can be caused by bacterial contamination during insertion or premature loading, before an adequate bone to implant interface has been established leading to bone micro-fractures. Implant insertion in a site with a pre-existing inflammation (bacteria, inflammatory cells, and/or remaining cells from a cyst, granuloma) can also lead to an active peri-apical implant lesion. These lesions are initiated at the apex of the implant but they have to capacity to spread coronally and facially. Retrograde peri-implantitis should furthermore not be mistaken for non-integration. E.g. when during placement the apex of an implant touches the tooth and/or when the implant is inserted in an active endodontic lesion from an adjacent tooth the implant may exfoliate completely and thereby will non-integrate.

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Sussman (Sussman and Moss 1993; Sussman 1998) described 2 basic pathways of peri- apical implant pathology: Type 1: Implant-to-Tooth pathway. This Implant-to-Tooth lesion will develop when implant insertion (by direct trauma or indirect damage) results in tooth devitalization. This may occur when the implant is placed with an insufficient distance from a neighbouring natural tooth or when the bone was overheated during osteotomy preparation. When a osteotomy has caused direct trauma to the root of a natural tooth, this will destroy the blood supply to the pulp and also cause an Implant-to-Tooth type lesion. In this way the resulting periapical implant lesion will contaminate the fixture (Sussman and Moss 1993; Brisman 1996; Sussman 1997, Sussman 1998). Type 2: Tooth-to-Implant pathway. The lesion will occur quite shortly after fixture installation when an adjacent tooth develops peri-apical pathology (operative damage, caries involvement, external root resorption (Christensen 1997; Sussman 1997) or reactivation of a previously existing apical lesion or the removal of an endodontic seal (Sussman 1997). The majority of authors consider an endodontic pathology of the natural tooth replaced by the oral implant (or an adjacent tooth) to be the most likely cause for apical peri-implant pathology (Sussman 1997; Quirynen et al., 2005). Ayangco and co-workers (Ayangco et al., 2001) published a series of reports were oral implants were placed in sites were apical surgery failure had occurred. The reported that, even with a thorough curettage of the sockets and a prolonged healing time before implant placement, bacteria have the capacity to remain present in the bone and may cause development of lesions on the placed implants. Brisman and co-workers (Brisman et al., 2001) reported that even asymptomatic endodontically treated teeth with a normal peri-apical radiographic appearance could be the cause of an implant failure. They also suggested that micro-organisms may persist even though the endodontic treatment was considered radiographically successful, because of inadequate obturation or incomplete seal. Lefever and co-workers (Lefever et al., 2013) examined the peri-apical status of the tooth at the implant site and the neighbouring teeth prior to implant placement primarily on digital intra-oral radiographs. If such radiograph was

not available, an extra-oral panoramic radiograph was used to judge the periapical condition. The peri-apical status of the tooth at the implant site and the neighbouring teeth prior to extraction was explored and identified as: (a) no endodontic treatment and no peri-apical lesion - (b) a peri-apical lesion at the root combined with or without an endodontic treatment, - and (c) an endodontic treatment without clear signs of a peri-apical lesion. If the tooth showed no signs of a peri-apical lesion and had no endodontic treatment, the incidence of an apical pathology was 2.1%. On the other hand, if an endodontic treatment or a peri-apical lesion at the apex of the tooth was present at the moment of extraction, a peri-apical lesion could be found around the implant in 8.2% and 13.6% of the cases, respectively. If the neighbouring teeth, either on the mesial or the distal side, showed no signs of pathology or did not receive endodontic treatment, only 1.2% of the implants presented with a peri-apcial lesion. When an endodontic treatment was performed in the past, but no signs of peri-apical pathology could be detected, no peri-apical lesions around the implants could be found. However, if there were signs of peri-apical pathology at the neighbouring teeth, 25% of the implants also showed a peri-apical lesion. When proper protocols are followed at has been shown that the immediate implant placement of oral implants into fresh extraction sockets is a valuable treatment strategy (Hammerle et al., 2004). The immediate implant placement in infected sites however remains a topic of discussion. Several authors have considered immediate implant placement in infected sites a contraindication (Barzilay 1993; Becker et al., 1990; Schwartz-Arad et al., 1997) as these sites may compromise an uneventful osseointegration (Quirynen et al., 2003) and may result in the development of an implant peri-apical lesion (Ayangco et al., 2001; Quirynen et al., 2005). Alsaadi and co-workers reported on a greater tendancy for implant failure in sites with apical pathology (Alsaadi et al., 2007). In a recent case series study Marconcini and co-workers (Marconcini et al., 2012) immediately placed 20 implants in 20 patients. All teeth were extracted due to periodontal disease. They report on an uneventful healing within all patients and 100% of osseointegration. They conclude that immediate implant placement in sites infected due to periodontal disease is a valuable treatment strategy, if adequate pre- and postoperative care is taken. Crespi and co-workers (Crespi et al., 2010) immediately placed 15 implants in peri-apical infected sites and 15 in non-infected sites. They conclude that at the 24-month follow-up, endosseous

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implants placed immediately in extraction sites affected by peri-apical infection rendered an equally favorable soft and hard tissue integration of the implants, revealing a predictable outcome. Lindeboom and co-workers (Lindeboom et al., 2006) placed 50 implants in chronic peri-apical infected sites. 25 were placed immediately after extraction, 25 were placed after a mean healing period of 3 months. They report a survival rate of 92% for the immediately placed implants versus 100% in the control group. Furthermore mean implant stability quotient values (ISQ), gingival aesthetics, radiographic bone loss and microbiological characteristics were not different. They concluded that the immediate implant placement into chronically peri-apical infected sites may be a valuable treatment option. In a study by Fugazzotto (Fugazzotto et al., 2012) a retrospective analysis of 418 implant immediately placed after extraction in sites showing peri-apical pathology. Cumulative survival rates were similar to implants immediately placed in sites showing no peri-apical pathology. In a recent study by Jung and co-workers (Jung et al., 2012) the immediate placement of implants in sites with peri-apical pathology was compared to immediate placement in healthy sites. All implants were further observed during a 5-year period. They concluded that the replacement of teeth exhibiting peri-apical pathologies by implants placed immediately after tooth extraction can be a successful treatment modality with no disadvantages in clinical, aesthetical and radiological parameters to immediately placed implants into healthy sockets. Even though most authors consider a microbiological factor important in the pathogenesis of an active peri-implant lesion, investigations remain scarce. Romanos and co-workers (Romanos et al., 2011) histologically investigated 32 implant with peri-apical infection, however only in 1 case bacteria were found. Chan and co-workers (Chan et al., 2011) found the presence of E. corrodens in the surgically treated peri-apical lesion by microbial testing. Lefever and coworkers (Lefever et al., 2013) treated 21 cases, where a microbial sample of the peri-apical lesion was taken at the moment of treatment. These samples were analysed for enterococcus species, Aggregatibacter actinomycetemcomitans, Campylobacter rectus, Fusobacterium nucleatum, Prevotella intermedia and Porphyromonas gingivalis. Furthermore, also the total count of aerobic and anaerobic bacteria was explored. Bacteria were found in nearly all sites, but only in 9/21 in concentrations â&#x2030;Ľ log 4. The proportion of anaerobic species was always higher when compared to aerobic species. P. gingivalis and P.

intermedia were detected in reasonable concentrations at 6 and 4 sites respectively. The other specific species tested (A. actinomycetemcomitans, C. rectus and F. nucleatum, Enterococci) never reached the threshold level for identification. Further factors related to implant peri-apical pathology are: presence of residual root fragments or foreign bodies (Reiser et al., 1995; Piattelli et al., 1998), the placement of an oral implant in the proximity of an infected maxillary sinus (Scarano et al., 2000), placement of the implant in the nasal cavity (Silva et al., 2010) and excessive tightening of the implant during insertion causing compression of the bone (Scarano et al., 2000). The aetiopathogenesis of an active apical peri-implant lesion remains controversial and it is believed to have a multifactorial pathogenesis (Piattelli et al., 1998; Rosendahl et al., 2009).

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PREVALANCE The prevalence of this peri-apical implant pathology is rather low. Quirynen and co-workers obtained a prevalence of 1.6% in the maxilla and 2.7% in the mandible in a retrospective study comprising 539 implants (Quirynen et al., 2005). On 3800 implants, Reiser and Nevins found a prevalence of 0.26% implants with peri-apical implant pathology (Reiser et al., 1995).

DIAGNOSIS The diagnosis of an implant peri-apical lesion is based on both clinical and radiological findings. As mentioned before these lesions are classified into 2 groups: the inactive form and the active form. The inactive lesions are asymptomatic and a radiologically found due to a radiolucency around the apex of the implant. The lesions do not need further treatment, although they need to be controlled radiographically on regular basis, as the growth of the radioluceny may indicate the need for further treatment. Active lesions are frequently (but not necessarily) clinically symptomatic. Clinical findings may comprise constant and intense pain (even persistent after analgesic treatment)(Scarano et al., 2000), inflammation (Oh et al., 2003), dull percussion, the presence of a fistulous tract (Piattelli et al., 1998; Ayangco et al., 2001), the absence of mobility. Although these clinical findings are no prerequisite. If pain is present this will not increase due to implant percussion because the bone-implant interface is direct. Because of the fact that there is no pressure to create a fistulous tract, and that purulent materials can emerge through the still not fully consolidated interface between implant and bone, this clinical finding is not always present (Penarrocha-Diago et al., 2006). According to Penarrocha-Diago and co-workers the diagnosis must include the determination of the evolution stage of the lesion in order to apply the best treatment strategy (Penarrocha-Diago et al., 2012). The authors divide the evolution of the periapical implant lesion into 3 parts: â&#x20AC;˘ (1) the non-suppurated acute peri-apical implant lesion: an acute inflammatory infiltrate is detectable and clinically it is characterized by the presence of acute spontaneous and localized pain, not increasing with percussion. The mucosa can be swollen and sometimes painfull. Percussion of the implant will produce a tympanic sound. Radiographically there are no changes in bone density around the apex of the implant.

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â&#x20AC;˘ (2) the suppurated acute peri-apical implant lesion: a purulent collection is formed around the apex of the implant. This collection will result in bone resorption as it searches for a pathway for drainage. When this pathway has been established the next stage is reached. Clinical signs are comparable with the non-suppurated stage. Radiographically however, a radiolucency can be detected around the apex of the implant. â&#x20AC;˘ (3) suppurated-fistulized peri-apical implant lesion: depending on whether the bone-to-implant junction in the coronal part well established a fistulous tract can develop from the apex of the implant to the cortex of the buccal plate. If the coronal junction is not well established, the peri-implant bone will also be destroyed in a coronal direction and eventually this will lead to implant loss. Clinical signs are various, radiographically bone resorption around the implant can be seen. Care should be taken because two dimensional peri-apical radiographs does not always show the correct size of an intra-bony defect. Only when the junctional area is involved, these kinds of defects can be identified. Therefore it might be possible that some peri-apical pathologies are not recognized on two dimensional radiographs, which is a limiting factor in the diagnosis. A cone beam CT can be used to overcome this limitation (Van Assche et al., 2009).

TREATMENT Authors (Penarrocha-Diago et al., 2012; Zhou et al., 2012) consider a correct and early diagnosis a prerequisite for treatment and the prevention of implant failure. As mentioned before, peri-apical lesions around dental implants are considered to have a multifactorial aetiology. Due to this fact there is no consensus regarding the therapy. A search trough the literature leads to predominantly case-reports of possible treatment options. Some case authors report on nonsurgical treatments. Chang and co-workers (Chang et al., 2011) treated one case without surgical intervention. They used amoxicillin, clavulanic acid, prednisolone and mefenamic acid where after the patientâ&#x20AC;&#x2122;s symptoms completely subsided and radiographically the lesion disappeared and after a follow-up time of 2 years the implant remained stable. Waasdrop and Reynolds (Waasdrop and Reynolds 2010) also treated 1 patient in a non-surgical way with the use of antibiotics. The radiographical lesion gradually resolved after the course of the following 9 months without further treatment. Some authors however concluded that the initial treatment with antibiotics were not effective in controlling active lesions (Dahlin et al., 2009). So the question arises whether the resolvement of peri-apical implant lesions in the before mentioned studies was due to prescribed drugs or whether these lesions where inactive. In order to prevent osteomyelitis and since the retaining of the implant can lead to further and irreversible bone loss, some authors advise explantation of the infected implant(s)(Sussman 1998; Scarano et al., 2000; Silva et al., 2010; Ataullah et al., 2006; Rokadiya et al., 2008). Most authors, however, agree that the apex of the implant should be surgically exposed. How the therapy should be continued after exposure remains a topic of discussion. Reiser and Nevins (1995) and Oh and co-workers (2003) that a surgical approach is mandatory, whereby the elimination of the infection, and an implant apical resection or implant removal depends on the extent of the infection and the stability of the implant

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Zhou and co-workers (2012) treated 6 implants in 6 patients, showing periapical pathology trough trepanation and curettage (without resection of the apical part and use of a bone substitute material). The lesion was copious irrigated with saline and chlorhexidine solution and the residual bone defects were further treated with tetracycline paste. Radiographically the lesion disappeared and the implants were normally loaded after 3 months. Other authors also used irrigation agents , such as saline solution (Ayangco et al., 2001; Quirynen et al., 2005; Penarrocha-Diago et al., 2009), chlorhexidine solution (Chan et al., 2011; Ataullah et al., 2006; Penarrocha-Diago et al., 2009) or tertracycline pastes, for the decontamination of the implant surface. Whether any of these agents are efficient in decontaminating the implant surface remains questionable. Some authors report on the use of bone regeneration materials, with or without the use of membranes, to achieve a complete resolution of the bony defect. Quirynen and co-workers (2005) performed treatment on 10 cases of peri-apical implant pathology (out of a total of 426 solitary implants). The protocol for treatment (Figure 1) of retrograde lesions in the upper jaw included: elevation of a full-thickness flap, complete removal of all accessible granulation tissue with hand instruments (special attention to reach both apical and oral part of the implant surface), and curettage of the bony cavity walls. In half of the defects deproteinised bovine bone mineral was used as bone substitute (at the decision of the surgeon), while the other defects were left empty. In the lower jaw an explorative flap mostly revealed an absence of a perforation of the cortex so that a trepanation of the bone had to be performed. They concluded that that the removal of all granulation tissue is sufficient to arrest the progression of the bone destruction. Furthermore, implants from which only the coronal part is osseointegrated can successfully resist occlusal load, at least in the single tooth replacement condition for years. Bretz and co-workers (1997) surgically treated 1 case of peri-apical implant pathology elevation of a full-thickness flap, curettage of the apical lesion, irrigation with chlorhexidine gluconate, placement of demineralized freeze-dried bone, and coverage of the site with an absorbable collagen membrane. The problem was resolved and the prosthesis was still in function after 17 months of follow-up. Lefever and coworkers retrospectively analysed 59 implants with peri-apical lesions. Different treatment options had been chosen: explantation of the affected implant (17/59), curettage of the defect and application of a bone substitute in the defect (14/59), curettage

and administration of systemic antibiotics (10/59), simply curettage (11/59), no treatment (2/59), only systemic antibiotics without curettage (2/59), curettage with the usage of a barrier membrane without application of a bone substitute (2/59), and curettage and application of autogenous bone chips (1/59). Of the 42 non explanted implants, 9 implants were lost during follow-up, all during the first 4 years of loading. The cumulative survival rate for an implant showing a peri-apical lesion is 46.0%. When the explanted implants were excluded, the cumulative survival rate reached 73.2 % after 10 years. They conclude that a clear-cut selection of â&#x20AC;&#x153;best treatment strategyâ&#x20AC;? could not be found. Another group of authors suggested an apicoectomy on the affected implants. Balshi and co-workers (2007) used this approach on 39 cases. After flap elevation, they used a high-speed drill to create a bony window that was slightly larger than the lesion itself. The bony defect was thoroughly debrided and irrigated with a saline/tetracycline solution. In 72% of the cases a deproteinised bovine bone mineral was used to graft the bony defect. In 38% a resorbable collagen membrane was used to cover the surgical site and to fulfil the GBR principle. A total of 39 implants in 35 patients were treated with this intraoral apicoectomy procedure. Thirty-eight of the 39 implants (97.4%) remained stable and continued in function with no further complication up to 5 years. This could suggest that an apicoectomy procedure should be preferred above a GBR procedure. Other studies used the some surgical protocol with good results.

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CONCLUSION Different factors have been proposed to play a role in the development and emergence of a peri-apical implant lesion. Regarding, this it can be concluded that, to date, there is no consensus about the etiology and therefore peri-apical lesions around dental implants are considered tot have a multifactorial etiology. The diagnosis of an implant peri-apical lesion should be based on both clinical and radiological findings and in order to apply the best treatment strategy the evolution of the lesion should be taken into account. The treatment of these kind of lesion, however, is still empiric. Data, from primarily case reports, seem to indicate that the removal of all granulation tissue is a first step to arrest the progression of the bone destruction. The removal of the apical part of the implant seems a valuable treatment strategy.

Figures Figure 1 Clinical examples of peri-apical implant lesions encountered at the Department of Periodontology.

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Figure 2

Figure 3

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Concluding Discussion

General Discussion and Future Perspectives PART 1: Bone quantity (Chapters 1-4) More and more evidence is available that 3D images are the gold standard when it comes to planning of implant related surgeries (Dagassan-Berndt et al., 2016; Danesh-Sani et al., 2016; Dau et al., 2016; Greenstein et al., 2015), but also in other fields of periodontology (Banodkar et al., 2015; Bayat et al., 2016). In Chapter 1 it was concluded that a panoramic radiograph (PAN) underestimates the amount of residual bone height (RBH) present anterior to the maxillary sinus with about 33% (Temmerman et al., 2011). This results in a possible overestimation of the need for sinus floor elevation (SFE) procedures and the choice of the appropriate technique (Chapter 2). Furthermore, PAN was not able to detect important anatomical structures such as the Posterior Superior Alveolar Artery (PSAA). This artery is the main artery in the blood supply of the maxillary sinus (Traxler et al., 1999) and should be taken into account when performing SFE procedures using a lateral window approach, as damage to the artery can occur, causing haemorrhage and hampering surgery. Due to the fact this artery runs in the lateral wall of the maxillary sinus, arterial bleeding is difficult to manage and may lead to necrosis of the lateral maxillary sinus wall and the graft (Watanabe et al., 2014). In the radiological study described in Chapter 1, the prevalence, width and length of another (at that time possibly newly detected) bony canal at the palatal aspect of the upper canine was discussed. This canal, harbouring a neurovascular bundle, and called ‘canalis sinuosis’ was first described in 1999 (Shelley et al., 1999). This case report, however, didn’t threw much of attention. Since our publication in 2011, various groups have investigated the prevalence of the canalis sinuosis. De Oliveira-Santos and co-workers, in a study trying to assess the presence of additional foramina and canals in the anterior region of the palate, concluded that over 15% of the studied population (178 subjects) had additional foramina (between 1 mm and 1,9 mm wide). In most cases the canals of these foramina were an extension of the canalis sinuosis (de Oliveira-Santos et al., 2013). Von Arx and co-workers (von Arx et al., 2013) could find a slighty higher prevalence (27,8%) of bony canals (other than the nasopalatine canal). This prevalence is in accordance with the study in Chapter 1 (32,9% with a mean width of 1,2 mm). Furthermore, Von Arx & Lozanoff could verify, on cadaver heads, that the canalis sinuosis harbours the ASAN (von Arx and Lozanoff, 2015).

This information, which is only visible on 3D cross sectional imaging, is of importance for surgeons in order to avoid damage to this anatomical structure during interventions in the infraorbital region of the maxilla and SFE procedures. Further studies are mandatory to give more information on the possible risks and consequences when damaging these structures. Whenever a SFE procedure is mandatory, clinicians and surgeons can rely on the amount of scientific back-up these procedures have gathered in the last decades (Wallace and Froum, 2003; Del Fabbro et al., 2013; Pjetursson and Lang, 2014). Today, there is no doubt that these procedures have excellent clinical outcomes (equal to oral implants placed in pristine bone in the maxilla). Nevertheless, research is continuing and is focusing on other aspects of SFE procedures. New types of SFE procedures have been described (Chan et al., 2013; Troedhan et al., 2014) in an attempt to minimize the shortcomings of the established techniques such as lateral sinus floor elevation procedures (lSFE) and transcrestal sinus floor elevation (tSFE) procedures. The existing evidence for the new types of SFE techniques is scarce. Nevertheless, the study in Chapter 2 showed that the IntraLift (IL) SFE technique might be promising. We could conclude that the post-operative discomfort when using this technique is minimal (as compared with lSFE and tSFE). Furthermore this technique seems to be able to augment the sinus antrum with volumes comparable with lSFE techniques. However, our study also showed an enhanced decrease of graft volume after 6 weeks when applying this technique. Possible explanations for this, might be the enhanced detachment of the Schneiderian membrane and the not dense packing of the bone substitutes, although this is just speculative. Against our assumption we found in our study that the so called ‘minimally invasive’ tSFE technique’ causes the most post-operative discomfort and pain for the patient, especially during the first 2 days after surgery. Thereafter, no differences could be found between the techniques. To our best knowledge this is the first study to have explored the post-operative discomfort and pain of different SFE techniques. The results on the post-operative pain and discomfort are in contradiction with a publication by Francheschetti and co-workers (Franceschetti et al., 2016). These authors concluded that the tSFE is well tolerated by the patient and is associated with low post-operative discomfort and pain. Possible explanations for this conflict in results might be technique applied during tSFE. Francheschetti and co-workers (Franceschetti et al., 2016) used the technique as described by Trombelli and co-workers (Trombelli et al., 2010).

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This technique uses specially designed drills and osteotomes. Other groups (Esposito et al., 2014; Checchi et al., 2010), who used altered techniques for tSFE (without osteotomes) found less post-operative pain and discomfort. The study described in Chapter 2 uses regular drills, osteotomes and mallets. Taking the above into account is seems logical that the tapping of the osteotome with a mallet can be the most important factor when it comes to post-operative discomfort. Probably the impact of the mallet on the osteotome is bigger than was assumed in the past (Crespi et al., 2012; Akcay et al., 2016; Giannini et al., 2015). Clinicians using the tSFE, including osteotomes, should be aware of this. To overcome this problem, when choosing the tSFE technique, electric osteotomes might be the technique of choice (Crespi et al., 2012). New aspects for future research on SFE techniques include the materials used for filling the sinus antrum. A recent systematic review (SR)(Danesh-Sani et al., 2016) concluded that the use of autologous bone as graft material will result in the highest amount of new bone formation in comparison to other graft materials. However bone substitutes materials (allografts, alloplastic materials and xenografts) seem to be very good alternatives to autologous bone. Inherently these biomaterials avoid the disadvantages of autologous bone: morbidity rate, limited availability and high volumetric changes. SRs are not able to show any superiority for one particular biomaterial (Wu et al., 2016). In the study described in Chapter 2, we used a combination of deproteinised bovine bone matrix (DBBM) biomaterial (xenograft) together with L-PRF in a 60/40 percentage. Studies suggest that when this mixture is used, bone formation in graft sites can be significantly enhanced (Xuan et al., 2014). L-PRF membranes were also used to cover the lateral osteotomy. These L-PRF membranes represent an easy and successful method to cover the sinus membrane and lateral osteotomy window (Ali et al., 2015). The amount of bone available for implant placement is often a limiting factor, both in height and width. To overcome this problem the clinician can chose from a wide range of bone augmentation techniques. Within these techniques autologous bone remains the gold standard. Whenever a minor augmentation has to be performed, intra-oral donor sites (eg. mandibular symphysis region (Altiparmak et al., 2016), ramus mandibulae (Barbu et al., 2015) and palate (Gluckman et al., 2016; Moussa et al., 2016)) are widely used to provide bone blocks. Autologous bone chips can also be harvested during the drilling of

the osteotomy site or from shraping the bone during surgery. Whenever major augmentations need to be performed, the clinician needs to utilize extra-oral donor sites (eg. ileac crest and calvarium). DBBM shows good capacities to integrate in newly formed bone and resorbs very slowly. By no means this discussion has the intention to give an overview of all existing bone augmentation techniques. The studies described in Chapter 3-4 are focusing on altering the dimensions of the oral implants. In situations were a impaired bone height is available, short implants seem to be a successful alternative to long implants in combination with complex augmentation procedures. Short implants represent a less invasive treatment option, accompanied with lower costs, shorter treatment time and decreased morbidity (Calvo-Guirado et al., 2015; Esposito et al., 2015; Felice et al., 2015; ten Bruggenkate et al., 1998). In cases of vertical ridge defects, the use of short implants will increase the height of the restoration (increased C/I ratio). As shown the study in Chapter 3 this does not seem to interfere with implant survival rates. These results are in line with other studies (Garaicoa-PazmiĂąo et al., 2014; Mangano et al., 2016). Nevertheless, there are still clinical indications were, from an esthetical point of view, vertical bone augmentations are the option of choice (Urban et al., 2016; Urban et al., 2014). In this chapter, short locking-taper plateau implants have been used. This type of implant, and definitely the Integrated Abutment Crown is very specific. This crown consists out of a titanium abutment with composite on top. The implant is placed, accordig to the manufacturers guidelines, 2 mm apical to the bone crest. In this way, when uncovering the implant, specially designed reamers are used to create the bony architecture for the definitive titanium abutment. Further research on the clinical behaviour of these implants, when placed equicrestal seems to be of critical importance, as the amount of bone necessary to place a 6 mm implant increases with 1-2 mm in order to place the implant submerged. In the present study 6 implants were lost before functional loading due to non-integration (or only partial integration). A potential explanation for these failures could be the incorrect placement of the implant, being equicrestal (according to the guidelines of the manufacturer). One has to be aware of the fact that, where the internal connection of a screw-type implant is closed with a cover screw (when using a submerged protocol), the inside of a locking taper, plateau shaped implant is sealed using a cover plug. The composition and the biocompatibility of this plug is unknown. However, whenever this type of implant is placed equicrestal and this cover plug penetrates during the healing phase, this results in the loss of marginal bone. This phenomenon has already been described by

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Van Assche and co-workers (Van Assche et al., 2008). The loss of this marginal bone is of utmost importance due to the fact that the implant itself is short (5-6 mm). In situations were an impaired bone width is available small diameter implants seem to be an alternative. As described in the study in Chapter 4; 3,5 mm diameter oral implants were used in patients with a residual bone width of <4,5 mm. This means that the implant is surrounded by <1 mm of bone around the neck of the implant. Different surgical techniques to prepare the osteotomy site were used (eg. condensation and selective cutting piezosurgical devices). Over a period of 3 years follow-up these implant seem to experience very small MBL alterations, as measured on 2D peri-apical radiographs, mesially and distally from the implant. The data presented in Chapter 4 should be however addressed carefully, as 90% of the implants were placed in the upper maxilla. The inherent bony properties and characteristics of the maxilla, make a selective preparation and osteocondensation more easy to perform, when compared to the mandible. This 2D radiological follow-up might be the main shortcoming of this study, as these radiographs do not give any information on the marginal bone level (MBL) alterations in bucco-oral dimension. In this context a recent study by Merheb and co-workers (Merheb et al., 2016) might be of critical importance. In this study the buccal bone thickness was measured during implant surgery at several distances from the implant shoulder using a custommade device, which allowed buccal bone thickness measurements without the elevation of a muco-periosteal flap. The measurements were repeated after 12 months. The authors concluded that oral implants with an initial bone thickness <1 mm did not lose significantly more bone than the oral implants with an initial buccal bone thickness of >1 mm. Although this is, to our knowledge, the first study to measure the evolution of the buccal bone, this might explain the good clinical outcome of implants placed in thin alveolar ridges. When implants are further reduced in diameter the risk for fractures increases with it. Improved titanium/zirconium composition of implants might be the solution the overcome this problem due to an increased tensile strength (Altuna et al., 2016). So called â&#x20AC;&#x2DC;mini-implantsâ&#x20AC;&#x2122; with a diameter of <3,0 mm might be an opportunity for further research in an attempt to further decrease the need for bone augmentation procedures. First results on this matter seem to be very promising (Aunmeungtong et al., 2016; Zygogiannis et al., 2016).

PART 2: Bone quality (Chapter 5-7) The study described in Chapter 5 focuses on the treatment of osteoporotic women with oral implants via a large-scale multi-centric trial. A recent SR concluded that osteoporotic patients present with higher rates of implant failure. There seems to be a lower evidence to strengthen the hypothesis that osteoporosis may have detrimental effect on bone healing, due to the fact that there are no RCTs available (Giro et al., 2015). To our best knowledge, this is the first clinical trial of its kind. The 1-year results showed no significant difference in osseointegration rates and MBL alterations between healthy or osteoporotic subjects. The 5-year results (to be published in 2017) will be of critical importance to make a statement on the long-term prognosis of oral implant treatment in osteoporotic patients. The patient population of the study described in Chapter 5 was also used to investigate (Merheb et al., 2015) the possible relationship between skeletal (as measured by dual X-ray absorptiometry (DXA)) and maxillary bone density (as measured by Hounsfield Units (HU) on multislice CT (MSCT)). Based on the measurements of bone density of the maxilla, it was possible to predict if the patient was osteoporotic or not with a specificity of 83% and a sensitivity of 65%. So there seems to be a direct correlation between the density of the skeleton and the density of some sites of the maxilla. This might be a useful tool in the screening of osteoporosis. Furthermore, some clinical recommendations can be given when treating osteoporotic patients with oral implants (such as longer healing times and safe protocols) due to the fact that implant stability seems to be influenced by both local and skeletal bone densities (Merheb et al., 2016). The search for ridge preservation techniques, to decrease the amount of bone resorption following tooth extraction, is still ongoing. It is a popular item for enhanced research. Most of these surgical techniques use one or more biomaterials to fill or cover the extraction socket (eg. AraĂşjo et al., 2015; Atieh et al., 2015; Barone et al., 2008; Barone et al., 2016; Iasella et al., 2003). A SR by Vignoletti and co-workers concluded that although the potential benefit of ridge preservation techniques has been demonstrated (resulting in significantly less vertical and horizontal contraction of the alveolar ridge) no clear guidelines with regards to the type of biomaterial and the surgical technique can be provided (Vignoletti et al., 2012). In the study described in Chapter 6, L-PRF was used as a socket filling material for ridge preservation. In order to make comparisons

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between other studies, the same type of measurements as recorded by Jung and co-workers (Jung et al., 2013), were performed. This gave us the chance to compare in an indirect way, the outcome of L-PRF with DBBM+collagen and a soft tissue punch. Results were approximately identical. The use of L-PRF as a ridge preservation technique therefore can be considered very beneficial for the patient, as is reduces dramatically the costs when compared to biomaterials. Furthermore, the use of L-PRF seemed to influence the bone quality after 3 months. An interesting topic for further research is the combined use of L-PRF with biomaterials. A shortcoming of the data described in Chapter 6 is the current lack of evidence of the long term dimensional stability of the bony architecture when using this technique. In Chapter 2 & 6 the post-operative discomfort of the patients who underwent the respective treatments was assessed. This post-operative discomfort and pain is generally assessed using questionnaires. These questionnaires are language sensitive and it is rather difficult to find questionnaires in Dutch, let alone theyâ&#x20AC;&#x2122;ve been assessed for their validity and their reliability. Nevertheless, in these 2 chapters the questionnaires used proved to be rather successful to show a difference between post-operative discomfort and pain between the treatment groups. In the studies described in chapter 2 & 6 a split-mouth designs was used. This split mouth design is popular in oral health research (Antczak-Bouckoms et al., 1990), not in the least because its reduces lots of inter-individual variability (Lesaffre et al., 2009) from the estimates of the treatment effects with a potential increase in statistical power (each subject being its own control). This design is especially suited to determine a patients preference towards a surgical intervention. Split-mouth trials are frequently included in systematic reviews, in an attempt to use all the available evidence. The main characteristic of a split-mouth trial is that comparisons are made on a within-patient basis and therefore not a between-patient basis. A potential disadvantage is that treatments performed in one side of the mouth can affect the treatment responses in other parts of the mouth. This disadvantage makes it difficult to estimate treatment affects, unless specific assumtions about carry-across effect can be made (Hujoelan DeRouen, 1992). However, these assumptions cannot be tested and valid estimation procedures ar hypothesis tests about treatment effects require an a priori knowledge that carry-across effects do not exist. Further-

more, the presence of these carry-across effects cannot be detected using statistical tests and therefore a split-mouth estimate of a treatment effect can be confounded by a carry-across effect. Therefore the results, presented in Chapter 2&6 need to be adressed with care. One has to be aware that the statistical analysis of split-mouth RCTs differs from that of parallelarm RCTs because of the paired nature of data (Lesaffre et al., 2009; Hujoel, 1998). Lesaffre and co-workers (Lesaffre et al., 2007) advice to metaanalyze split-mouth and parallel-arm trials in separate subgroups analyses. Nevertheless, a recent SR could not only few SR and meta-analyses have taken this advice into consideration (SmaĂŻl-Faugeron et al., 2014). Future authors, using the above mentioned chapters and the studies described in it, should be aware of this.

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â&#x20AC;˘ Zygogiannis K, Wismeijer D, Parsa A (2016). A Pilot Study on Mandibular Overdentures Retained By Mini Dental Implants: Marginal Bone Level Changes and Patient-Based Ratings of Clinical Outcome.

International Journal of Oral and Maxillofacial Implants 31: 1171â&#x20AC;&#x201C;1178.

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Summary

Summary Patients losing one, several or even all teeth are lost, are often faced with some problems. Firstly, tooth loss is a problem when talking about the masticatory comfort. Patients with a fully removable prosthesis therefore often suffer to chew properly. Besides this chewing comfort, we should not neglect the aesthetics and factors of general â&#x20AC;&#x2DC;well-being, that are associated with tooth loss. It goes without saying that the discovery of the principle of the osseointegration, wherein titanium merges with the bone and even promotes bone formation, was a great leap forward in the treatment of patients who have lost teeth. In this way, artificial titanium roots (screws) could be placed in the jaw bone. Initially, the placement of dental implants was performed according to the standard protocol and followed a two-stage procedure. First, the titanium implant was placed in the jaw bone, beneath the periosteum. Gums and soft tissues were thereafter hermetically closed. In this way, the titanium implants could start their osseointegration period, which took serveral months. During a second surgery, titanium pillars (abutments) were connected to the implants. These abutments were left transmucosal and could be used to support a new tooth or prosthesis. Medical research is always continuing. Pretty soon, the search for alternatives to the standard protocol started. A good example is the surface of the titanium implant. The surface of the implant was subject to numerous changes that the dentist today enables, depending on the patient, to shorten treatment time. Indeed, new implant surfaces can accelerate the osseointegration. Titanium implants, today, are very often loaded within one week to support new teeth. The aging of the population makes the dentist more often come into contact with patients suffering from one or more systemic medical conditions. A number of these conditions can, to some extent, interfere with the bone (and hence also the jaw bone) of the patient. In addition, there is also more and more evidence that some medications may exert an influence on the bone. An implant treatment should therefore always start with a good comprehensive medical history.

Since the principle of osseointegration is based on the fact that there is an intimate contact between the bone and the implant surface, it is not inconceivable that the bone quality and the bone quantity of a patient are important factors in implant related treatments. This thesis has focused on the evaluation of a number of treatment strategies for patients with impaired bone quality and / or a impaired bone quantity. The use of radiology, for proper diagnosis is not indispensable within the implant treatment. The dentist has the choice between 2D and 3D radiological entities. The 2D images have several advantages: minimal radiation exposure for the patient, fast and cheap. Their main drawback is the fact that they will project a 3D structure as a 2D object. Due to this, precious and important diagnostic information gets lost, putting the dentist on the wrong track. Three-dimensional radiological images have the disadvantage that they were associated with higher radiation exposure. Also, the patient had to go to the hospital and they provoked high costs for the community. The entry of the CBCT, which made the use of 3D radiological recordings possible outside the walls of the hospital and a lower radiation dose (compared to the conventional CT images) was a huge leap forward in the radiological diagnosis of implant treatments. Chapter 1 shows that 3D CBCT imaging, is and remains the gold standard, in the diagnosis and planning implant related surgical procedures and visualisation of bone quantity and anatomical landmarks. Many patients looking for tooth replacement have lost their teeth for a longer period of time. Unfortunately, the removal (extraction) of teeth is associated with loss of bone volume. In this way, after extraction, the bone will not only narrow down but also become less high. Since a dental implant has a certain size and diameter, the amount of bone available at the time of surgery sometimes is too little for standard implant placement. Again, science has been searching for possible solutions. One option is to rebuilt the lost bone. To allow this, different materials have been proposed ranging from the patientâ&#x20AC;&#x2122;s own bone (which is removed in a different place and transplanted) to biomaterials. Whatever technique is chosen to rebuild lost bone; these all have a number of inherent disadvantages. First, the burden on the patient is greater. Autologous bone grafting not only causes a second operation but every bone augmentation procedure makes the treatment more complex. The use of biomaterials

269

has limited the use of autologous bone, but then again these biomaterials have the disadvantage being associated with a greater cost for the patient. In chapter 6 attempts were made to find an answer whether the use â&#x20AC;&#x2DC;platelet concentratesâ&#x20AC;?, obtained after centrifugation of blood from the patient, could be a possible strategy to reduce the loss of bone height and bone width after tooth extraction It was also examined whether these blood concentrates may limit the postoperative discomfort for the patient. In conclusion, it could be stated that they are very suitable for these purposes. Chapters 3 and 4 are based on the fact that also the dimensions of dental implants can be altered. Chapter 3 uses of short implants. The use of short implants may have as an advantage that a deficiency in bone height does not necessarily lead to vertical bone augmentation procedures. The results are very encouraging. Short implants are thus becoming an important alternative treatment strategy. Lots of further research is conducted on this topic. In chapter 4, implants with a reduced diameter were used. They were placed in patients who showed an impaired bone width. Implants were placed by by using altered surgical techniques. It was shown that these implants have a very good chance of survival after 3 years. These patients are now continuously followed for long periods of time. Future papers with long-term results will have major impact on treatment strategies of these types of patients. Despite the topics described above, a bone augmentation procedure cannot always be avoided. A typical example of is the posterior zone of the upper jaw. Here, after the removal of teeth, the bone is not only reduced in height and width. Due to the presence of the maxillary sinus the bone will further be reduced in height. In these types of patients, even short implants may not be an alternative anymore. A bone augmentation within the sinus be called a sinus augmentation or sinuslift. Such procedures have been around for decades and have a large scientific backup. In chapter 2 different sinus augmentation procedures were used in patients to determine their influence on post- operative discomfort and the soft tissues (mucosal lining â&#x20AC;&#x201C; Schneiderian membrane) in the sinus. The amount of augmented bone was described with respect to the type of surgical technique. In contrast to our expectations, we could conclude that the complexity of the surgery cannot always define the amount of post-operative discomfort for the patients. Several factors have to be taken into account.

A good surgical technique for tooth extraction using â&#x20AC;&#x153;platelet concentratesâ&#x20AC;? may not only be beneficial in maintaining more bone. It can also interact with the bone quality (Chapter 6). Patients with osteoporosis have, by definition, an impaired bone quality. Osteoporosis is a systemic disease that affects more than 5 million people in Europe, Japan and the United States. Approximately 30% of all postmenopausal women will develop osteoporosis. This condition is characterized by a decreased bone mineral density. This provokes a reduction in bone strength and an increased risk of fractures. Today, the international scientific does not agree on the fact whether osteoporosis might also have an impact on the success of dental implants. This was largely due to the lack of well-executed and controlled studies. In chapter 5, a large study was initiated with several participating centres throughout Europe. To our best knowledge this is the first controlled clinical study in which both healthy and osteoporotic post-menopausal women were treated within a clinical trial. The results after 1 years show that there is no difference in osseointegration capacity between the two groups. Patients are now being followed for longer periods of time. Just a few patients should be scheduled for the 5-year follow-up check-up. These results will be an important milestone on the topic of dental implants in osteoporotic patients. Bone quality appears responsible for infections around the top (apex) of a dental implant. In Chapter 7, the literature was searched for articles that could provide information on the prevention and possible causes of infections around the top of dental implants. Furthermore, clinical treatment recommendations were formulated when these problems do occur. The results of the studies, which are described in this thesis, will significantly affect (and possibly already have affected) the way patients with an impaired bone quality and impaired bone quality are treated.

271

Samenvatting

Samenvatting Patiënten die één, meerdere of zelfs alle tanden verloren hebben, hebben niet zelden te kampen met een aantal problemen. Vooreerst komt het verlies van tanden het kauwcomfort niet ten goede. Patienten met een volledige uitneembare prothese hebben daardoor vaak last om goed te kauwen. Naast dit kauwcomfort mogen we ook het belang van de factoren esthetiek en algemeen ‘bien-être’, die gepaard gaan met het verlies van tanden, niet uit het oog verliezen. Het spreekt voor zich dat de toevallige ontdekking van het principe van de osseointegratie, waarbij titanium fuseert met het bot en zelfs botvorming promoot, een grote stap voorwaarts betekende in de behandeling van patiënten met verloren gegane tanden. Op deze manier kunnen artificiële titanium wortels (schroeven) aangebracht worden in het kaaksbeen. Dit gebeurde volgens het standaardprotocol, door een 2-fasige procedure te volgen. Vooreerst werd het titanium implantaat in het kaaksbeen geplaatst, onder het beenvlies. Het tandvlees en de zachte weefsels werden nadien hermetisch gesloten. Op deze manier konden de titanium implantaten beginnen aan hun maandenlange osseointegratie periode. Tijdens een tweede ingreep werden titanium pijlers op de implantaten aangebracht. Aangezien deze door de zachte weefsels heen steken, kunnen deze gebruikt worden om een nieuwe tand of prothese te ondersteunen. De wetenschap staat niet stil en dat betekent dan ook dat vrij snel naar alternatieven voor het standaardprotocol werd gezocht. Een mooi voorbeeld hiervan is de oppervlakte van het titanium implantaat. De oppervlakte van het implantaat was onderhevig aan talrijke veranderingen die de arts vandaag in staat stelt om, afhankelijk van patiënt tot patiënt, de behandeltijd te verkorten. Inderdaad, nieuwe implantaatoppervlaktes kunnen het osseointegratieproces versnellen. Vandaag de dag, worden titanium implantaten, dan ook niet zelden binnen de week belast als ondersteuning van nieuwe tanden. De vergrijzing van de populatie doet de (tand)arts steeds vaker in contact komen met patiënten die lijden aan één of meerdere systemische medische aandoeningen. Een aantal van deze aandoening kan interfereren met het bot (en dus ook het kaaksbeen) van de patiënt. Tevens is er ook meer en meer bewijs dat dergelijke geneesmiddelen een invloed kunnen uitoefenen op het bot. Een implantaatbe-

handeling dient dus altijd te starten met een goede en uitgebreide medische anamnese. Aangezien het principe van de osseointegratie gebaseerd is op het feit dat er een intiem contact bestaat tussen het bot en het implantaatoppervlak, is het niet ondenkbaar dat de botkwaliteit en de botkwantiteit belangrijke factoren zijn bij een implantaatbehandeling. Deze thesis heeft zich vooral gericht naar de evaluatie van een aantal behandelingsstrategieën bij patiënten met een mindere goede botkwaliteit en/of een minder grote botkwantiteit. Voor een goede diagnostiek is het gebruik van radiologie is niet meer weg te denken binnen de behandeling met implantaten. De arts kan op dit moment kiezen tussen 2D en 3D vormen van radiologische opnames. De 2D opnames hebben verschillende voordelen: minimale stralingsbelasting voor de patient, snel en goedkoop. Hun grootste nadeel is het feit dat zij een 3D structuur zullen projecteren als een 2D object. Logischerwijs gaat hierdoor een deel van de kostbare en belangrijke diagnostische informatie verloren, waardoor de arts op het verkeerde been kan worden gezet. Driedimensionale radiologische opnames hadden het nadeel dat zij gepaard gingen met hogere stralingsbelasting. Tevens moest de patiënt zich hiervoor ver-plaatsen naar het ziekenhuis en gingen zij hand in hand met een hoge kostprijs. De komst van de CBCT, welke het gebruik van 3D radiologische opnames mogelijk maakte buiten de muren van het ziekenhuis en een lagere stralingsbelasting hanteerde (in vergelijking met de klassieke CT opnames) was een enorme sprong voorwaarts in de radiologische diagnostiek bij implantaatbehandelingen. Hoofdstuk 1 toont aan dat de CBCT, de gouden standaard is en blijft, bij de diagnostiek en planning in functie van botkwantiteit. Niet zelden hebben patiënten reeds een geruime tijd tanden verloren wanneer zij op zoek gaan naar oplossingen voor dit probleem. Spijtiggenoeg, gaat door tandverlies (extractie van tanden) het bot niet alleen smaller, maar ook minder hoog worden. Aangezien een tandimplantaat een bepaalde grootte en diameter heeft, komt het meermaals voor dat patiënten een te kleine hoeveelheid aan bot hebben om op een standaard manier implantaten te plaatsen. Ook hier is de wetenschap op zoek gegaan naar mogelijke oplossingen. Een mogelijkheid is om het verlorengegane bot te herstellen en opnieuw op te bouwen. Hiervoor kunnen verschillende materialen worden gebruikt gaande van bot van de patiënt zelf (welke op een andere plaats wordt weggenomen en getransplanteerd) tot biomaterialen. Welke techniek ook gekozen wordt om verloren gegaan bot op te bouwen, zij hebben een aantal inherente nadelen.

275

Vooreerst is de last voor de patiënt groter. Lichaamseigen bot transplanteren veroorzaakt niet alleen een tweede operatie. Elke botopbouwprocedure zorgt ervoor dat de ingreep complexer wordt. Het gebruik van biomaterialen heeft het gebruik van lichaams-eigen bot beperkt, maar deze biomaterialen hebben dan weer als nadeel dat ze gepaard gaan met een grotere kost voor de patiënt. In hoofdstuk 6 werd getracht een antwoord te vinden op de vraag of het gebruik van ‘plaatjesconcentraten’, bekomen na centrifugatie van bloed van de patient, een mogelijke strategie zou kunnen zijn om het verlies van bothoogte en botbreedte te beperken wanneer een tandextractie dient te gebeuren. Tevens werd nagegaan of deze bloedconcentraten de nalast voor de patiënt kunnen beperken. Als conclusie kon worden gesteld dat zij zeer geschikt zijn voor deze doeleinden. In hoofdstukken 3 en 4 werd uitgegaan van het feit dat ook de dimensies van de tandimplantaten kunnen veranderd worden. In hoofdstuk 3 werd gebruikt maakt van korte implantaten. Het gebruik van dergelijke korte implantaten zou als voordeel kunnen hebben dat een tekort aan bothoogte niet noodzakelijk dient te leiden tot botopbouw procedures. De resultaten zijn zeer bemoedigend. Korte implantaten zijn vandaag de dag dan ook een belangrijke alternatieve behandelingsstrategie geworden, waar heel wat verder onderzoek naar wordt uitgevoerd. In hoofdstuk 4 werd gebruikt van implantaten met een beperkte diameter. Zij werden geplaatst bij patiënten die een tekort vertoonden aan botbreedte. Door gebruik van de maken een alternatieve chirurgische procedure kon worden aangetoond dat deze implantaten een zeer goede 3-jaars overlevingskans hebben. Deze patiënten worden verder opgevolgd om uiteindelijk te kunnen beschikken over langetermijnsresultaten (5-10jaar). Ondanks de mogelijkheden hierboven beschreven, kan in sommige gevallen een botopbouwprocedure niet uit de weg gegaan worden. Een typisch voorbeeld daarvan is de achterste zone van de bovenkaak. Hier zal na het verwijderen van tanden het bot niet alleen in hoogte en breedte afnemen, maar zal, door de aanwezigheid van de sinus, het bot nog verder afnemen. Niet zelden zijn korte implantaten dan ook geen alteratief meer. Een opbouw van bot binnen de sinus worden een sinus augmentatie genoemd. Dergelijke procedures bestaan al tientallen jaren en ze zijn zeer goed wetenschappelijk onderbouwd. In hoofdstuk 2 werden verschillende sinus augmentatie procedures gebruikt in patienten om na te gaan wat hun invloed is om de post-operatieve nalast en op de zachte weefsels in de sinus.

De hoeveelheid aan opgebouwd bot werd per sinus augmentatie beschreven. Tegen de verwachtingen in werd besloten dat de omvang de chirurgie niet altijd de hoeveelheid aan post-operatieve nalast voor de patiënt kan definiëren. Een goede chirurgische manier van tandextractie met behulp van ‘bloedplaatjesconcentraten’ zorgt niet alleen voor een beter botbehoud, het kan ook inwerken op de botkwaliteit (hoofdstuk 6). Patiënten met osteoporose hebben, per definitie, een minder goede botkwaliteit. Osteoporose is een systemische aandoening die meer dan 5 miljoen mensen in Europa, Japan en de Verenigde Staten treft. Ongeveer 30% van de post-menopauzale vrouwen ontwikkelt osteoporose. Deze aandoening wordt gekenmerkt door een afgenomen densiteit in botmineraliteit. Dit zorgt voor een reductie in botsterkte en een toegenomen risico op breuken. Tot op de dag van vandaag is de wetenschap het niet eens of osteoporose ook een invloed heeft op het slagen van tandimplantaten. Dit kwam grotendeels door het gebrek aan goed uitgevoerde en gecontroleerde studies. In hoofdstuk 5 werd een grote studie opgezet over verschillende centra in Europa. Naar onze kennis is dit de eerste gecontroleerde klinische studie die zowel gezonde als osteoporotische post-menopauzale vrouwen behandelt binnen studieverband. De resultaten na 1 jaar tonen aan dat er geen verschil is in osseointegratie capaciteit tussen beide groepen. De patiënten worden momenteel verder opgevolgd. Elnkele patiënten dienen nog terug gezien te worden voor de 5 jaars opvolging. Deze resultaten zullen een belangrijke mijlpaal zijn binnen het onderzoek van tandimplantaten bij osteoporotische patiënten. Botkwaliteit blijkt in belangrijke mate verantwoordelijk voor infecties rondom de top (apex) van een tandimplantaat. In hoofdstuk 7 werd verder ingegaan op voorkomen en de mogelijke oorzaken van infecties rondom de top van tandimplantaten. Tevens werden adviezen geformuleerd omtrent mogelijke behandelingen wanneer deze problemen zich voordoen. De resultaten van de onderzoeken, welke in deze thesis beschreven worden, zullen in belangrijke mate invloed hebben (en reeds gehad hebben) op de manier waarop patiënten met een mindere botkwaliteit & botkwaliteit worden behandeld.

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“IT ALWAYS SEEMS IMPOSSIBLE UNTILL IT’S DONE” Nelson Mandela (1918-2013)

Curriculum Vitae

Curriculum Vitae Andy Temmerman Andy Waalsland 15 9080 Lochristi Belgium Born 1982, Ghent, Belgium andy_temmerman@hotmail.com andy.temmerman@uzleuven.be www.implantopar.be www.paro.be sTudies, academic degrees 2000

Secondary School option Latin-Sciences, Sint-Lievenscollege, Gent Graduated

2007

University of Ghent, Faculty of Medicine Graduated (cum laude) as dentist (DDS)

2010

Catholic University of Leuven, Department of Oral Health Sciences, Section of Periodontology Graduated (cum laude) as EFP certified periodontologist

2010 -2016

Catholic University of Leuven, Department of Oral Health Sciences, Section of Periodontology

•

PhD-training (part-time) Promotor Prof. Dr. M. Quirynen, co-promotors Prof. Dr. R. Jacobs & Prof. Dr. J. Duyck entitled “Osseointegration and impaired bone quality and quantity: evaluation of treatment strategies”.

•

clinical consultant

professional career acknoWledgemenTs 2010

Specialist in Periodontology Certification by the ‘European Federation for Periodontology (EFP)

2012

Certification for the use of CBCT in dentomaxillofacial diagnostics

2013

Certification for the use of nitrous oxide in dental pratice

2014

Best Research Award, DentsplyImplants™, during the EAO in Rome, Italy

2015

European (surgically related) Research and best oral presentation Award of the European Association for Osseointegration, during the EAO in Stockholm, Sweden

privaTe pracTice 2008-present

ParoPlus (Practice for Periodontology and Implant Dentistry) in Aalst & Brussels (associated with Stefan Matthijs, Luc Van den Bossche & Natalie Schneps)

publicaTion & lecTure lisT papers in peer-revieWed journals • L-PRF membranes for increasing the width of keratinized mucosa around implants: a split-mouth, randomized, controlled pilot clinical trial.

Cleeren Gert-Jan, Temmerman Andy, Teughels Wim & Quirynen Marc.

Journal of Clinical Periodontology (2017) submitted.

• The impact of different sinus floor augmentation procedures on the amount of augmented bone volume & Schneiderian membrane: a pilot clinical trial.

Temmerman Andy, Vandessel Jeroen, Cortellini Simone, Jacobs Reinhilde, Wim Teughels Wim & Quirynen Marc.

Journal of Clinical Periodontology (2016) accepted.

• Regenerative potential of Leucocyte- and Platelet Rich Fibrin (L-PRF). Part A:

intrabony defects, furcation defects, and periodontal plastic surgery. A systematic review and meta-analysis.

Castro Ana, Meschi Nastaran, Temmerman Andy , Pinto Nelson , Lambrechts Paul, Teughels Wim, Quirynen Marc.

Journal of Clinical Periodontology (2017) 44: 225-234.

• Regenerative potential of Leucocyte- and Platelet Rich Fibrin (L-PRF). Part B: sinus floor elevation, alveolar ridge preservation, and implant therapy. A systematic review and meta-analysis.

Castro Ana, Meschi Nastaran, Temmerman Andy , Pinto Nelson , Lambrechts Paul, Teughels Wim, Quirynen Marc.

Journal of Clinical Periodontology (2017) 44: 67-82.

• The use of leucocyte and platelet-rich fibrin in socket management and ridge preservation: a split-mouth, randomized, controlled clinical trial.

Temmerman Andy, Vandessel Jeroen, Castro Ana, Jacobs Reinhilde, Teughels Wim, Pinto Nelson, Quirynen Marc.

Journal of Clinical Periodontology (2016) 43: 990-999.

• Influence of Skeletal and Local Bone Density on Dental Implant Stability in Patients with Osteoporosis.

Merheb Joe, Temmerman Andy, Rasmusson Lars, Kübler Alexander, Thor Andreas & Quirynen Marc.

Clinical Implant Dentistry Related Research (2016) 18: 253-60.

281

• An open, prospective, non-randomized, controlled, multicentre study to

evaluate the clinical outcome of implant treatment in women over 60 years of age with osteoporosis/osteopenia: 1-year results.

Temmerman Andy, Rasmusson Lars, Kubler, Thor Andreas, Quirynen Marc.

Clinical Oral Implants Research, (2017) 28:95-102.

• Oral implant placement and restoration by undergraduate students: clinical outcome and student perspectives.

Temmerman Andy, Dhondt Rutger, Meeus Marc, Coucke Wim, Wierinck Els, Naert Ignace, Quirynen Marc.

European Journal of Dental Education (2015) 20: 73-83,

• The outcome of oral implants placed in bone with limited bucco-oral dimensions: a 3-year follow-up study.

Temmerman Andy, Keestra Hans, Coucke Wim, Teughels Wim, Quirynen Marc.

Journal of Clinical Periodontology (2015) 42: 311-8.

• Etiology and treatment of periapical lesions around dental implants. Andy Temmerman, David Lefever, Wim Teughels, Thomas Balshi, Stefan Balshi & Marc Quirynen

Periodontology 2000 (2014) 66: 247-54.

• The accuracy of guided surgery via mucosa-supported stereolithographic surgical templates in the hands of surgeons with little experience.

Van de Wiele Gerlinde, Teughels Wim, Vercruyssen Marjolein, Coucke Wim, Temmerman Andy & Quirynen M.

Clinical Oral Implants Research (2015) 26: 1489-1494.

• Relationship between spongy bone density in the maxilla and skelletal bone density.

Merheb Joe, Temmerman Andy, Coucke Wim, Rasmussen L, Kubler A, Thor Andreas, Quirynen Marc.

Clinical Implant Dentistry and Related Research (2015) 17: 1180-1187.

• Etiology and treatment of periapical lesions around dental implants. Temmerman Andy , Lefever David, Teughels Wim, Balshi Thomas, Balshi Stefan & Quirynen Marc.

Periodontology 2000 (2014) 66: 247-54. Review.

• Aetiology, microbiology and therapy of periapical lesions around oral implants: a retrospective analysis.

Lefever David, Van Assche Nele, Temmerman Andy, Teughels Wim & Quirynen Marc.

Journal of Clinical Periodontology (2013) 40: 296-302.

• Are panoramic images reliable in planning sinus augmentation procedures? Temmerman Andy, Hertelé Stijn, Teughels Wim, Dekeyser Christel, Jacobs Reinhilde & Quirynen Marc.

Clinical Oral Implants Research (2011) 22: 189-94.

• Dentifrices: an evaluation based on the current literature. Temmerman Andy, Dekeyser Christel, Declerck Dominique, Quirynen Marc.

Revue Belge Medicine Dentaire (2010) 65: 60-86. Review.

• Electric toothbrushes. Temmerman Andy, Marcelis Koen, Dekeyser Christel, Declerck Dominique, Quirynen Marc.

Revue Belge Medicine Dentaire (2010) 65: 52-9. Review.

• Does a good oral hygiene guarantee the maintenance of a healthy periodontium?

Temmerman Andy, Dekeyser Christel, Quirynen Marc.

Revue Belge Medince Dentaire (2010) 65: 4-11. Review.

chapTers in TexTbooks • Chapter 64: Leucocyte & Platelet Rich Fibrin: properties and clinical applications.

Carranza’s Clinical Periodontology (13th Edition), 2017.

Elsevier Saunders

• Weefselregeneratie door middel van L-PRF: ‘van mythe tot realiteit’. Andy Temmerman, Iris De Coster, Ana Castro Sarda, Nelson Pinto, Wim Teughels en Marc Quirynen.

Het tandheelkundig jaar 2017. Bohn Stafleu van Loghum ISBN 978-90-368-1029-6

• Rationale van initiële parodontale therapie. Andy Temmerman, Christel Dekeyser & Marc Quirynen.

Handboek Parodontologie, Hoofdstuk F1. Bohn Stafleu van Loghum

• Rationale van initiële parodontale therapie. Andy Temmerman, Christel Dekeyser & Marc Quirynen.

Studieboek Parodontologie (2009), Bohn Stafleu van Loghum ISBN 978 90 313 6886 0

283

arTicles in non-peer-revieWed journals • L-PRF: de toekomst voor weefselregeneratie in de tandheelkunde?! Andy Temmerman, Wim Teughels, Christel Dekeyser, Nelson Pinto, Marc Quirynen.

VVT magazine - november 2013 p. 10, 11, 13 Tandartsenkrant december 2013

posTer presenTaTions aT naTional / inTernaTional congresses • Are panoramic radiographs reliable in planning sinus augmentation procedures? Temmerman Andy, Hertelé Stijn, Teughels Wim, Dekeyser Christel, Jacobs Reinhilde & Quirynen Marc.

Europerio 6, Stockholm, 2009.

• Implant placement and limited vestibulo-oral dimensions: a radiographical study. Johan AJ Keestra, Joe Merheb, Marc Quirynen & Andy Temmerman.

Europerio 7, Wenen, 2012

• Etiology, microbiology and treatment options of periapical lesions around oral implants. Lefever David, Van Assche Nele, Temmerman Andy, Teughels Wim & Quirynen Marc.

Osteology, Monaco, 2013.  VVT-congres, Oostende, 2013.

• Oral implant placement and restoration by undergraduate students: clinical outcomes and student perceptions.

Temmerman Andy, Marc Meeus, Rutger Dhondt, Els Wierinck, Ignace Naert, Wim Teughels & Marc Quirynen

EAO-Congres, Rome 2014.

lecTures / shorT oral communicaTions • Sinus Augmentation procedures: “less is more” Najaarscongres Nederlandse Vereniging voor Parodontologie

Novembre 25, Utrecht, The Netherlands

• The use of L-PRF in ridge augmentation, esthetic plastic periodontal surgery and periodontal infra-bony defects.

1st European Meeting on Enhanced Natural Healing in Dentistry (ENHD)

Octobre 15, Leuven, Belgium

• Evolutie binnen de orale implantologie. VVT Noord-Oost Brabant NOB,

10 december 2015, Gasthof Ter Venne, Langdorp.

• Spring Meeting - TFI (Together for Implantology) Academy (2-day course) Prof. Dr. Stefan Vandeweghe & Drs. Andy Temmerman

20-21 November 2015, Istanbul, Turkije

• Tissue regeneration with L-PRF. Prof. Dr. M. Quirynen & Drs. Andy Temmerman

EAO Stockholm, Main Auditorium Session,

20 september 2015, Stockholm, Sweden.

• An open, prospective, non-randomized, controlled, multicentre study to evaluate the clinical outcome of implant treatment in women over 60 years of age with osteoporosis/osteopenia: 1-year results. Drs. Andy Temmerman

EAO Stockholm, Short Oral Communication

21 september 2015, Stockholm, Sweden

• Spring Meeting - TFI (Together for Implantology) Academy (2-day course) Prof. Dr. Stefan Vandeweghe & Drs. Andy Temmerman

8-9 May 2015, Adana, Turkije

• Leucocyte & Platelet Rich Fibrin (L-PRF): from fiction to reality? + WORKSHOP Prof. Nelson Pinto, Drs. Andy Temmerman, Dr. Yannick Spaey, Mick Demanet

5 March 2015, UZ Leuven, Campus Sint-Rafaël

• The use of Leucocyte and Platelet Rich Fibrin in Oral Surgery. Stafleden Mond,- Kaak, & Aangezichtsheelkunde,

11 December 2014, AZ Sint-Jan, Brugge

• Leucocyte and Platelet Rich Fibrin (L-PRF): Preparation and Surgical handling + WORKSHOP

Prof. Dr. Nelson Pinto & Andy Temmerman

Permanente Vorming KU Leuven, Iers College, Leuven.

• Periapical Implant Lesions: Etiology and treatment options. Belgische Vereniging voor Parodontologie, Failure Festival Meeting,

Provinciehuis, Leuven.

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• Sinuslifting: “Less is more!?” Symposium Afdeling Prothetische Tandheelkunde & Parodontologie,

Congrescentrum Lamot, Mechelen.

• Leucocyte and Platelet Rich Fibrin (L-PRF): Preparation and Surgical handling + WORKSHOP

UZ Sint-Raphaël, Leuven.

• Het gebruik van L-PRF in de orale chirurgie. Symposium 35 jaar Parodontologie aan de KU Leuven,

20 september 2014, Onderwijs en Navorsing, Campus Gasthuisberg

• Beginselen van de orale implantologie. VVT Studieclub Limburg,

27 november 2014, Domein Bokrijk, Hangar 58

• Are panoramic radiographs reliable in planning sinus augmentation procedures? EFP, Post-Graduate Meeting, Istanbul, Turkije.

• Are panoramic radiographs reliable in planning sinus augmentation procedures? Belgische Vereniging voor Parodontologie,

Free Communications Day, Brussel.

• De (on)betrouwbaarheid van de panoramische radiografie. Symposium 30 jaar Parodontologie KU Leuven, Leuven.

• Hedendaagse behandelconcepten binnen de Parodontologie. Andy Temmerman, Koen Marcelis & Kim Vermeulen

Permanente vorming KU Leuven, Leuven.

• Membragel™: een nieuw vloeibaar membraan. + WORKSHOP Straumann Product Lancering,

Brugge & Gent.

• Basics in Periodontology: part 1.

VVT Studieclub Linkebeek, VVT Studieclub Ge-Ni-Aal, VVT Studieclub Limburg

• Parodontologie en algemene gezondheid. Andy Temmerman & David Lefever

VBT Studieavond, Groot Bijgaarden.

• The use of piezosurgical devices in oral surgery + WORKSHOP Prof. Dr. M. Wainwright & Andy Temmerman

Permanente vorming KU Leuven, Leuven.

• Basics in Periodontology: part 2. Andy Temmerman & David Lefever

VVT Studieclub Ge-Ni-Aal, VVT Studieclub Limburg.

• Ethisch verantwoorde behandelingsconcepten met orale implantaten bij patiënten met een smalle kaak.

Symposium “30 jaar osseointegratie aan de KU Leuven”,

Kinepolis Leuven.

• Piezosurgery @ Periodontology KU Leuven + WORKSHOP Prof. Dr. M. Wainwright & Andy Temmerman

Permanente vorming KU Leuven, Leuven.

• Letsels van de harde weefsels. Andy Temmerman & Stefan Matthijs

Symposium 20 jaar ParoPlus, Congrescentrum De Montil, Affligem

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