BIODEGRADABLE PLATES AND SCREWS IN ORAL AND MAXILLOFACIAL SURGERY by francesco biaggini

BIODEGRADABLE PLATES AND SCREWS IN ORAL AND MAXILLOFACIAL SURGERY

Thesis

Jappe Buijs

The research presented in this thesis was performed at the Department of Oral and Maxillofacial Surgery, University Medical Centre Groningen, The Netherlands. This research was financially supported by: Board of the UMCG, www.umcg.nl Straumann, www.straumann.com Camlog, www.pro-cam.nl Nobel Biocare, www.nobelbiocare.com BioComp, www.biocomp.eu Inion Ltd., www.inion.com ConMed Linvatec Biomaterials Ltd., www.conmed.com KLS Martin, www.klsmartin.com Synthes, www.synthes.com Dental Union, www.dentalunion.nl Henry Schein, www.henryschein.nl NVGPT, www.nvgpt.nl Fred Rib么t tandtechniek, www.fredribot-tandtechniek.nl Examvision, www.examvision.nl

RIJKSUNIVERSITEIT GRONINGEN

BIODEGRADABLE PLATES AND SCREWS IN ORAL AND MAXILLOFACIAL SURGERY

Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op woensdag 14 september 2011 om 16.15 uur door Gerrit Jacob Buijs

漏 Gerrit Jacob Buijs, 2011 All rights reserved. No parts of this publication may be transmitted, in any form or by any means, without permission of the author. Bookdesign: Sgaar Groningen Printed by: Drukkerij van der Eems Heerenveen ISBN: 978-90-367-4966-4

geboren op 18 november 1980 te Purmerend

Promotores:

Prof. dr. R.R.M. Bos Prof. dr. B. Stegenga Prof. dr. G.J. Verkerke

Copromotor:

Dr. J. Jansma

Beoordelingscommissie:

Prof. dr. dr. K.L. Gerlach Prof. dr. J. de Lange Prof. dr. D.B. Tuinzing

Paranimfen:

N.B. van Bakelen H.J.W.E. de Lange

CONTENTS 99

Chapter 1 General introduction

Chapter 6 Reference List

Chapter 2 Efficacy and Safety of Biodegradable Osteofixation Devices in Oral and Maxillofacial Surgery: a Systematic Review G.J. Buijs, B. Stegenga, R.R.M. Bos Published in: J Dent Res. 2006 Nov;85(11):980-9.

Chapter 7 Summary

115

Chapter 8 Dutch summary

121

Chapter 3.1 Torsion Strength of Biodegradable and Titanium Screw Systems: a Comparison G.J. Buijs, E.B. van der Houwen, B. Stegenga, R.R.M. Bos, G.J. Verkerke Published in: J Oral Maxillofac Surg. 2007 Nov;65(11):2142-7.

Dankwoord

127

Chapter 3.2.1 Mechanical Strength and Stiffness of Biodegradable and Titanium Osteofixation Systems G.J. Buijs, E.B. van der Houwen, B. Stegenga, R.R.M. Bos, G.J. Verkerke Published in: J Oral Maxillofac Surg. 2007 Nov;65(11):2148-58.

Chapter 3.2.2 Mechanical Strength and Stiffness of the Biodegradable SonicWeld Rx Osteofixation System G.J. Buijs, E.B. van der Houwen, B. Stegenga, R.R.M. Bos, G.J. Verkerke Published in: J Oral Maxillofac Surg. 2009 Apr;67(4):782-7.

Chapter 4 Biodegradable and Titanium Fixation Systems in Oral and Maxillofacial Surgery: a Randomized Controlled Trial G.J. Buijs, N.B. van Bakelen, J. Jansma, J.G.A.M. de Visscher, Th.J.M. Hoppenreijs, J.E. Bergsma, B. Stegenga, R.R.M. Bos Submitted

Chapter 5 General discussion and future perspectives

CHAPTER 1

GENERAL INTRODUCTION

Field of interest Traumatic injuries in the maxillofacial region and dentofacial anomalies may have considerable physical and psychological impact on patients. Therefore, major efforts should be carried out to anatomically and aesthetically restore form and function of the maxillofacial hard and soft tissues in such cases (6). The maxillofacial skeleton consists of 3 parts: the cranium, the mid-face, and the mandible. The mandible articulates with the base of the skull at the left and right temporomandibular joint and at the level of the dental occlusion, and is powered by forceful masticatory muscles. This biomechanical system allows people to perform important functions, such as chewing, swallowing, laughing, and speaking. Physically, the mandible is a heavily loaded bony structure and, consequently, its cortex is thick and compact. By contrast, the mid-face consists of thinwalled cavities, strengthened by bony buttresses absorbing forces exerted through the muscles of the maxillofacial skeleton (7). The diagnosis and treatment of facial fractures and dentofacial anomalies play a prominent role within oral and maxillofacial surgery. Through population growth, increase of traffic, industrialization, violence and sport, the field of traumatology has considerably increased. Today, of the fractures, approximately 55% are caused by traffic accidents, 20% by accidental falls, and 17% by assaults (8). The wearing of helmets and seatbelts and the general introduction of airbags in automobiles were major steps forward in the prevention of trauma. In general, good clinical results are currently achieved in both maxillofacial traumatology and dentofacial orthopedics primarily because of advanced diagnostic radiographic methods as well as refined surgical techniques and fixation materials. Diagnostic radiographic methods Diagnostic radiographic methods are essential (1) to determine the exact extent of suspected maxillofacial fractures, and (2) for the diagnosis and treatment planning of osteotomies. Three-dimensional (3D) visualization of the bony skeleton and the dentition can be obtained by Computed Tomography (CT) and is the golden standard for fractures. The images are very precise and the surgeon can determine preoperatively where the plates and screws should be placed to acquire immobilization of the bone fragments. A disadvantage of CT examination is the relatively high radiation exposure. Recently, Cone Beam Computed Tomography (CBCT) has been developed, which is faster and produces less radiation (9). Conventional images, such as a panoramic radiograph and a frontosuboccipito radiograph, are the standard recordings to assess mandibular fractures. In case of (para)median fractures, axial radiograph may provide additional information. A panoramic radiograph and a lateral cephalogram are the standard radiographs for osteotomies of the mandible and maxilla.

Requirements for adequate bone healing Essential aspects for bone healing of fractures and osteotomies are sufficient vascularization, anatomical reduction, and immobilization of bone segments (7;10). The treatment of nearly all maxillofacial fractures and osteotomies is currently performed by an open surgical approach to have a better control of the (re)positioning of bone fragments (6;11). Immobilization is obtained using fixation plates and screws. Various compressive, tensile, and torsion forces need to be counteracted by the plates and screws at the fracture crevice and the osteotomy site. After most of the mandibular fractures, the bone takes over compressive forces, whereas the osteosynthesis devices counteract the lost tensile forces. This is called load sharing between the bone and the plates and screws. In case of bony defects, comminuted fractures and bi-lateral sagittal split osteotomies, a plate is fully loaded for bending forces and is called load bearing. Load sharing allows plate and screw dimensions that are much smaller than those necessary for load bearing. The next sections comprise a review of the development of different fixation systems used for immobilization. Refined surgical techniques and development of fixation material Closed fracture management – In the first half of the past century maxillofacial traumata were predominantly treated in a closed (i.e. non-surgical) manner. Immobilization of bone segments was achieved with InterMaxillary Fixation (IMF) in most cases. Stainless steel ligatures were tied up along the dental arches so that the correct dental occlusion could be achieved, whereas in more difficult cases the upper or the lower jaw could additionally serve as a template. Sophisticated external frame fixation devices were applied to achieve immobilization in severe multi-fragment situations (12). An external frame was usually secured with plaster of Paris, bandages or plastic head caps (13). Figure 1. Man with fixation ‘apparatus’ fixed with plaster of Paris. These devices were generally uncomfortable, patient-unfriendly and had a rather gruesome appearance (6;13). They immobilize the temporomandibular joints resulting in cartilage degeneration. Moreover, the requirements for optimal bone healing could not be acquired. For example, fractures and osteotomies above the Le Fort I level were difficult to immobilize with these external devices (6). The transfer pins from the bone segments to the external fixtures facilitate an easy entry of bacteria to the healing bone. Treatment without an open intervention impedes surgeons to anatomically re-position the bone segments. Figure 1. Man with fixation ‘apparatus’ fixed with plaster of Paris Open fracture management – In the second half of the past century there was a shift from closed to open surgical treatment. Besides the improved anaesthetic techniques and infection control, especially the development of the so-called training- or function-stable fixation materials, was responsible for this shift. Training-stable means ‘moving without loading’ whereas function-stable means ‘moving and loading’.

CHAPTER 1

GENERAL INTRODUCTION

The plates and screws were relatively small and the plates were easier to bend. With delicate intra-oral incisions, bone segments could be visualized so that they could be repositioned anatomically while the plate could be easily inserted and gently adapted to the curvature of the maxillofacial bones. Subsequently, the screws could be inserted monoFigure 2. Favourable location of plates and screws on the mandible

CHAPTER 1

Starting with wire osteosynthesis, surgeons made bur holes through both bone fragments after careful stripping of the periostium. Subsequently, a wire was tied up through the bur holes and the ends were twisted along each other (14). Due to the open fracture management, there was a better control of repositioning the dislocated fragments (6). The fragments could better be stabilized with wire osteosynthesis compared to external fixation devices. Nonetheless, wire osteosynthesis were not able to optimally stabilize bone fragments in order to acquire training- of even function-stable fixation. The first fixation systems that obtained sufficient stability to immediately restore the functions of the maxillofacial skeleton were developed in 1957 by the “Arbeitsgemeinschaft für Osteosynthese fragen” (AO), a Swiss study group. This study group used the ideas of the fixation of fractures of the long bones published by Danis in 1947 (15). The emergence of these plates and screws heralded, in the 60s of last century, the era of training- and function-stable osteosynthesis system. With these systems fracture fragments could anatomically be stabilized and held in position, and could be directly and functionally loaded. With these plates and screws, it was possible to obtain a certain stress on the fracture segments against each other. Because of this stress, the fracture crevice obtained a resistance to friction and mobility. This so-called compression system was later ingeniously built into the screw holes of the plates, where the screw heads, with eccentric screw placement, could build up the required axial interfragmental compression between the bone fragments. These plates are called dynamic compression plates, or DCP plates (16-18). During the healing period, stability of the fracture is maintained for approximately 6 to 8 weeks. The acquired compression does not lead to bone necrosis, whereas the remodelling of the bone compensates for the instability that might arise from the gradual decrease of the compression. When using this type of fixation, the formation of callus, estimated as a sign of lack of stability could be prevented. Initially, plates for application in the lower jaw with bicortical screws were developed to achieve the desired stability analogous to the fixation of fractures in long bones (19-21). Given the choice for bicortical anchoring of the screws and in order to avoid damage to the roots of the teeth and nerve structures, the only safe place for these systems was the lower border of the mandible. In terms of mechanical stress, this was the most demanding and the least favourable position to compensate dislocating forces. Often, these plates were applied via an extra-oral approach and required a disadvantageous large skin incision and wide stripping of the periostium to insert and apply the voluminous plates. An advantage of these relatively large and bulky plates was that they were strong enough to bridge bony defects, bone grafts, and comminute fractures used for reconstructions. Late in the 70s, a mini-plate system for the mandible was introduced by Champy et. al. (22;23). These small plates have much smaller dimensions than the AO-plates that were used for the fixation of fractures of the facial skeleton. The system was derived from the ‘midface’ fixation system launched by Michelet in 1973 (24). The size of the miniplates was adapted to a mechanically more favourable location for fixation of mandibular fractures (Figure 1).

cortically, leading to a firm stabilization. In this way, bone segments, even of complicated fractures and of osteotomies, could be accurately stabilized (25). Using this system, all (dislocated) mandibular fractures can be stabilized in a ‘training-stable’ way with the exception of fractures involving a defect to be bridged (26). This simpler technique, as well as the benefits of an intraoral approach, meant a shift in the preference of surgical treatment of mandibular fractures in favour of the mini-plate method (27). Initially, the appearance of the mini-plate method led to a fundamental discussion of the proponents of the bicortical fixed plates obtaining absolute stability (function stable fixation) and the advocates of mono-cortically fixed mini-plates (training stable fixation). The latter were convinced that with less material on mechanically favourable locations, an adequate fixation of the fracture segments followed by undisturbed fracture healing could be achieved. Research has now shown that undisturbed healing can be achieved with both methods, provided that appropriate repositioning (i.e. anatomical reduction) of the fracture parts is combined with sufficient plate material in strength and number. By increasing the complexity of the fracture, more plate material is necessary (28-30). The materials used in this area were originally stainless steel plates, whereas titanium plates and screws are currently the golden standard. The successful development of metallic osteosynthesis devices used to stabilize fractured bone fragments was a major impulse for further development of the surgical techniques used to treat dentofacial anomalies. Orthognatic surgery went through a similar develop-

Characteristics of titanium devices Titanium plates and screws are made of pure titanium or titanium alloys. The biocompatibility (31) and the strength of titanium has been thoroughly investigated in many scientific studies. Conventional titanium fixation devices have several disadvantages, which can be summarized as follows: 1. in some patients, particularly those with thin soft tissues, the edges of the inserted (large) plates and screws can be felt. Dehiscence can also occur in situations where the overlying mucosa or skin is very thin. In extreme climates, plates and screws can lead to sensitivity to high or low temperatures; 2. migration and displacement represents the limitation of the use of titanium plates and screws in the growing bones of children or infants; 3. exact bending of the plates is an essential requirement for successful repositioning of the bone fragments. This pre-shaping is time consuming, especially when using voluminous plates; 4. titanium plates and screws interfere with imaging techniques, such as computed tomography and magnetic resonance imaging. The interference with radio-therapeutic treatment techniques is also disadvantageous. The plates and screws can block the radiotherapeutic beam resulting in an inadequate treatment; 5. the most significant disadvantage is probably the continued presence of plates and screws in the human body after the material has fulfilled its function. Despite its biocompatibility, titanium still is a foreign body for the human organism. This generates controversies among experts as to whether implant removal is necessary or not. There is consensus that a follow-up implant removal operation is sometimes indicated (5 - 40%) (32-34), particularly in young patients with growing bone. Implant removal implies an additional surgical procedure with all its associated disadvantages of time, costs, infection risk, discomfort, and anaesthesia. Characteristics of biodegradable devices Since about 4 decades, there is a continuous drive to explore the feasibility of biodegradable devices for the fixation of fractures and osteotomies. The introduction of biodegradable implants can be helpful in eliminating and reducing the disadvantages of titanium plates and screws. Research has revealed that biodegradable materials have limitations as well:

1. most biodegradable plates or meshes must be heated before they can be shaped. The screw holes must be drilled and tapped. This is disadvantageous for difficult and timeconsuming craniofacial operations where many plates and screws must be used; 2. low mechanical stability still represents an important issue of the biodegradable systems, particularly when used in load bearing areas such as the mandible; 3. the manufacturers of the biodegradable fixation devices have increased the dimensions due to the low mechanical strength and stiffness of the polymer based fixation devices. The enlarged dimensions could result in difficult wound closure and an increased risk to develop dehiscence; 4. to our best knowledge, there is no definitive evidence that demonstrates that biodegradable (co)polymers can be fully degraded and resorbed by the human body. However, the possible advantage of disappearing fixation devices still seems to be an appealing alternative to fix bone segments in specific situations.

AIMS OF THIS THESIS The performance of the currently used titanium fixation systems has been thoroughly evaluated. Titanium systems have been proven to be adequate fixation devices except for the disadvantageous aspects mentioned above. Biodegradable fixation devices seem to be an attractive alternative as these systems can reduce or even erase the negative aspects of titanium systems. During the search for the ideal fixation system, the local anatomical circumstances, the forces exerted through the maxillofacial skeleton, as well as the advantages and disadvantages of titanium and biodegradable fixation devices should be taken into account. The general aim of this research project was to establish the effectiveness and safety of biodegradable plates and screws to fix bone segments in the maxillofacial skeleton as a potential alternative to metallic ones. More specifically, the aims of this research project were: - to review the currently available scientific evidence for the applicability of biodegrad able plates and screws for the fixation of bone segments in the maxillofacial skeleton (chapter 2); - to establish the torsion strength of titanium and biodegradable fixation screws (chapter 3.1); - to establish the tensile strength and stiffness, bending stiffness, and torsion stiffness of titanium and biodegradable fixation systems (chapter 3.2.1 and 3.2.2) - to establish the short term effectiveness and safety (chapter 4) of biodegradable plates and screws used for fixation of fractures and osteotomies in the maxillofacial skeleton compared to conventional titanium plates and screws.

CHAPTER 1

ment for its fixation materials as did cranio-maxillofacial traumatology starting with wire osteosynthesis in combination with IMF to only plate and/or screw fixation and postoperative guiding elastics. With orthognatic surgery osteotomized jaws are put into new positions thus changing facial anatomy and dental occlusion. In a way this can be considered as non-anatomical reposition and fixation of facial fractures, often leaving gaps that are bridged with osteosynthesis plates. The mechanical properties of the fixation materials used for this type of surgery are therefore of utmost importance and can probably not be compared with fracture treatment on a one-to-one ratio.

CHAPTER 2

EFFICACY AND SAFETY OF BIODEGRADABLE OSTEOFIXATION DEVICES IN ORAL AND MAXILLOFACIAL SURGERY: A SYSTEMATIC REVIEW

G.J. BUIJS B. STEGENGA R.R.M. BOS

Published in: J Dent Res. 2006 Nov;85(11):980-9.

Abstract: Background - The use of osteofixation devices should be evidence-based in order to secure uncomplicated bone healing. Numerous studies describe and claim the advantages of biodegradable over titanium devices as a bone fixation method. Objective - To systematically review the available literature to determine the clinical efficacy and safety of biodegradable devices compared with titanium devices in oral and maxillofacial surgery. In addition, related general aspects of bone surgery are discussed. Methods & materials - A highly sensitive search in the databases of MEDLINE (19662005), EMBASE (1989-2005) and CENTRAL (1800-2005) was conducted to identify eligible studies. Eligible studies were independently evaluated by two assessors using a quality assessment scale. Results - The study selection procedure revealed four methodologically â&#x20AC;&#x2DC;acceptableâ&#x20AC;&#x2122; articles. Owing to the different outcome measures used in the studies, it was impossible to perform a meta-analysis. Therefore, the major effects regarding the stability and morbidity of fracture fixation using titanium and biodegradable fixation systems were qualitatively described. Conclusion & discussion - Any firm conclusions regarding the fixation of traumatically fractured bone segments cannot be drawn due to the lack of controlled clinical trials. Regarding the fixation of bone segments in orthognathic surgery, only a few controlled clinical studies are available. There does not appear to be a significant short-term difference between titanium and biodegradable fixation systems regarding stability and morbidity. However, definite conclusions, especially with respect to the long-term performance of biodegradable fixation devices used in maxillofacial surgery, cannot be drawn. Abbreviations used in this paper are: CENTRAL, Cochrane Central Register of Controlled Trials; MeSH, Medical Subject Heading; VAS, Visual Analogue Scale; and W, weight. Key words: Biodegradable, osteofixation, treatment, stability, morbidity, systematic review.

Background Maxillofacial traumatology and orthognathic surgery are major fields of oral and maxillofacial surgery. Internal rigid fixation systems are used for fixation and stabilization of osteotomized or fractured bone segments (35;36). Plates and screws are generally made of titanium and are currently regarded as the golden standard (4;37;38). Titanium fixation systems can be used safely and effectively (35;39). The intrinsic mechanical properties ensure that the device dimensions are kept within acceptable limits. The handling characteristics of titanium systems are simple and efficient (40). However, titanium devices also have disadvantages. These systems interfere with radiotherapy (37;41;42) and imaging techniques. Besides, titanium implants have been associated with complications such as growth restriction and brain damage (43;44), infection, and possible mutagenic effects (45). A second intervention to remove the implants implies additional surgical discomfort, risks, and associated socio-economical costs (43;46-48). A plate removal percentage of 11.1% in Le Fort I osteotomies due to infection and plate exposure has been reported (49). In a retrospective study of 279 patients with isolated mandibular fractures, a plate removal percentage of 11.5% has been reported (50). In another study (32-34), 23 oral and maxillofacial surgeons were interviewed regarding removal of mini-plates. The authors concluded that the plate removal percentage varies between 5% and 40%. Biodegradable osteofixation systems have the possibility to degrade, thus preventing the need for a second intervention (51;52). Another advantage of biodegradable devices is their radiolucency, implying good compatibility with radiotherapy and imaging techniques (42;53;54). Besides, osteoporosis can be prevented due to the gradual transfer of functional forces to the healing bone during the disintegration process of biodegradable devices (55;56). Since the introduction of biodegradable devices in 1966 (57), the development of their mechanical properties and degradation characteristics has been extensive (58). Numerous in vitro, animal, and clinical studies have been published about positive (59-65) as well as negative results (66-69). Despite the supposed advantages of biodegradable osteofixation devices, these systems did not replace the titanium systems and are currently applied in only limited numbers (43;70). The mechanical properties are less favourable and ultimate resorption has not been proven (71). Another significant factor of the limited use is the resistance by surgeons to modify their conventional, well experienced, treatment techniques (72). The major drawback for general use of biodegradable devices is the lack of clinical evidence.

CHAPTER 2

INTRODUCTION

CHAPTER 2

GENERAL ASPECTS OF BONE SURGERY Various in vitro and in vivo studies must be performed before innovative interventions can be used safely and effectively in the clinic (75). Studies that have been important for understanding the behaviour and characteristics of biodegradable and titanium osteofixation systems are reviewed in the subsequent sections. Mechanism of bone healing Fractured bone or locally damaged bone causes disruption of many blood vessels. This disruption results in local haemorrhage followed by the formation of a blood clot. Osteocytes at both sides of the fracture die due to deprivation of blood perfusion. Restoration of the fracture area starts with the clearance of the blot clot, death cells and bone matrix under the influence of revascularization. Periosteum, endosteum and surrounding tissues respond by cell proliferation. The tissue that arises between both fracture ends, and serves as a temporary bridging, is called callus. Its composition varies with site and circumstances (76;77). Cartilage is formed in parts of the callus that are not sufficiently saturated with blood. Subsequently, cartilage is transformed into bone by enchondral bone formation. If sufficient blood saturation occurs, a direct network of bars of plexiform bone is formed by endesmale bone formation. As a strong bony callus arises, it can be subjected to normal tension- and compression forces (78). Resorption and formation of bone is a dynamic and continuously changing process, which has an equilibrium defined by internal factors (mainly hormones) and external factors (mainly mechanical forces). Inadequate immobilization during the healing process causes disruption of the revascularization process. This results in the formation of a fibrous callus followed by an incomplete healing of the fracture. Too rigid fixation, on the other hand, may also cause problems. Lack of normal functional stimuli in the final stages of bone healing will inhibit the formation of new bone, while the resorption of bone still proceeds (79;80). This could result in local osteoporosis (76;77;81).

Mechanical aspects Various muscles of the maxillofacial skeleton exert a wide variety of forces in different directions. This implies that it is difficult to estimate the required mechanical properties of a fixation system. Decisions regarding the required plates and screws are rarely evidence-based (82). The primary mechanical strength and stiffness of biodegradable osteofixation devices are less favourable compared to their conventional titanium counterparts. This is inherent to the use of biodegradable polymers. However, the question is whether their mechanical properties are sufficient for resisting the local deforming forces (83). The main objective in orthognathic and trauma surgery is fast, anatomical and painless functional reunion of bone segments (84). Revascularization plays an essential role in this process (78;85). Titanium plates and screws are intrinsically small, strong, and biocompatible (37). As a result, the main objectives regarding fixation management can be met. The rigidity of titanium fixation systems might also be disadvantageous. The system probably inhibits the transfer of functional forces to healing (or healed) bone, which may result in osteoporosis as was mentioned in the previous section (55;56;81). By contrast, the strength and stiffness of biodegradable fixation systems decrease with time because of the disintegration of the polymer chains, in this way ensuring progressive loading during the subsequent stages of bone healing. To compensate for the less favourable primary mechanical strength and stiffness of biodegradable devices, manufacturers increase their dimensions. This may interfere with tensionless wound closing, making the wound area more prone to infection. Enlarged dimensions restrict easy application in small areas which are difficult to access (e.g. paediatric surgery) (40). These factors imply that the field of application of biodegradable devices, in particular regarding bone fixation in the maxillofacial area, is restricted (43), whereas titanium systems may be applied almost anywhere. Despite the disadvantages of the enlarged dimensions of biodegradable systems as mentioned above, several patient series have been published regarding the successful use of biodegradable fixation systems applied in different (e.g. heavy load bearing) situations (e.g. mandibular fractures and bilateral sagittal split osteotomies). The treatment of 1883 patients, in whom craniomaxillofacial deformities were fixed with the biodegradable LactoSorb fixation system, was evaluated in a recent study (60). Regarding to the rapidly growing cranial vault, the authors noted, that fewer potential complications occurred using the biodegradable system compared with the titanium plates and screws. The BioSorb FX biodegradable fixation system has been found to be an appealing alternative for titanium fixation systems regarding orthognathic, trauma and cancer surgery, corrective cranioplasty, and fixation of bone grafts in another recent study (86). Considering the biomechanical aspects, selecting plates and screws is not always that straightforward. The surgeon should consider the (1) local deforming forces and (2) which system (biodegradable or titanium) could optimally resist the deforming forces (87), and in what configuration (number of screws in both fracture ends).

CHAPTER 2

Objectives The use of biodegradable osteofixation devices should be evidence-based in order to secure uncomplicated bone healing (73). Numerous studies describe and claim the advantages of biodegradable over titanium devices as a bone fixation method (60;74). In the present study, the currently available literature regarding the clinical efficacy and safety of biodegradable osteofixation devices compared with titanium osteofixation devices in oral and maxillofacial surgery was systematically reviewed. The research question was phrased as follows: â&#x20AC;&#x153;is there a difference in stability and morbidity regarding the fixation of bone segments with biodegradable or titanium fixation devices in orthognathic and trauma surgery?â&#x20AC;? The available literature regarding current relevant aspects of bone surgery will also be discussed.

have reported varying in vivo results. A recent histologic study (106) reported complete resorption of Resorb® X and LactoSorb screws after 12 and 14 months, respectively, found by the use of a fluorescence microscope. However, bone re-modelling was not completed after 26 months. The degradation process of biodegradable implants has also been investigated through MRI (107). The authors concluded that no complete resorption had occurred after 34 months. Based on these findings, large-scale, long-term controlled clinical trials can be recommended to verify the ultimate biocompatibility and resorption characteristics of biodegradable implants and to establish evidence-based treatment methods. Characteristics of “ideal” osteofixation devices Considering the aspects mentioned in the previous sections, an ideal osteofixation device should (82;92): (1) be fabricated and designed with appropriate initial strength to meet the bio-mechanical demands, (2) not cause tissue responses necessitating device removal, (3) be easy to use and handle, (4) be cost-effective, and (5) be compatible with radiotherapy and imaging techniques. Regarding biodegradable osteofixation devices, the following aspects should additionally be incorporated: (6) degrade in a predictable fashion and allow for safe progressive loading during each stage of bone healing and (7) disappear completely.

CONTROLLED CLINICAL STUDIES – A SYSTEMATIC REVIEW METHODS Literature search To identify studies on the efficacy and safety of biodegradable osteofixation devices, a highly sensitive search was carried out in the databases of MEDLINE (1966-2005) and EMBASE (1989-2005). The search was supplemented with a systematic search in the ‘Cochrane Central Register of Controlled Trials’ (CENTRAL) (1800-2005). Free text words and the applied thesaurus (MeSH) regarding the search strategy are summarized in Table I. Several experts in the field of biodegradable osteofixation devices were contacted to ensure eligible studies were not overlooked. Moreover, leading oral and maxillofacial journals were screened for missing articles. To complete the search, reference lists in the obtained literature were checked for additional relevant articles. No language and time restrictions have been included in the search strategy. The search strategy was focused on three aspects: (1) terms to search the ‘health’ condition of interest (i.e. fracture and osteotomies of the maxillofacial skeleton); (2) terms to search for the intervention(s) evaluated (i.e. biodegradable and titanium osteofixation device(s)); and (3) terms to search for the types of study design to be included (i.e. clinical controlled trials) (108). Free text words and MeSH terms were formulated precisely, resulting in a scrupulous primary exclusion of ‘non clinical trials’ as well as studies which are rarely topic related.

CHAPTER 2

Biocompatibility and resorption aspects Biocompatibility refers to how a material elicits a host response in a specific situation. Tissue responses to implanted material are numerous and complex. The term biocompatibility also describes aspects of interactions between implanted material and the host (88;89). The process of removal of a material by cellular activity and/or dissolution in a biological environment, is called resorption (90). Degradation is the disintegration of material into smaller parts. Biocompatibility, resorption and degradation are closely interrelated. The biocompatibility of biodegradable internal fixation devices is strongly influenced by the degradation and resorption behaviour of the polymers used (75;91). These systems are made of different polymers (e.g. poly(L-lactide), poly(D-lactide), poly-glycolide, polydioxanone, trimethylene carbonate). These materials degrade and resorb in two phases (92). During the first phase, water molecules hydrolyze the long polymer chains into shorter fragments. The molecular weight and the polymer strength decrease during this process. The second phase consists of a physiologic response of the body in which macrophages phagocyte and metabolize the short fragments which subsequently enter the citric acid cycle (93-95). Water and carbon dioxide remain and are subsequently excreted from the body, mainly through respiration. The mass of the biomaterial rapidly disappears during phase two (57;96). In addition, enzymes are supposed to play a considerable role in the degradation (97;98). Degradation and resorption processes of biodegradable polymers frequently elicit adverse tissue responses. This represents an inherent biologic tissue response (75) as occurs with every implanted material (67). Regarding orthopedic surgery, the general incidence of adverse tissue responses using fixation devices made of poly-glycolide varies from 2.0 to 46.7% (75). The incidence of adverse tissue responses is generally lower for plates and screws made of poly-lactide (75). The time between implantation and appearance of adverse tissue responses varies from 10-12 weeks (48;67;99) to 4-5 years (66;100;101) for respectively poly-glycolide and poly-lactide. The clinical characteristics of the adverse tissue responses vary from a local swelling without signs of inflammation (66) to a suddenly emerging painful, erythematous, fluctuating papule which reveals a sinus discharge of liquid remnants of disintegrated implant materials (75). Radiographs obtained at the time of manifestation show osteolytic changes around the implanted material in 50% of the patients (68;102). The histopathologic picture has been characterized by an abundant polymeric debris, being surrounded by mononuclear phagocytes and multinucleated foreign-body giant cells (67;68;103;104). The possible risk factors for developing adverse tissue responses seem to be associated with the extent of vascularization, which inherently depends on the site of implantation. Moreover, the implant design appears to affect the response rate. Cylindrical pins and rods show a lower incidence of adverse tissue responses than screws. Foreign-body response rates seem to be independent of patients’ age and gender as well as the implanted polymer volume. The long-term ultimate biocompatibility and resorption of biodegradable plates and screws have frequently been investigated, yet remain to be established (75;105). Researchers

Table II. Quality of study tool (109)

#1 surger* or fracture* or trauma* or reconstruction* or orthoped* or injur* #2 explode “Maxillofacial-Injuries”/ all subheadings #3 explode “Facial-Bones”/ all subheadings #4 maxillofacial* or craniomaxill* or craniofacial* #5 jaw* or mandib* or maxill* #6 #1 and ( #2 or #3 or #4 or #5) #7 “Absorbable-Implants”/ all subheadings #8 “Bone-Plates”/ all subheadings #9 “Bone-Screws”/ all subheadings #10 “Internal-Fixators”/ all subheadings #11 plate* or screw* or miniscrew* or miniplate* or implant* or osteosynth* or osseointegrat* or osteofixation* or osteotom* or internal fixation #12 bioresorb* or biodegrad* or bioabsorb* or bioadsorb* or absorb* or resorb* or adsorb* #13 #12 and (#7 or #8 or #9 or #10 or #11) #14 ((clinical* in ti,ab) and (trial* in ti,ab)) or (PT:MEDS = clinical-trial) or (“Clinical-Trials” / all subheadings) Search MEDLINE/EMBASE: #6 and #13 and #14 Search Cochrane Controlled Trial Register: #6 and #13

Dimension

Run data search: 17-10-2005

Inclusion and exclusion of studies To identify eligible studies suitable for methodological appraisal, relevant studies underwent a second selection procedure based on the completeness of the report. The following implant-related outcome measures should be evaluated: a. union/non-union of the fracture within the follow-up period; b. wound healing/infection; c. intervention with biodegradable as well as titanium osteofixation device; d. proper (control) group; e. diagnoses and indications for treatment must be well established by clinical and radiographic evaluation. Studies, meeting the above-mentioned criteria, were subjected for further methodological appraisal.

Study selection The relevance of studies was evaluated by a first selection based on title and abstract. Since the research question focuses on the efficacy and safety of biodegradable osteofixation devices in comparison with titanium devices, only controlled clinical trials (CCT) were considered for inclusion in the systematic analysis. The review was focused on studies concerning the treatment of fractures and the performance of osteotomies of the maxillofacial skeleton (i.e. Le Fort I, Le Fort II, and Le Fort III fractures and osteotomies, cranial fractures, malar fractures, mandibular fractures, and sagittal split osteotomies of the mandible). Studies involving children were also considered for inclusion. Disagreement about whether or not a study should be included was resolved by a consensus discussion. Full-text documents were retrieved of all relevant articles. The study selection procedure is outlined in figure 1.

Weighting (W)

Control group

Randomization

Measurement outcome(s)

Study design

Conclusion(s)

‘Intention to treat’ analysis

Statistical analysis

Adherence to study protocol

Blinding

Research question

Loss to follow-up

Outcomes

Reporting of findings

Patient compliance And other variables

4 3

Total

100

Quality assessment of studies A quality assessment of the remaining studies was performed to control the influence of bias in a systematic analysis, to gain insight into potential comparisons, and to guide interpretation of findings (108). A registered methodologist and oral and maxillofacial surgeon (BS) as well as a PhD resident (GJB) assessed the methodological quality with the ‘quality of study tool’ developed by Sindhu et al. (109). The ‘quality of study tool’

CHAPTER 2

Table I. Search strategy

Identified articles - MEDLINE search: n = 122 - EMBASE search: n = 29 - CENTRAL search: n = 87

Excluded articles: - Non clinical trials - Rarely topic related

CHAPTER 2

Relevant articles - Fracture or osteotomy in the maxillofacial skeleton - Biodegradable osteofixation device - Clinical trials n = 35

Excluded articles: - Non controlled trials - No fracture or osteotomy in the maxillofacial skeleton - No biodegradable osteofixation devices used

Eligibility criteria controlled clinical trials

Union/non-union of fracture/osteotomy Wound healing/infection Intervention with biodegradable and titanium osteofixation device Clinical and radiological evaluation Follow up period > 1/2 year Proper control group n=5

Excluded articles: Inadequate reporting of Methods and Results (1)

Included for methodological appraisal n=4

Excluded articles: Similarity of outcome measures insufficient (2-5)

Included for meta-analyses n=0

consists of 53 items in 15 dimensions and is outlined in Table II. Each dimension has a specific weight (W). The included articles revealed an independent score by the two observers according to the 15 dimensions (range 0-100). Agreement regarding the weight of the individual sub-dimensions and the required minimum ‘methodological’ values for each dimension was reached in a consensus meeting. Based on these minimum values, summation yielded a threshold value, which in this study was 54. If feasible, a meta-analysis was carried out provided that the primary outcome measures (defined in the individual studies) could be meaningfully combined in an overall effect-size. Statistical analysis The degree of agreement between the two observers regarding eligible studies before the consensus meeting is expressed as a percentage of agreement of unweighted Cohens’s kappa. Where applicable, Cochrane Review writing software (RevMan) was used to calculate the overall effect sizes by means of the random-effects model.

RESULTS The MEDLINE, EMBASE and CENTRAL search identified 122, 29 and 87 publications, respectively. Systematic assessment of these 238 articles according to the specified ‘eligibility’ criteria revealed 5 possible eligible publications. Inclusion of a ’titanium control group‘ appeared to be the limiting criterion in this selection, however essential for answering the research question. Inclusion of a control group and, preferably, random assignment are major aspects for controlling unknown influences and possible confounders (108;110). Checking references of relevant articles and contacting experts did not reveal additional articles. Methodological assessment of the 5 eligible publications revealed 4 methodologically ‘acceptable’ articles. One article was excluded because of inadequate reporting of the methods and results (1). Inter-assessor agreement on the methodological quality of each study was 96% (unweighted kappa, 0.90; 95% CI: 0.85 to 0.96). Disagreements were generally caused by slight differences in interpretation and were easily resolved in a consensus meeting. Three studies used randomization to allocate patients to the treatment groups (2;4;5). One study allocated patients consecutively (3). LactoSorp® plates and screws (W. Lorenz Surgical, Jacksonville, Florida) were used to fix bone segments in two studies (2;3). The LactoSorp® fixation system has a copolymer composition of 82% L-lactide and 18% glycolide. Ferreti et al. (2002) studied mandibular splits fixed with three bi-cortical screws whereas Norholt et al. (2004) investigated the stability and relapse of Le Fort I osteotomies. One other methodologically ‘acceptable’ study (4) investigated the fixation of different osteotomies using BioSorb FX plates and screws (Linvatec Biomaterials Ltd.). The BioSorb FX fixation system is made of self-reinforced (70% L-lactide, 30%DL-lactide) poly lactic acid. The most recent study (5) investigated the changes in condylar long axis and skeletal stability after bilateral sagittal split ramus osteotomy using 100% poly-L-lactic acid plates and screws (Fixsorb®-MX, Takiron Co., Osaka, Japan).

CHAPTER 2

Figure 1. Algorithm of study selection procedure

MMOP, Maximum Mouth Opening Range; TMD, TemporoMandibular Disorder. Arranged according the publication date Follow up 1 year Maxillary subapical osteotomy Mandibular subapical osteotomy Mandibular body osteotomy 2

Ferretti et al., 2004

Cheung et al., 2004

Controlled

Randomized Norholt et al., 2004 29

Le Fort 1 osteotomy Titanium Mandibular split BioSorb FX Wunderer and Schuchardt3 Genioplasty, Hofer4 Step5 osteotomy Mandibular split Titanium LactoSorb

20 20

30 30

24 24

20 20

No significant difference regarding clinical stability and clinical morbidity

No significant difference regarding clinical stability and clinical morbidity 79,5

Very low morbidity Tendency for impaction in titanium group, no impaction in the degradable group 82 21 25 30 30 Le Fort I osteotomy Randomized

Titanium LactoSorb

Mandibular split Randomized Ueki et al., 2005

Titanium Fixorb® MX

20 20

No difference regarding pain on chewing and MMOR# More TMD# symptoms in degradable group No difference regarding skeletal stability

Conclusion Quality score Included Completed

Patients2

Type of fixation Type of treatment Design trial

Morbidity The morbidity of osteofixation devices is evaluated in all of the included studies (2-5). Ueki et al. (5) evaluated different aspects regarding morbidity: pain on chewing (using a visual analogue scale), maximum mouth opening range (measuring the distance between the edges of the upper and lower incisors) and temporomandibular disorder (TMD) symptoms mainly based on sound (click and crepitus) on movement. Pain on post-operative chewing revealed lower VAS scores compared to pre-operative chewing in both groups. The VAS scores between both groups were nearly similar. Maximum mouth opening range did not

Study1

Stability Stability of fixed bone segments is an important outcome measure since the aim of fixation systems is to establish a functional, anatomical and pain-free reunion of bone segments. In the four included articles, the stability of the osteotomized segments was assessed with different methods. Cephalometric analysis was used in three of the four included studies to accurately assess the skeletal stability (2;3;5). Regarding bilateral sagittal osteotomies (5), the outcome measures SNA, SNB and ANB did not significantly differ for the titanium and PLLA group. The interincisor angle, occlusal plane angle, mandibular length, overbite, overjet, and convexity were also similar in both groups. The location of the pogonion neither showed a significant difference. In the second study (2), Le Fort I osteotomies fixed with biodegradable plates and screws revealed a significant difference in vertical dimension of the upper jaw (mean difference 0.6 mm) after 6 weeks post-operatively. The osteotomies fixed with titanium plates and screws did not present a significant difference. The authors (2) concluded that the statistical significant difference of the vertical dimension in the biodegradable group (LactoSorp®) was not clinically relevant. Ferretti et al. (3) evaluated the relapse (skeletal stability) of bilateral sagittal osteotomies. The mean transposition of the mandible fixed with three bi-cortical screws was 4.7 (sd = 1.3) and 5.5 (sd = 1.7) millimetres for respectively the titanium and biodegradable group. The mean relapse was 0.25 (sd = 1.25) and 0.83 (sd = 1.25) millimetres, respectively (not statistically significant). The clinical mobility of the bone segments was evaluated in two included studies (2;4). The first study (2) reported a slight mobility during the first 6 weeks (6 in the biodegradable group and 3 in the titanium group) whereas one case presented mobility in the biodegradable group 1 year post-operatively. The second study (4) reported that the clinical stability improved gradually over time. No difference in this respect was revealed between titanium and biodegradable fixation. In all patients, the mobility was very mild and present in the maxilla. The mobile maxillae became stable and firm in the sixth week, and no further mobility could be detected during the follow-up period.

Table III. General characteristics

CHAPTER 2

Because of the different effect-sizes used in the methodologically ‘acceptable’ studies, it was impossible to perform a meta-analysis. Therefore, the major effects regarding the stability and morbidity of fracture fixation are qualitatively described in the subsequent sections.

GENERAL DISCUSSION Mechanical aspects Regarding the mechanical aspects, the selection of an adequate fixation system remains difficult due to varying local situations (fracture line(s), anatomy, patients and muscle activity). To guide decisions regarding the required fixation system in different clinical situations, a comparison of the initial mechanical strength and stiffness of biodegradable and titanium systems could be valuable. Moreover, the surgeon is predominantly interested in the device (functional unit) characteristics of a fixation system rather than in the material characteristics. The variability of biodegradable osteofixation systems (i.e. co-polymer composition and geometry) makes a well-funded selection difficult (82). Besides the initial mechanical characteristics of osteofixation systems, the torsion strength and stiffness of the screws are important. The screws fix the osteofixation plate against the bone segments and prevent sliding of the bone segments and the fixation system relative to each other. This ensures adequate stabilization of the bone segments. Screws also generate inter-fragmentary compression to stabilize mandibular splits, which will enhance fracture healing. The torsion strength and stiffness of the biodegradable screws are less favourable (111) compared to titanium screws, which have been reported as a disadvantage by several authors (111;112). Moreover, biodegradable polymeric screws relax when a force is continuously applied (111). These aspects may result in decreased fracture stability and possible compromised fracture healing.

Biocompatibility and resorption aspects Long-term ultimate biocompatibility, as is the goal of any implanted material, is difficult to establish. Despite considerable clinical experience of fracture fixation using biodegradable materials, long term clinical studies are scarce. Moreover, studies reporting the long-term complications (66;67;101) probably represent one end of a continuous spectrum of biological responses. The majority of the cases pass sub-clinically and remain unnoticed despite the elicitation of a (small) biological host response as is the case with every implanted material (67). The degradation and resorption characteristics as well as the possibility to develop adverse tissue responses, depend largely on the nature of the implanted materials. Polylactide is a major component of the biodegradable fixation devices and the time to elicit a considerable host response is 4 to 5 years (66;100;101;113). Therefore, studies reporting the biocompatibility and degradation characteristics regarding this material should last for at least 5 years (114). However, few laboratory animals live long enough and, consequently, long-term biocompatibility experiments are difficult to design. The development of adverse tissue responses seems to originate from several different physiologic and chemical processes. Crystalline remnants and a decrease of pH (115) during degradation are probably responsible for the adverse effects of biodegradable polymers, although the local tissue tolerance and the local clearing capacity seem to be important aspects as well (67;100;116;117). The rate of crystalline remnants and decrease of pH are partly determined by the molecular structure of the biomaterial (118). Amorphous polymers degrade faster than crystalline polymers, resulting in a rapid decrease of the pH. Crystalline polymers may remain in situ for decades (92). A high blood flow rate is an essential prerequisite for successful implantation of biodegradable fixation materials, since adequate blood flow secures sufficient removal of degradation products preventing a decrease in pH (114). PDLLA implants enriched with calcium phosphates have been investigated in rats to prevent a local decrease in pH (119). The control group received pure PDLLA implants. The PDLLA implants enriched with calcium phosphates showed an increased tissue response after 72 weeks. The authors concluded that the ‘enriched’ implants are not suitable for clinical use. Clinical aspects The major objective of this systematic review was to evaluate the clinical efficacy and safety of biodegradable osteofixation devices in comparison with titanium osteofixation devices used in oral and maxillofacial surgery. Unfortunately, we cannot draw any firm conclusions regarding the fixation of traumatically fractured bone segments, owing to the lack of controlled clinical trials. Studies using two randomized treatment groups are difficult to design and not (yet) available. Regarding the fixation of bone segments in orthognathic surgery, only a few controlled clinical studies (2-4) are available. There does not appear to be a significant difference in outcome between titanium and biodegradable fixation systems. Definite conclusions regarding the long-term performance of biodegradable fixation devices used in maxillofacial surgery cannot be drawn.

CHAPTER 2

reveal a significant difference. The number of symptomatic joints in the titanium group was significantly less compared to the PLLA group. General clinical aspects (infection, wound dehiscence, plate exposure and palpability of plates and screws) are objectively assessed in two included studies (2;4). The inflammatory responses gradually decreased with time. The first study (2) reported wound dehiscence in 1 patient in the biodegradable group whereas the second study (4) revealed wound dehiscence in 3 patients in the titanium group (10%) and in 2 patients in the biodegradable group (6.7%). No complications occurred as result of the dehiscence. The palpability of biodegradable plates and screws decreased with time in both studies, while the palpability of titanium plates and screws increased. In the study of Cheung et al. (4), plate exposure affected 1.02% and 1.21% of the patients in the titanium group and biodegradable group respectively whereas Norholt et al. (2) discussed one patient in the biodegradable group with plate exposure (4.2%). One included study (4) reported the removal of 3 titanium (1.53%) and 6 (3.36%) biodegradable plates (as a percentage of all plates and screws used). Ferreti et al. (3) reported briefly the clinical appearance of the surgical ‘sites’. They appeared to be abnormal with respect to the evaluation criteria (swelling, discharge, pain, or discoloration of the mucosa and skin) during the post-operative 12 months. The general characteristics, results and conclusions of the included studies are summarized in Table III.

suggested that it could be caused by the ongoing degradation of the plates and screws. The known causes of infection are loosened screws and wound dehiscence (4). In one of the included trials, the authors (4) report the infection percentages in terms of individual plates (1.53% in the titanium group and 1.82% in the biodegradable group) and in terms of individual patients (10% in each group). In the discussion, the authors advocate that it is more reasonable to use the plate and screw as the unit for calculation, because an infection will occur if any single component fails. However, in our opinion it is more reasonable to use the individual patient infection-percentages to calculate the percentage of infection. After all, infection percentages in terms of individual patients will gain more insight in the extent of actual re-operating procedures. Moreover, cost-effectiveness analyses are more meaningful using infection percentages in terms of individual patients. However, cost-effectiveness analysis regarding the use of biodegradable fracture fixation devices were not reported in any of the included trials (2-5).

SUMMARIZING AND CONCLUDING REMARKS The implications for the clinical applicability of biodegradable osteofixation systems on the long-term remain inconclusive. There is evidence available from randomized controlled trials to support the conclusion that there is no significant difference between biodegradable and titanium osteofixation devices with regard to short-term clinical outcome, complication rate and infections in the area of orthognathic surgery. Reoperation rates do not significantly differ in the biodegradable and titanium group. A sufficient follow up (of at least 5 years) is necessary in order to draw decisive conclusions regarding the use of biodegradable implants in oral and maxillofacial surgery. Until then, we can conclude that decisions with respect to plate and screw size, number of plates and screws, and biodegradable or titanium must be made on individually relevant aspects. Relevant factors include the nature of the injury, technical considerations, and the experience of the surgeon. Since this systematic review has some implications for future research, there is an urgent need for sufficiently powered, high quality and appropriately reported randomized controlled trials with respect to biodegradable osteofixation devices versus nondegradable osteofixation devices for well-defined maxillofacial fractures and osteotomies. Future studies should include a cost-effectiveness analysis in which hospital admission costs, surgical costs (material), and the costs associated with sick leave of the patients should be analyzed. Acknowledgments The authors thank Ms. S van der Werf from the Groningen University medical library for her assistance in the elaboration of the search strategy. The authors also thank Ms. S. Shaw for correcting the American English language.

CHAPTER 2

The methodologically ‘acceptable’ studies contain much heterogeneity. The studies individually defined the outcome measures for stability and morbidity. Moreover, the treatment modalities performed in these studies were different (Le Fort I, sagittal split osteotomies and various osteotomies). The biodegradable fixation system (LactoSorb) used, was similar in only 2 studies (2;3). Because of the heterogeneity, pooling of outcome measures was not meaningful. A primary way to establish whether a fixation system has functioned successfully is to assess the extent of clinical mobility. However, objective mobility measurements in the maxillofacial skeleton are difficult to perform. One study reports the stability according to a nominal scale: none-, slight- and gross mobility (2) while another study reports the mobility according to a binary scale: immobility versus mobility (4). One methodologically ‘acceptable’ study did not even report the extent of mobility (3). In our opinion, it is essential to report the extent of mobility when investigating the clinical efficacy and safety of biodegradable osteofixation systems. Therefore, we advise the use of a binary scale. The aim of an osteofixation device is to achieve functional, pain-free re-union within a reasonable period of time (6 weeks) (120). Compromised healing or slight mobility after 6 weeks should be defined as non-union. The most recent study (5) applied postoperative inter-maxillary fixation (IMF) for 2 weeks to prevent adverse alterations of the post-operative occlusion. The authors did not know whether the PLLA plates were strong enough to stabilize the bone segments. Today, IMF is not the state of art and thus, in our opinion, improper to apply when comparing the skeletal stability of bilateral sagittal split osteotomies fixed with titanium or PLLA plates. One of the major drawbacks of the reviewed literature is the lack of sufficient follow-up. Three of the included studies (2;3;5) followed their patients only 1 year post-operatively. Another included recent study (4) followed a few of their patients for 2 years (6 out of the titanium group and 7 out of the biodegradable group) and 24 patients in both groups were evaluated for 1 year. In our opinion, the follow up periods are too short to draw definite conclusions as to whether these biodegradable implants could serve as a safe and reliable fixation method on the long term. Many authors (60;70;86) have reported patient series with longer follow up periods. As mentioned earlier, since these patient series lack a control group, an adequate comparison with titanium fixation devices has not been made in these studies. Future clinical trials should, from a biocompatibility and resorption point of view, evaluate patients for at least 5 years as mentioned in the previous section (4.2). The onset of infections seems to differ for fixation of fractures with titanium or biodegradable devices. One included study (4) reported that the infections in the biodegradable group were diagnosed after 6 weeks, 3 months, and 6 months, while those in the titanium group were diagnosed after 2 weeks, 6 weeks, and 3 months. Another included study (2) reported that 1 infection in the titanium group was diagnosed after 1 week, whereas 2 infections in the biodegradable group were diagnosed after 6 months. These clinical findings suggest that the onset of infections tend to occur later in the biodegradable groups. The authors could not explain this tendency, although one (2)

CHAPTER 3.1

TORSION STRENGTH OF BIODEGRADABLE AND TITANIUM SCREW SYSTEMS: A COMPARISON

G.J. BUIJS E.B. VAN DER HOUWEN B. STEGENGA R.R.M. BOS G.J. VERKERKE

Published in: J Oral Maxillofac Surg. 2007 Nov;65(11):2142-7.

Abstract: Objectives- To determine: (1) the differences in maximum torque between 7 biodegradable and 2 titanium screw systems, and (2) the differences of maximum torque between ‘hand tight’ and break of the biodegradable and the titanium osteofixation screw systems. Materials & Methods- Four oral and maxillofacial surgeons inserted 8 specimens of all 9 screw systems in polymethylmethacrylate (PMMA) plates. The surgeons were instructed to insert the screws as they would do in the clinic (‘hand tight’). The data were recorded by a torque measurement meter. A PhD resident inserted 8 specimens of the same set of 9 screw systems until fracture occurred. The maximum applied torque was recorded likewise. Results- (1) the mean maximum torque of the 2 titanium screw systems was significantly higher than that of the 7 biodegradable screw systems, and (2) the mean maximum torque for ‘hand tight’ was significantly lower than for break regarding 2 biodegradable, and both titanium screw systems. Conclusion & discussion- Based on the results, we conclude that the 1.5- and 2.0 mm titanium screw systems still present the highest torque strength compared to the biodegradable screw systems. When there is an intention to use biodegradable screws, we recommend the use of 2.0 mm BioSorb FX, 2.0 mm LactoSorb or the larger 2.5 mm Inion CPS screws. Keywords: screw; osteofixation; biodegradable; titanium; torsion strength; properties.

Background Fast, anatomical and pain-free re-union of bone fragments are the essential goals in orthognathic and trauma surgery (84). Adequate reposition, stabilization and fixation of fractured or osteotomized bone segments are essential preconditions (7;121). Plates and screws are generally used for the internal stabilization and fixation of the bone segments (35;36). Screws are used to fix osteofixation plates or to position bone segments (e.g. sagittal split osteotomies) (3). During insertion, the screws occasionally break (4). Fracture of a screw occurs when the applied torque is higher than the maximum allowable torque of the screw. Removal of broken screws and re-application of screws is expensive and timeconsuming. Besides, additional operations may result in complications and subsequent compromised bone healing. It is generally acknowledged that biodegradable screws have different torsion characteristics than titanium screws. Some clinical studies reported a higher number of broken biodegradable screws compared to titanium screws (2;4). Several authors have reported this experience as a considerable disadvantage (40;111;112). The maximum torque strength differs for the various screws mainly because of the use of different materials for manufacturing (biodegradable) screws, and different geometry of those screws. The manufacturers do not specify the torque for inserting the screws. The torque to be applied for adequate tightening the screws can be defined as ‘hand tight’. The maximally applied torque is, to some extent, controlled by the construction of the screwdriver handles (diameter, hand posture, geometry, and texture). But with most handles, the maximum torque that can be applied exceeds the torque strength of the screws, so fracture of the screws might occur. An estimate of a safe torque for screws of different diameter and length is difficult, especially for biodegradable screws (82). Moreover, many surgeons are not that experienced in using polymeric screws. To guide decisions regarding the selection and application of different osteofixation screws, clarification of the differences in torque strength of biodegradable as well as titanium osteofixation screw systems could be valuable (122). Objectives The objectives of this study were to determine: (1) the differences in maximum torque between 7 biodegradable and 2 titanium screw systems, and (2) the differences in maximum torque between ‘hand tight’ and break of the biodegradable as well as the titanium screw systems.

MATERIALS AND METHODS Seven (5 x 2.0-mm, 1 x 2.1-mm, and 1 x 2.5-mm) commercially available biodegradable as well as two (1.5- and 2.0-mm) commercially available titanium screw systems were

CHAPTER 3.1

INTRODUCTION

 = Length of screws (according the specifications of the manufacturers) Ø = Diameter of screws (according the specifications of the manufacturers) * = Polymer composition not specified through the manufacturer

RESULTS The mean maximum torque and standard deviation of the 9 osteofixation screws systems for ‘hand tight’ are graphically plotted in figure 1. The mean maximum torque of the biodegradable systems was significantly lower compared to the mean maximum torque of both titanium systems (table II). The standard deviations of the titanium screw systems were considerable larger than those of the biodegradable screw systems. Figure 2 represents the mean maximum torque of the 9 osteofixation screw systems at break. The standard deviations of the titanium systems showed in figure 2, were lower than those of the biodegradable systems, especially when compared to the results showed in figure 1. The plot of the 2.0-mm titanium screw system did not show a standard deviation because the torque for

Statistical analysis The data were analyzed using the Statistical Package of Social Sciences (SPSS), version 14.0. Descriptive statistics was used to calculate means and standard deviation. The measured maximum torque of the 32 different specimens (8 specimen times four surgeons) of each screw system were averaged. To determine whether there were significant differences between the biodegradable and the titanium osteofixation screw systems, the mean maximum torques were subjected to a One-Way ANalysis Of VAriance (ANOVA). A correction for multiple testing was performed according to Dunnet T3 (equal variances not assumed). The differences between maximum torque of ‘hand tight’ and break of the various screw systems were statistically compared with Student’s t-tests. Differences were considered to be significant when p < 0.05 for all tests.

CHAPTER 3.1

6.0 mm

KLS Martin

Sterile Titanium (pure) Gebrüder Martin GmbH & Co. (Tuttlingen, Germany)

1.5 mm Titanium (pure) Gebrüder Martin GmbH & Co. (Tuttlingen, Germany)

KLS Martin

Titanium screws

Sterile

Expired 70L/30DL PLA

MacroPore

MacroPore BioSurgery Inc. (Memphis, USA)

2.0 mm

6.0 mm

6.0 mm 2.0 mm

6.0 mm Sterile

Polymax

Mathys Medical Ltd. (Bettlach Switzerland)

70L/30DL PLA

2.0 mm

7.0 mm Sterile

LactoSorb

Walter Lorenz Surgical Inc. (Jacksonville, Florida)

82 PLLA/18 PGA

2.0 mm

7.0 mm Sterile

Inion CPS 2.5

Inion Ltd. (Tampere, Finland)

LDL Lactide/TMC*

2.5 mm

7.0 mm Sterile

Inion CPS 2.0

Inion Ltd. (Tampere, Finland)

LDL Lactide/TMC*

2.0 mm

7.0 mm Sterile 100 DL-Lactide

Resorb X

Gebrüder Martin GmbH & Co. (Tuttlingen, Germany )

2.0 mm Sterile SR 70L/30DL PLA

Biodegradable screws

BioSorb FX

Linvatec Biomaterials Ltd. (Tampere, Finland)

2.1 mm

6.0 mm

Screw * Screw #Ø Sterility Composition Manufacturer (city and state) Brand name

Table I. Characteristics of included osteofixation screws

CHAPTER 3.1

investigated. The biodegradable and titanium implants were gratuitously supplied by the manufacturers. The manufacturers, with one exception (MacroPore BioSurgery Inc.), supplied sterile implants. The Macropore implants exceeded the expiry date by 6-12 months. Nevertheless, we decided to include these implants in the tests. The general characteristics of the investigated screw systems are summarized in table I. Four oral and maxillofacial surgeons were requested to insert 8 specimens of all 9 screw systems in polymethylmethacrylate (PMMA) plates. The holes were predrilled for both the titanium as for the biodegradable screws and subsequently pre-tapped (as prescribed) for the biodegradable screws according to the prescriptions of the individual manufacturers (with prescribed burs and taps). The surgeons were instructed to insert the screws as they would do in the clinic (‘hand tight’). A PhD resident inserted 8 specimens of the same set of 9 screw systems until fracture occurred. The screws were inserted at room temperature, as this is the regular operating room temperature. Before insertion of the screws, the holes were irrigated with physiological fluid to simulate the in situ lubrication. The maximally applied torque was recorded by a torque measurement meter (Nemesis Howards Torque Gauge, Smart MT-TH 50 sensor; accuracy 2.5 mNm, range 0-500 mNm; supplied by Hartech, Wormerveer, The Netherlands).

Mean maximum torque (mNm)

Degradable Non degradable

600.0

500.0

400.0

300.0

200.0

100.0

0.0

ta ni um

0 2.

5 1.

1 2.

Figure 3. Mean maximum torque of four surgeons organized by method and surgeon Mean maximum torque of four surgeons

Degradability Degradable Non degradable

400.0

300.0

200.0

100.0

0.0

Chirurg

600.0

Mean maximum torque (mNm)

500.0

Surgeon 1 Surgeon 2 500.0

Surgeon 3 Surgeon 4

400.0

300.0

200.0

100.0

0.0

ta ni

0 2.

5 1.

1 2.

m m

0 2.

5 2.

0 2.

M or

0 2.

S CP

0 2.

5 1.

1 2.

S CP

0 2.

b m

5 2.

0 2.

S CP

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = maximum torque measured during insertion Points in figure: represents mean maximum torque Bars: represents the standard deviation of the mean maximum torque

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = maximum torque measured during insertion Points in figure: represents mean maximum torque Surgeons: represents the four surgeons who inserted the screws

CHAPTER 3.1

0 2.

M or

5 2.

0 2.

5 2.

S CP

In b

Method: Hand tight

Mean maximum torque (mNm)

Degradability

700.0

CHAPTER 3.1

Method: Break

Figure 1. Mean maximum torque regarding method ‘Handtight’ organized by screw system

Figure 2. Mean maximum torque regarding method ‘Break’ organized by screw system

breaking the screws exceeded the maximum limit of the torque measurement apparatus. The mean maximum torque was set at 680 mNm (as measured by the torque measurement apparatus, however not with the accuracy of 2.5 mNm). The mean maximum torque of both titanium screw systems were significantly higher than the 7 different biodegradable screw systems. With respect to the 7 biodegradable screw system, the Inion CPS 2.5 screw system represented a significantly higher torque than the other biodegradable systems for the method ‘handtight’. Regarding the method break, the mean maximum torque of the BioSorb FX, Inion CPS 2.5 and LactoSorb screw systems were significantly higher than the four remaining biodegradable screw systems. Different comparisons regarding significant differences of the various screw systems for ‘hand tight’ and break are outlined in table II. Figure 3 represents the mean maximum torque of the screw systems organized by surgeon and screw system. The surgeons showed a wider distribution of the mean maximum torque of the titanium screw systems compared to the biodegradable screw systems. This corresponds to the large standard deviations for ‘hand tight’ presented in figure 1. Table III presents a summary of the descriptive statistics. The mean, standard deviation, 95% confidence interval, and the range are presented and organized by method. Table III revealed that for each screw system, the mean maximum torque at break was above the mean maximum torque at ‘hand tight’. A statistical comparison of the mean maximum torque of ‘hand tight’ and break for the LactoSorb, Inion CPS 2.5, titanium 1.5 mm, and titanium 2.0 mm screw systems revealed that the mean maximum torques for break were significantly higher than the mean maximum torque for ‘hand tight’ (diagonal of Table II).

42 43

NS S NS S S S S S

Inion CPS 2.0 mm Inion CPS 2.5 mm LactoSorb 2.0 mm Macropore 2.0 mm Polymax 2.0 mm Resorb X 2.1 mm Titanium 1.5 mm Titanium 2.0 mm

366.60

Titanium 1.5 mm Titanium 2.0 mm

85.08 181.34 188.80 77.19 89.48 72.86 396.48 680.00

Inion CPS 2.0 mm Inion CPS 2.5 mm LactoSorb 2.0 mm Macropore 2.0 mm Polymax 2.0 mm Resorb X 2.1 mm Titanium 1.5 mm Titanium 2.0 mm SD = Standard Deviation *in mNm

192.20

BioSorb FX 2.0 mm

0.00

9.01

11.85

8.92

5.05

15.74

5.49

14.18 12.29

Mean*

SD*

122.11

89.10

11.47

14.30

10.23

System

Method = Break

55.40 246.90

Resorb X 2.1 mm

61.60 56.70

LactoSorb 2.0 mm Polymax 2.0 mm

96.90

Inion CPS 2.5 mm Macropore 2.0 mm

17.98 23.51

12.22

73.42 156.85

23.41

SD*

Inion CPS 2.0 mm

80.23

Mean*

BioSorb FX 2.0 mm

System

Method = ‘Hand tight’

Inion CPS 2.5 mm

Table III. Summary of descriptive statistics

Inion CPS 2.0 mm

Method = ‘Hand tight’ Method = Break Diagonal = ‘Hand tight’ versus Break S = Significant NS = Non Significant

BioSorb FX 2.0 mm

System

Polymax 2.0 mm

377.18

27.48

65.98

67.26

72.23

107.48

167.44

84.01

90.81

672.72

389.19

65.58

82.19

69.90

181.47

174.09

77.79

184.92

Lower Bound*

687.28

403.76

80.15

96.76

84.47

196.03

188.66

92.36

199.48

Upper Bound*

95% Confidence Interval

356.01

236.30

44.81

46.08

51.06

86.31

146.27

62.84

69.64

Upper Bound*

95% Confidence Interval

Macropore 2.0 mm

Lower Bound*

LactoSorb 2.0 mm

Table II. Statistical differences between osteofixation screws

680.00

388.20

58.00

71.80

69.60

160.10

173.8

63.00

175.40

611.00

379.70

69.80

89.30

83.40

139.30

182.5

94.20

132.40

680.00

416.30

96.80

98.90

83.80

216.00

189.2

104.20

210.50

Highest value*

Range Lowest value*

194.20

94.40

27.80

30.10

35.70

62.80

105.00

37.30

38.10

Titanium 2.0 mm

Highest value*

Range

Titanium 1.5 mm

Lowest value*

Resorb X 2.1 mm

The differences in maximum torque found for the studied systems can be explained by the different screw diameters (1.5-, 2.0-, 2.1- and 2.5 mm), different (co-polymer) compositions, different geometry (pitch and shaft) of the screws, different tools used to insert the screws, different ages of the screws, and different methods to sterilize the screws. As expected, the use of titanium for manufacturing osteofixation screws revealed a high maximum torque strength whereas the use of polymers revealed a significantly lower torque strength. A surprising finding was the significant mean maximum torque difference of the BioSorb FX, Inion CPS 2.5 and LactoSorb screw systems compared to the remaining four biodegradable screw systems for the method break. The self-reinforced polymers of the BioSorb FX screw system, the larger dimensions of the 2.5 mm Inion CPS screws, and the ponderous geometry of the LactoSorb screws are probably responsible for the high maximum torque. The large standard deviations of the 2 titanium screw systems presented in figure 1 are probably caused by the higher maximum torque. After all, when surgeons apply higher torque forces, this inevitably implies loss of accuracy. The comparison of the maximum torque of ‘hand tight’ and break for the individual screw systems revealed statistically significant differences for 4 (LactoSorb, Inion CPS 2.5, titanium 1.5 mm, and titanium 2.0 mm) of the 9 osteofixation screw systems (diagonal Table II). In the case of individual biodegradable screws (Inion CPS 2.0 mm, Inion CPS 2.5 mm, Macropore 2.0 mm, and Resorb X 2.1 mm), the lowest torque at break was not always above the highest torque of ‘hand tight’. Besides, the 95% confidence intervals of the maximum torque with respect to break and ‘hand tight’ of biodegradable screws did overlap (Table III). These two aspects indicate that the torsion characteristics of biodegradable screws are not always that repeatable. For analyzing the results, the data of the four surgeons have been combined in order to reduce the influence of outliers and to determine statistical significant differences. The results of the independent surgeons are graphically presented in figure 3. Note the large differences in mean maximum torque regarding the 2 titanium systems compared to the 7 biodegradable systems. Statistical analysis yielded no significant differences between most surgeons except for two surgeons. This is largely due to the statistical influence of the large differences in mean maximum torque for titanium screws. Despite the significant difference between the two surgeons, the data were combined. After all, combining the results of the four surgeons should be allowed because the insertion torque of screws of maxillofacial surgeons should be approximately equal. Investigating 7 different biodegradable screws theoretically implies 7 learning curves, as is the case with every new technique (64;123;124). These learning curves could influence the results and consequent statistically significant differences. To find out whether the learning curves affected the results, the screw 1- and 2- data have been deleted for every surgeon and system. The raw data were then analyzed (6 instead of 8 screws) again.

Eliminating the first 2 screws did not reveal different statistically (significant) results between the osteofixation screw systems. Statistically significant differences do not necessarily imply differences to be clinically relevant. With respect to the investigated osteosynthesis screws in this study, it is questionable whether the statistically significant differences are clinically relevant. The large significant differences between titanium screws and biodegradable screws in mean maximum torque are clinically relevant, although the field of application may be different. In contrast, the statistically significant differences between some of the 7 biodegradable devices regarding the method ‘hand tight’ are not clinically relevant, because they are considered to be too small. Moreover, it has been reported that biodegradable devices physically relax under constant force (a process called creep). In this case, the applied torque is ‘counteracted’ by the reorganizing polymer chains (111). Titanium screws do not undergo this material relaxation. The significant differences between some of the 7 biodegradable devices for the method break are of clinical importance, because biodegradable screws can fracture easily during insertion. The significant differences of maximum torque for ‘hand tight’ and break of 2 biodegradable (Inion CPS 2.5, and LactoSorb) as well as both titanium screw systems presented in the current study are clinically relevant. After all, screws will break easily during insertion, when the differences between ‘hand tight’ and break are small. The objectives of this investigation were to determine: (1) the differences in mean maximum torque between 7 biodegradable and 2 titanium screw systems, and (2) the differences of mean maximum torque between ‘hand tight’ and break of the biodegradable as well as the titanium osteofixation screw systems. This study has presented that: (1) the mean maximum torque of titanium screw systems was significantly higher than of the biodegradable screw systems, and (2) the mean maximum torque of all 9 screw systems at break was (significantly) higher than at ‘hand tight’. Based on the results and discussion points mentioned above, we can conclude that the 1.5- and 2.0 mm titanium screw systems still present the highest torque strength compared to the biodegradable screw systems. When there is an intention to use biodegradable screws, we would recommend the use of 2.0 mm BioSorb FX, 2.0 mm LactoSorb or the larger 2.5 mm Inion CPS screws. Acknowledgements We would like to thank, prof. dr. G.M. Raghoebar, dr. F.K.L. Spijkervet and dr. J. Jansma for inserting the osteofixation screws. The authors also would like to thank dr. H. Groen and dr. M.M. Span for their statistical assistance. The gratuitously supply of biodegradable screws through the manufacturers (Linvatec Biomaterials Ltd., KLS Martin, Inion Ltd., Walter Lorenz Surgical Inc., Synthes, and Macropore Inc.) was gratefully appreciated.

CHAPTER 3.1

DISCUSSION

CHAPTER 3.2.1

MECHANICAL STRENGTH AND STIFFNESS OF BIODEGRADABLE AND TITANIUM OSTEOFIXATION SYSTEMS

G.J. BUIJS E.B. VAN DER HOUWEN B. STEGENGA R.R.M. BOS G.J. VERKERKE

Published in: J Oral Maxillofac Surg. 2007 Nov;65(11):2148-58.

Abstract: Objective - The objective of this study was to present relevant mechanical data in order to simplify the selection of an osteofixation system for situations requiring immobilization in oral and maxillofacial surgery. Materials & Methods - 7 biodegradable and 2 titanium osteofixation systems were investigated. The plates and screws were fixed to 2 polymethylmethacrylate (PMMA) blocks to simulate bone segments. The plates and screws were subjected to tensile, side bending, and torsion tests. During tensile tests, the strength of the osteofixation system was monitored. The stiffness was calculated for the tensile, side bending, and torsion tests. Results - The two titanium systems (1.5 mm and 2.0 mm) presented significantly higher tensile strength and stiffness compared to the 7 biodegradable systems (2.0 mm, 2.1 mm, and 2.5 mm). The 2.0 mm titanium system revealed significantly higher side bending and torsion stiffness than the other 7 systems. Conclusion & discussion - Based on the results of the current study, it can be concluded that the titanium osteofixation systems were (significantly) stronger and stiffer than the biodegradable systems. The BioSorb FX, LactoSorb, and Inion CPS 2.5 mm systems have high mechanical device strength and stiffness compared to the investigated biodegradable osteofixation systems. With the cross-sectional surface taken into account, the BioSorb FX system (with its subtle design), proves to be the far more superior system. The Resorb X and MacroPore systems present to be, at least from a mechanical point of view, the least strong and stiff systems in the test. Key words: osteofixation system; biodegradable; titanium; mechanical; strength; stiffness; properties.

Background Sufficient revascularization, anatomical reduction, and proper immobilization of bone segments are essential aspects of the healing of fractures and osteotomies (7;10). Immobilization of bone fragments is currently obtained by the use of osteofixation plates and screws (125;126). The plates and screws are applied subperiostally in order to secure sufficient revascularization (7). These fixation devices must withstand the local deforming forces that are exerted through the maxillofacial muscles. Currently, titanium fixation systems are successfully used to realize adequate immobilization (39). These systems, however, have several disadvantages: (1) the need for a second intervention to remove the devices, if indicated (46-48), (2) interference with imaging or radio-therapeutic techniques (37;41;127), (3) possible growth disturbance or mutagenic effects (37;41;43-45), (4) brain damage (44;128), (5) and thermal sensitivity (129). Biodegradable ‘dissolving’ fixation systems could reduce the problems associated with titanium systems (74). However, these systems are mechanically weaker than titanium systems due to the use of biodegradable polymers. Moreover, adverse reactions to the degradation products have been reported (66;67;100;114). Despite these disadvantages, there is a continuous drive to explore fixation devices which will ‘dissolve’ when bone healing has been occurred (4). In order to investigate whether biodegradable systems are proper alternatives for titanium systems, they have been the subject of research for decades (58). Nevertheless, the mechanical properties of biodegradable systems have hardly been objectively compared in the scientific literature. In addition, many biodegradable fixation systems with a great variety in dimensions and co-polymer compositions are commercially available. As a result, the mechanical characteristics differ substantially, which consequently hampers surgeons to select an adequate fixation system for a specific situation (82). Determining the different mechanical properties of titanium and biodegradable osteofixation systems could support the procedure of finding the right fixation system for the right situation (122). Objectives The objective of this study was to present relevant mechanical data in order to simplify the selection of an osteofixation system for situations requiring immobilization in oral and maxillofacial surgery.

MATERIALS AND METHODS The specimens to be investigated were 7 commercially available biodegradable (5 x 2.0 mm, 1 x 2.1 mm, and 1 x 2.5 mm) and 2 commonly used commercially available titanium (1.5 mm and 2.0 mm) osteofixation systems. The general characteristics of the included plates and screws are summarized in table I.

CHAPTER 3.2.1

INTRODUCTION

* = according the specifications of the manufacturers.

Sterile Titanium (pure) Gebrüder Martin GmbH & Co. (Tuttlingen, Germany)

KLS Martin

Figure 1. Tensile test set-up

CHAPTER 3.2.1

1.0 mm 5.0 mm 25.5 mm 6.0 mm

18.5 mm 6.0 mm 1.5 mm Sterile Titanium (pure) Gebrüder Martin GmbH & Co. (Tuttlingen, Germany)

KLS Martin

Titanium systems

Expired 70L/30DL PLA MacroPore BioSurgery Inc. (Memphis, USA)

MacroPore

2.0 mm

0.6 mm 3.5 mm

1.2 mm 6.7 mm 25.0 mm 6.0 mm

Sterile 70L/30DL PLA Mathys Medical Ltd. (Bettlach Switzerland)

Polymax

2.0 mm

1.3 mm 6.0 mm 28.0 mm 6.0 mm

Sterile 82 PLLA 18 PGA Walter Lorenz Surgical Inc. (Jacksonville, Florida)

LactoSorb

2.0 mm

1.3 mm 7.0 mm 28.5 mm 7.0 mm

Sterile LDL Lactide/TMC/PGA Inion Ltd. (Tampere, Finland)

Inion CPS 2.5 mm

2.0 mm

1.6 mm

1.3 mm 7.0 mm

8.5 mm 32.0 mm

28.0 mm 7.0 mm

6.0 mm

Sterile LDL Lactide/TMC/PGA Inion Ltd. (Tampere, Finland)

Inion CPS 2.0 mm

2.5 mm

Sterile 100 DL-Lactide Gebrüder Martin GmbH & Co. (Tuttlingen, Germany )

Resorb X

2.0 mm

1.1 mm 6.0 mm 26.0 mm 7.0 mm

25.5 mm 6.0 mm 2.0 mm Sterile SR 70L/30DL PLA

BioSorb FX

Biodegradable systems

Linvatec Biomaterials Ltd. (Tampere, Finland)

2.1 mm

5.5 mm

1.3 mm

Plate Plate Width* Thickness* Plate Length* Screw Screw Diameter* Length* Sterility Manufacturer (city and state) Brand name

Table I. Characteristics of included osteofixation systems

CHAPTER 3.2.1

Composition

The non-sterile titanium plates and screws were sterilized in our department in the usual manner. The manufacturers of the biodegradable systems supplied sterile implants, with the exception of the MacroPore implants of which the expiry date was passed (average 6-12 months). The plates under investigation were 4-hole extended plates. Eighteen plates and 72 screws of each system were subjected to three different mechanical tests. The osteofixation plates and screws were fixed to 2 polymethylmethacrylate (PMMA) blocks that simulated bone segments. There was no interfragmentary contact to simulate the most unfavourable clinical situation. Two screws were inserted in both PMMA blocks according to the prescriptions of the individual manufacturer (with prescribed burs and taps). The applied torque for inserting the screws was measured to check whether it was comparable to the clinically applied torque (‘hand tight’) defined in a previous study (130). The holes were irrigated with saline before insertion of the screws, to simulate the in situ lubrication. The two PMMA blocks, linked by the osteofixation device (1 plate and 4 screws) were restored in a water tank containing water of 37.2 degrees Celsius for 24 hours to simulate the relaxation of biodegradable screws at body temperature (111). The tests were performed in another tank containing water at the same temperature to simulate body temperature. Saline was not used because of possible corrosion of the test- and environment set-up. Omitting the use of saline was expected not to be of influence to the test results.

CHAPTER 3.2.1

The plates and screws were subjected to tensile, side bending, and torsion tests. The tensile test was performed as a standard loading test (figure 1). Side bending tests were performed to simulate an in vivo bi-lateral sagittal split osteotomy (BSSO) situation (figure 2). Torsion tests were performed to subject the osteofixation devices to high torque in order to simulate the most unfavourable situation (figure 3). The 2 PMMA blocks, linked by the osteofixation device, were mounted in a test machine (Zwick/Roell TC-FR2, 5TS. D09, 2.5kN Test machine. Force accuracy 0.2%, positioning accuracy 0.0001mm; Zwick/ Roell Nederland, Venlo, The Netherlands). Regarding the tensile tests, the 2 PMMA blocks and thus the osteofixation plate were subjected to a tensile force with a constant speed of 5 mm/min until fracture occurred (according to the standard ASTM D638M). For the side bending test the 2 PMMA blocks were supported at their ends whereas the plates were loaded in the centre of the construction with a constant speed of 30 mm/min (with this speed the outer fibers were loaded as fast as the fibers of the osteofixation system in the tensile test) until the plate was bended 30 degrees. For the torsion test the 2 PMMA blocks were twisted along the long axis of the osteofixation system with a constant speed of 90 degrees/min (with this speed the outer fibers were loaded as fast as the fibers of the osteofixation system in the tensile test) until the plate was turned 160 degrees. During testing the applied force was recorded by the load cell of the test machine. Both force and displacement were measured with a sample frequency of 500 hertz and graphically presented in force-displacement diagrams. During tensile tests, the strength of the osteofixation system was monitored. The stiffness was calculated for the tensile, side bending and torsion tests by linking the 25% and 75% points (to exclude inaccuracies of the start and end of the curves) of the maximum force on the force-displacement curves and determining the direction-coefficients of the curves.

Figure 3. Torsion test set-up

Statistical analysis Statistical Package of Social Sciences (SPSS, version 12.0) was used to analyze the data. Mean and standard deviation were calculated to describe the data. To determine whether there were significant differences between the biodegradable and the titanium osteofixation systems in (1) tensile strength and stiffness, (2) side bending stiffness, and (3) torsion stiffness, the maximum values were subjected to a One-Way ANalysis Of VAriance (ANOVA). A correction for multiple testing was performed according to Dunnet T3 (equal variances not assumed). Differences were considered to be significant when p < 0.05 for all tests.

RESULTS The torques used to insert the screws of the 9 osteofixation systems regarding the tensile, side bending, and torsion tests are outlined in table II. The mean torques as well as the standard deviations for each system in all three tests were nearly similar. The mean tensile strength and stiffness of the 9 osteofixation systems are graphically

CHAPTER 3.2.1

Figure 2. Side bending test set-up

Table II. Applied torque of inserted osteofixation screws System

Tensile

Method: Strength Tensile Test

Mean*

SD*

BioSorb FX

81.23

0.41

Inion CPS 2.0

74.29

0.31

Inion CPS 2.5

156.81

0.76

LactoSorb

97.96

0.48

MacroPore

62.42

0.47

Polymax

57.05

0.58

ResorbX

56.13

0.23

KLS 1.5

251.21

1.54

KLS 2.0

369.84

1.09

Side Bending

BioSorb FX

81.50

0.57

Inion CPS 2.0

74.40

0.54

Inion CPS 2.5

157.24

0.35

LactoSorb

97.63

0.32

MacroPore

62.17

0.75

Polymax

56.83

0.23

Figure 5. Mean tensile stiffness organized by system

ResorbX

55.90

0.26

Method: Stiffness Tensile Test

KLS 1.5

248.23

0.70

KLS 2.0

370.20

1.02

BioSorb FX

80.93

0.43

Inion CPS 2.0

74.50

0.83

Inion CPS 2.5

156.80

0.76

LactoSorb

97.88

0.56

MacroPore

62.21

0.45

Polymax

57.46

0.41

ResorbX

55.91

0.30

KLS 1.5

248.53

1.36

KLS 2.0

367.96

1.97

Degradability

800.0

Degradable Non degradable

Mean strength (N)

Test

Figure 4. Mean tensile strength organized by system

600.0

400.0

200.0

0.0

0 2.

5 1.

0 2.

CHAPTER 3.2.1

X m

0 2.

5 2.

Degradability

600.0

Degradable

Torsion

Non degradable

500.0

Mean Stiffnes (N/mm)

CHAPTER 3.2.1

M or

0 2.

S CP

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean strength in Newton’s Points in figure: represents mean strength Bars: represents the standard deviation of the mean strength

400.0

300.0

200.0

100.0

0.0

ta ni um

0 2.

5 1.

0 2.

*in mNm SD = Standard Deviation

Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean stiffness in Newton/mm Points in figure: represents mean stiffness Bars: represents the standard deviation of the mean stiffness

0 2.

5 2.

0 2.

M or

0 2.

S CP

System

XXXX

Titanium 2.0 mm

Table IV. Summary of descriptive statistics tensile test Tensile strength System

Mean^

95% Confidence Interval

SD^

S S S

XXXX S S

S XXXX S

S S S

NS S S

S S XXXX NS S NS

S NS NS XXXX S NS

S S S S XXXX S

S S S S S XXXX

162.00

3.18

155.16

168.85

Inion CPS 2.0 mm

101.98

5.11

95.13

108.82

Inion CPS 2.5 mm

219.82

13.43

212.98

226.67

LactoSorb 2.0 mm

175.17

2.40

168.33

182.02

MacroPore 2.0 mm

65.07

16.92

58.23

71.92

Polymax 2.0 mm

89.68

5.52

82.84

96.53

Resorb X 2.1 mm

59.87

4.73

53.02

66.71

Titanium 1.5 mm

266.71

6.74

259.86

273.55

Titanium 2.0 mm

741.21

4.08

734.36

748.05

System

Mean*

SD*

95% Confidence Interval

BioSorb FX 2.0 mm

248.00

24.28

Inion CPS 2.0 mm

87.56

Inion CPS 2.5 mm

79.52

LactoSorb 2.0 mm MacroPore 2.0 mm Polymax 2.0 mm

Lower Bound*

Upper Bound*

235.57

260.43

11.66

75.12

99.99

3.74

67.09

91.95

203.78

4.82

191.34

216.21

52.87

16.57

40.44

65.31

80.08

5.74

67.65

92.51

Resorb X 2.1 mm

42.86

5.82

30.44

55.30

Titanium 1.5 mm

448.56

24.68

436.12

460.99

Titanium 2.0 mm

521.27

18.56

508.84

533.70

Underline = Tensile strength Italic = Tensile stiffness S = Significant NS = Non Significant

S Titanium 2.0 mm

S Titanium 1.5 mm

S Resorb X 2.1 mm

S Polymax 2.0 mm

S MacroPore 2.0 mm

NS LactoSorb 2.0 mm

S Inion CPS 2.5 mm

S S NS S S S S Inion CPS 2.0 mm

XXXX

S S S S S S XXXX BioSorb FX 2.0 mm

Inion CPS 2.5 mm

BioSorb FX 2.0 mm

^ in N *in N/mm SD = Standard Deviation

BioSorb FX 2.0 mm

Inion CPS 2.0 mm

Upper Bound^

Tensile stiffness

System

Table III. Significance between osteofixation systems

LactoSorb 2.0 mm

MacroPore 2.0 mm

CHAPTER 3.2.1

Polymax 2.0 mm

Resorb X 2.1 mm

Titanium 1.5 mm

Lower Bound^

presented in figure 4 and 5, respectively. The two titanium systems (1.5 mm and 2.0 mm) presented significantly higher tensile strength and stiffness compared to the biodegradable systems (2.0 mm, 2.1 mm, and 2.5 mm). Regarding the biodegradable systems, the BioSorb FX, Inion CPS 2.5 mm, and LactoSorb systems presented a significantly higher tensile strength whereas the BioSorb FX and LactoSorb systems presented a significantly higher tensile stiffness compared to the other biodegradable systems. The differences between the systems are outlined in table III. The standard deviations for the systems regarding the tensile strength and stiffness were small. A summary of the descriptive statistics is presented in table V.

Degradable

XXXX

Degradability

Method: Stiffness Side Bending Test

Titanium 2.0 mm

Figure 6. Mean side bending stiffness organized by system

XXXX

Titanium 1.5 mm

XXXX

2.00

Resorb X 2.1 mm

Mean Stiffnes (N/mm)

Non degradable 4.00

0.0

CHAPTER 3.2.1

S S S

S NS S

S S S

XXXX S S

S XXXX S

S S XXXX

S S NS

S S

MacroPore 2.0 mm LactoSorb 2.0 mm

Degradability

Mean: Stiffness Torsion Test

Figure 7. Mean torsion stiffness organized by system

0 2.

5 1.

0 2.

Polymax 2.0 mm

0 2.

5 2.

Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean stiffness in Newton/mm (deducted unit) Points in figure: represents mean stiffness Bars: represents the standard deviation of the mean stiffness

S CP

0 2.

5 2.

CHAPTER 3.2.1

S CP

System

Underline = Side bending stiffness Italic = Torsion stiffness S = Significant NS = Non Significant

S Titanium 2.0 mm

S S Titanium 1.5 mm

S S Resorb X 2.1 mm

S NS Polymax 2.0 mm

S S MacroPore 2.0 mm

S S

XXXX S

S XXXX

S S

Inion CPS 2.5 mm Inion CPS 2.0 mm

LactoSorb 2.0 mm

0 2.

5 1.

0 2. m

Inion CPS 2.5 mm

X m

0 2.

5 2.

Inion CPS 2.0 mm

S CP

0 2.

XXXX

S CP

System

BioSorb FX 2.0 mm

0.0

BioSorb FX 2.0 mm

2.00

System

Mean Stiffnes (N/mm)

Non degradable 4.00

Table V. Significance between osteofixation systems

Degradable

Side bending stiffness

Â System

Mean*

95% Confidence Interval

SD*

CHAPTER 3.2.1

Lower Bound*

Upper Bound*

BioSorb FX 2.0 mm

1.55

0.13

1.28

1.81

Inion CPS 2.0 mm

0.57

0.06

0.31

0.84

Inion CPS 2.5 mm

0.82

0.08

0.55

1.08

LactoSorb 2.0 mm

0.75

0.06

0.48

1.01

MacroPore 2.0 mm

0.24

0.02

-.03

0.50

Polymax 2.0 mm

0.37

0.04

0.11

0.64

Resorb X 2.1 mm

0.25

0.03

-0.02

0.52

Titanium 1.5 mm

1.64

0.81

1.37

1.90

Titanium 2.0 mm

4.33

0.50

4.07

4.60

Mean*

SD*

BioSorb FX 2.0 mm

0.96

0.10

Inion CPS 2.0 mm

0.67

Inion CPS 2.5 mm

2.36

LactoSorb 2.0 mm MacroPore 2.0 mm Polymax 2.0 mm Resorb X 2.1 mm

Torsion stiffness Â System

95% Confidence Interval Lower Bound*

Upper Bound*

0.80

1.12

0.05

0.52

0.84

0.12

2.20

2.53

0.56

0.04

0.40

0.73

1.27

0.14

1.10

1.43

0.86

0.08

0.70

1.02

0.32

0.04

0.16

0.48

Titanium 1.5 mm

1.34

0.08

1.18

1.50

Titanium 2.0 mm

4.17

0.54

4.00

4.33

*in N/mm SD = Standard Deviation

The mean side bending stiffness of the 9 osteofixation systems is plotted in figure 6. The 2.0 mm titanium system revealed significantly higher side bending stiffness compared to the other 8 systems. The 1.5 mm titanium and the BioSorb FX system presented a nearly similar mean side bending stiffness. The side bending stiffness of the BioSorb FX system was significantly higher compared to the other 6 biodegradable systems, whereas significance was not reached for the 1.5 mm titanium system mainly because of the large standard deviation of the mean of the 1.5 mm titanium system (see table IV). The nonsignificant results were additionally illustrated by the 95% confidence interval of the 1.5 mm titanium system which overlaps the interval of the BioSorb FX system. The standard

deviations of the biodegradable systems were small, while the 2.0 mm titanium system revealed a higher standard deviation too (in table VI). The mean torsion stiffness of the 9 osteofixation systems is graphically plotted in figure 7. As presented with the side bending stiffness, the torsion stiffness of the 2.0 mm titanium system was significantly higher compared to the remaining systems. The standard deviations of the biodegradable and 1.5 mm titanium systems were small, particularly compared to the standard deviation of the 2.0 mm titanium system. The mean torsion stiffness for the 1.5 mm titanium and 2.0 mm MacroPore system were nearly equal revealing non significance between these two systems. The Inion CPS 2.5 mm system presented by far the highest torsion stiffness of the biodegradable systems. Comparisons of the differences between the 9 osteofixation systems are outlined in table IV. Table VI presents a summary of the descriptive statistics of the side bending and torsion tests.

DISCUSSION The differences in strength and stiffness can be explained by many different factors, including dimension (1.5 mm, 2.0 mm, 2.1 mm, and 2.5 mm), (co-polymer) compositions, geometry of the plates and screws, ageing of the plates and screws, and methods to sterilize and manufacture the plates and screws. Due to the fact that the differences between the osteofixation systems are multi-factorial, it remains difficult to pose (a) specific reason(s). The maxillofacial muscles exert high forces in different directions (7). Consequently, it is difficult to simulate the in situ conditions in in vitro situations. To obtain clinical valuable information regarding the selection of an osteofixation system, the tensile strength and stiffness, side bending stiffness, and torsion stiffness were investigated as mentioned above. Adequate tensile strength and stiffness of an osteofixation system is essential for fixation of fractures and osteotomies. The osteofixation system is inevitably exposed to tensile forces when adequately repositioned bone segments are exposed to local deforming forces (22;23;44;131). The side bending test has been performed in order to simulate the bi-lateral sagittal split osteotomies (BSSO) of the mandible (132). The BSSO procedure is often performed in oral and maxillofacial surgery (35). The torsion test was used to simulate the torsion forces that are developed in the area between the two canine teeth when a median fracture of the mandible is present. These torsion forces, however, are predominantly counteracted by the interfragmentary fracture segments (133). A second argument to subject the osteofixation system to the torsion test, is that torsion forces are extraordinary destructive for osteofixation systems. During torsion of the PMMA blocks, they were prevented to move along the long axis of the system in order to additionally load the system to tensile forces. This simulates the most unfavourable in situ situation imaginable. Another important aspect of simulating the in situ situation was to test the system as it is used and applied in the clinic. The plates and screws were fixed with prescribed burs and taps. Fixing the plates with corresponding screws will provide more

CHAPTER 3.2.1

Table VI. Summary of descriptive statistics torsion and bending test

the biodegradable systems, whereas the differences between the biodegradable systems also revealed significance in most cases with regard to tensile strength as well as stiffness. Moreover, it showed that the side bending stiffness of the titanium 2.0 mm was significantly higher than the 8 remaining systems. The BioSorb FX revealed high side bending stiffness too in comparison to the other biodegradable systems, with both Resorb X and MacroPore at the lower side. Finally, this study has shown that the torsion stiffness of the titanium 2.0 mm system was high compared to the other systems. Based on the results of the current study, it can be concluded the BioSorb FX, Inion CPS 2.5 and LactoSorb systems represent the highest strength and stiffness’s amongst the investigated biodegradable osteofixation systems. With the cross-sectional surface taken into account, the BioSorb FX system (with its subtle design), proves to be the far more strong and stiff system. The Resorb X and MacroPore systems are, at least from a mechanical point of view, the least strong and stiff systems in the test. Acknowledgements The gratuitously supply of titanium as well as biodegradable plates and screws through the manufacturers (Linvatec Biomaterials Ltd., Gebrüder Martin GmbH & Co., Inion Ltd., Walter Lorenz Surgical Inc., Mathys Medical Ltd., and MacroPore BioSurgery Inc.) was gratefully appreciated. The authors also would like to thank dr. H. Groen for his statistical assistance. Mr. J. de Jonge is acknowledged for the fabrication of the test set-ups.

CHAPTER 3.2.1

clinical relevant information rather than fix the plates with metal screws (122). In this way, information on the entire system’s (device) mechanical characteristics was obtained. The stiffness was calculated in all three tests (tensile, side bending, and torsion), while the strength is reported in just one case (tensile test). The stiffness of an osteofixation system is a more clinically applicable characteristic (134). Contrary to the stiffness, the maximum strength will ‘only’ become relevant when the bone segments are separated more than a few millimeters which inherently results in compromised bone healing. Enlargement of the healing period is the result, and loosening of the screws and plates, or infection is possible (134). The stiffness was calculated from the raw data as described in the materials and methods section. Determining the 25% Fmax and 75% Fmax point as well as the corresponding displacement implies loss of accuracy due to the limited sample frequency (500 Hz.). This results in higher relative standard deviations when comparing the tensile strength. The small standard deviations regarding the tensile strength (predominantly the titanium systems), elucidate that the method of testing and the test hardware were properly designed regarding reproducibility. The high standard deviations concerning the stiffness of the titanium systems, however, in both the torsion (titanium 2.0 mm) and side bending (titanium 1.5 en 2.0 mm) tests, did not support that obviously the assumption of proper method and hardware design. The explanation for these phenomena could be the measurement imprecision mentioned above or the variety in mechanical properties of the specimens of each system. Conspicuous are the torsion and side bending stiffness of the 1.5 mm titanium system and 4 (BioSorb FX, Inion CPS 2.0, Inion CPS 2.5, and LactoSorb) of the biodegradable systems which were nearly in the same range of stiffness. This is most probably a result of the smaller dimensions of the 1.5 mm titanium system. Table IV reveals significant differences between the side bending stiffness of the biodegradable systems (caused by the small standard deviations) while the differences between the 1.5 mm titanium and the biodegradable systems were non significant. Titanium osteofixation systems were (significantly) stronger and stiffer than biodegradable systems. Despite the favourable mechanical properties of these systems compared to the biodegradable systems, the question arises whether the biodegradable systems pose adequate resistance to the local deforming forces in order to achieve adequate bone healing in patients (83). After all, the disappearance of a fixation system when bone union of the bone segments has been obtained, is still very appealing. The question mentioned above, can only be answered through well-designed randomized clinical trials which compare biodegradable and titanium osteofixation systems. The present study, however, provides well-funded information to help surgeons to select a mechanically potent bone fixation system for restoring, fixing, and stabilizing bone segments in specific situations in the maxillofacial area. The objective of this study was to present relevant mechanical data in order to simplify the selection of an osteofixation system for situations requiring immobilization in oral and maxillofacial surgery. This study has presented that the tensile strength and stiffness of both titanium systems were significantly higher than

CHAPTER 3.2.2

MECHANICAL STRENGTH AND STIFFNESS OF THE BIODEGRADABLE SONICWELD RX OSTEOFIXATION SYSTEM

G.J. BUIJS E.B. VAN DER HOUWEN B. STEGENGA R.R.M. BOS G.J. VERKERKE

Published in: J Oral Maxillofac Surg. 2009 Apr;67(4):782-7.

Abstract: Objective - To determine the mechanical strength and stiffness of the new 2.1 mm biodegradable ultra-sound activated SonicWeld Rx (Gebrüder Martin GmbH & Co., Tuttlingen, Germany) osteofixation system in comparison with the conventional 2.1 mm biodegradable Resorb X (Gebrüder Martin GmbH & Co., Tuttlingen, Germany) osteofixation system. Materials & Methods - The plates and screws were fixed to 2 polymethylmethacrylate (PMMA) blocks to simulate bone segments and were subjected to tensile, side bending, and torsion tests. During testing, force and displacement were recorded and graphically presented in force-displacement diagrams. For the tensile tests, the strength of the osteofixation system was measured. The stiffness was calculated for the tensile, side bending, and torsion tests. Results - The tensile strength and stiffness as well as the side bending stiffness of the SonicWeld Rx system presented up to 11.5 times higher mean values than the conventional Resorb X system. The torsion stiffness of both systems presents similar mean values and standard deviations. Conclusion & discussion - The SonicWeld Rx system is an improvement in the search for a mechanically strong and stiff as well as a biodegradable osteofixation system. Future research should be done in order to find out whether the promising in vitro results can be transferred to the in situ clinical situation. Key words: plate; screw; biodegradable; titanium; mechanical; strength; stiffness; properties; SonicWeld Rx. Abbreviations: PMMA, PolyMethylMethAcrylate; SPSS, Statistical Package of Social Sciences; BSSO, Bi-lateral Sagittal Split Osteotomy;

Background Biodegradable plates and screws are used increasingly in today’s oral and maxillofacial practice. These biodegradable plates and screws have several advantages over conventional titanium plates and screws. There is (1) no need for a second intervention to remove the devices (46-48), (2) no interference with imaging or radio-therapeutic techniques (37;41;127), (3) no possible growth disturbance or mutagenic effects (37;41;43-45), (4) no potential brain damage (44;128), (5) and no thermal sensitivity (129). However, the use of biodegradable plates and screws also has introduced several disadvantages. First, the boreholes need to be tapped before the screws can be inserted which is time-consuming. A second disadvantage could be that the biodegradable plates and screws represent inferior mechanical strength and stiffness compared with conventional titanium plates and screws (135). In order to resolve these disadvantages, a new biodegradable osteofixation system, SonicWeld Rx, has been developed. In contrast to conventional biodegradable osteofixation systems, tapping of the cortical bone layer is not necessary before inserting the SonicWeld Rx biodegradable pins. A biodegradable pin is simply placed onto an ultrasound activated sonic electrode, called a sonotrode, and inserted into the borehole. As a result of the added ultra-sound energy, the thermoplastic biodegradable pin will melt, resulting in a flow of biodegradable polymers into the cortical bone layer and the cavities of the cancellous bone. There is no cellular reaction due to thermal stress during insertion (136). At the same time the biodegradable plate and pinhead fuse. Theoretically, the fusion of plate and pinhead will result into superior mechanical device characteristics in comparison with conventional biodegradable osteofixation systems. This has been claimed as a second advantage. The mechanical strength and stiffness of 7 biodegradable as well as 2 titanium osteofixation systems have recently been investigated (135). One of these investigated biodegradable systems is the Resorb X biodegradable osteofixation system. The SonicWeld Rx and the Resorb X biodegradable osteofixation systems are made of the same co-polymer compositions and have the same device dimensions. These systems are supplied by the same manufacturer (Gebrüder Martin GmbH & Co. (Tuttlingen, Germany )). The question arises to what extent the biodegradable ultra-sound activated SonicWeld Rx osteofixation system presents superior mechanical strength and stiffness as compared with the conventional biodegradable Resorb X osteofixation system. Objectives The objective of this study was to determine the mechanical strength and stiffness of the biodegradable ultra-sound activated SonicWeld Rx osteofixation system in comparison with the conventional biodegradable Resorb X osteofixation system.

CHAPTER 3.2.2

INTRODUCTION

Figure 1. Tensile test set-up

The specimens to be investigated were 2 commercially available biodegradable osteofixation systems (i.e. 2.1 mm Resorb X and 2.1 mm ultra-sound activated SonicWeld Rx). All the specimens consisted of biodegradable amorphous poly-(50%D, 50%L) Lactide. The plates under investigation were 4-hole extended plates. The manufacturer (Gebrüder Martin GmbH & Co., Tuttlingen, Germany) supplied sterile implants. The general characteristics of the included plates and screws are summarized in table II. Eighteen plates and 72 screws/pins of each system were available to perform three different mechanical tests. The osteofixation plates and screws were fixed in 2 different ways to 2 polymethylmethacrylate (PMMA) blocks (with polished surface) that simulated bone segments. For the Resorb X osteofixation system, the screws were inserted in both PMMA blocks according to the prescriptions of the manufacturer (using prescribed burs and taps). The applied torque for inserting the screws was measured to check whether it was comparable to the clinically applied torque (‘hand tight’) defined in a previous study (130). For the SonicWeld Rx system, the biodegradable pins were inserted into the boreholes (after the use of prescribed burs) with the sonotrode. The biodegradable polymers melted due to the ultra-sound vibrations of the sonotrode. Subsequently, the biodegradable material flowed into the borehole and the pinhead fused with the biodegradable plate. In both situations, the boreholes were irrigated with saline before insertion of the screws/pins to simulate the in situ lubrication. The two PMMA blocks, linked by the osteofixation device (1 plate and 4 screws/pins) were stored in a water tank containing water of 37.2 degrees Celsius for 24 hours to simulate the relaxation of biodegradable screws/pins at body temperature (111). The tests were performed in another tank containing water at the same temperature to simulate physiological conditions. The use of saline was omitted because of the associated corrosion problems of the test set-up. Omitting the use of saline was expected not to be of influence to the test results. The plates and screws/pins were subjected to tensile, side bending, and torsion tests. The tensile test was performed as a standard loading test (figure 1). Side bending tests were performed to simulate an in vivo bi-lateral sagittal split osteotomy (BSSO) situation (figure 2). Torsion tests were performed to subject the osteofixation devices to high torque in order to simulate the most unfavourable situation (figure 3). The 2 PMMA blocks, linked by the osteofixation device, were mounted in a test machine (Zwick/Roell TC-FR2, 5TS. D09, 2.5kN test machine. Force accuracy 0.2%, positioning accuracy 0.0001mm; Zwick/ Roell Nederland, Venlo, The Netherlands). Regarding the tensile tests, the 2 PMMA blocks, and thus the osteofixation plate, were subjected to a tensile force with a constant speed of 5 mm/min until fracture occurred (according to the standard ASTM D638M). For the side bending test the 2 PMMA blocks were supported at their ends whereas the plates were loaded in the centre of the construction with a constant speed of 30 mm/min (with this speed the outer fibers were loaded as fast as the fibers of the osteofixation system in

Figure 2. Side bending test set-up

CHAPTER 3.2.2

MATERIALS AND METHODS

CHAPTER 3.2.2

The mean tensile strength and stiffness of the Resorb X as well as the SonicWeld Rx biodegradable osteofixation systems are graphically presented in figures 4 and 5, respectively. Tensile strength and stiffness of the SonicWeld Rx system were significantly higher than those of the Resorb X system. The tensile strength of the SonicWeld Rx system was approximately 2 times the tensile strength of the Resorb X system, while the tensile stiffness of the SonicWeld Rx system was about 11.5 time that of the Resorb X system. The significant differences between the 2 systems are outlined in table III. The standard deviations for the systems regarding the tensile strength and stiffness were small. The mean side bending stiffness of the 2 biodegradable osteofixation systems is plotted in figure 6. The SonicWeld Rx system revealed significantly higher side bending stiffness than with the Resorb X system. The standard deviations of the 2 systems were small (table I). The significant results were additionally illustrated by the 95% confidence interval of the difference, which did not include zero. There was no significant difference between the mean torsion stiffness of the SonicWeld Rx and the Resorb X osteofixation system (Table III), as is graphically displayed in figure 7. Table I presents a summary of the descriptive statistics of the tensile strength and stiffness, side bending stiffness as well as torsion stiffness. Regarding the side bending test, no fracture at all of neither the plate nor the screws/ pins has been observed for both systems. For the tensile as well as the torsion test, shear of the screw-heads was observed regarding the Resorb X system whereas fracture of the plates was observed regarding the SonicWeld Rx system. the tensile test) until the plate was bended 30 degrees. For the torsion test the 2 PMMA blocks were rotated along the long axis of the osteofixation system with a constant speed of 90 degrees/min (with this speed the outer fibers were loaded as fast as the fibers of the osteofixation system in the tensile test) until the plate was turned 160 degrees. During testing the applied force was monitored by the load cell of the test machine. Both force and displacement were recorded with a sample frequency of 500 hertz and graphically presented in force-displacement diagrams. During tensile tests, the strength of the osteofixation system was measured. The stiffness was calculated for the tensile, side bending and torsion tests by determining the slope of the curve between 25% and 75% of Fmax on the force-displacement curves. Statistical analysis Statistical Package of Social Sciences (SPSS, version 14.0) was used to analyze the data. Means and standard deviations were calculated to describe the data. To determine whether there were significant differences between the 2 biodegradable osteofixation systems in (1) tensile strength and stiffness, (2) side bending stiffness, and (3) torsion stiffness, the maximum values were subjected to Independent-Samples T-Tests. Differences were considered to be statistically significant when p < 0.05 for all tests.

Table I. Summary of descriptive statistics tensile, side bending and torsion test

Mean*

SD*

Resorb X 2.1 mm

59.87

4.73

SonicWeld Rx

114.55

8.69

Resorb X 2.1 mm

42.86

5.82

SonicWeld Rx

496.74

33.95

Resorb X 2.1 mm

0.25

0.03

SonicWeld Rx

1.11

0.09

Resorb X 2.1 mm

0.32

0.04

SonicWeld Rx

0.32

0.4

System Tensile strength

Tensile stiffness

Side Bending stiffness

Torsion stiffness

*in N/mm SD = Standard Deviation

CHAPTER 3.2.2

RESULTS

Figure 3. Torsion test set-up

Figure 4. Mean tensile strength organized by system

Figure 6. Mean side bending stiffness organized by system

Test: Tensile Strength

Test: Side Bending Stiffness 1,20

120,00

Mean Stiffnes (N/mm)

Mean Strength (N)

1,00

100,00

80,00

0,80

0,60

0,40

SonicWeld Rx 2.1 mm Resorb X 2.1 mm

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean strength in Newtonâ&#x20AC;&#x2122;s Points in figure: represents mean strength Bars: represents the standard deviation of the mean strength

Figure 5. Mean tensile stiffness organized by system

SonicWeld Rx 2.1 mm

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean stiffness in Newton/mm (deducted unit) Points in figure: represents mean stiffness Bars: represents the standard deviation of the mean stiffness

Figure 7. Mean torsion stiffness organized by system

Test: Tensile Stiffness

Test: Torsion Stiffness 0,38

600,00

500,00

Mean Stiffnes (N/mm)

0,36

400,00

300,00

200,00

0,34

0,32

0,30

100,00

0,28

0,00 Resorb X 2.1 mm

SonicWeld Rx 2.1 mm

System Legend: X-axis = brand names of the investigated osteofixation systems Y-axis = mean stiffness in Newton/mm Points in figure: represents mean stiffness Bars: represents the standard deviation of the mean stiffness

SonicWeld Rx 2.1 mm

Resorb X 2.1 mm

CHAPTER 3.2.2

0,20 Resorb X 2.1 mm

Mean Stiffnes (N/mm)

CHAPTER 3.2.2

60,00

The differences in strength and stiffness between the SonicWeld Rx and the Resorb X biodegradable osteofixation systems can partly be explained by the difference in geometry of the screws and pins, but predominantly by the 2 different methods of application. Using a sonotrode to bring the plate and pin in a thermoplastic state fusing the plate and pin, results in a firm and stable fixation. The tensile strength and stiffness as well as the side bending stiffness of the SonicWeld Rx system presented significantly higher mean values compared with the conventional Resorb X system (table II). In contrast, the torsion stiffness of both systems presents remarkably similar means and standard deviations. The torsion test was used to simulate the torsion forces that exist in the area between the two canine teeth when a median fracture of the mandible is present. In various clinical cases however, these torsion forces are neutralized by the interdigitation of the fracture segments (133). The torsion forces exerted on the fixation devices are subsequently transferred to tensile forces in these cases. The biodegradable polymers used to manufacture the SonicWeld Rx plates and pins are melted through an ultra-sound activated sonotrode resulting in a fusion of the plate and screwhead/pinhead. As mentioned before, fusion results in a firm and stable device especially where shear strength and stiffness of the device are concerned. This is supported by the authors’ experience that in all test samples of the SonicWeld Rx system for both the tensile and side bending test, fracture of the plate occurred away from the pin, and not near the pin or of the pin or pin-head itself. Regarding the conventionally screwed Resorb X system, the authors experienced shear of the screw-heads in all test samples. These in vitro observations support the hypothesis that the principle of fusion of the plate and the pinheads results in better mechanical biodegradable device strength and stiffness. For orthopaedic and maxillofacial metallic plates and screws, this principle is well-known as locking plates. These locking plates present increased in vitro strength and stiffness of the device characteristics (137-139) as well as good clinical performances (137). As described in the Materials & Methods section, the Resorb X screws were applied with a specific torque defined in a previous study (130), resulting in a pressure of the plates to the PMMA blocks. For the SonicWeld RX pins this pressure was not specified; the pins were applied as the surgeon would do in clinical practice. This difference could theoretically confound the test results of especially the SonicWeld RX system. When looking to the test results, however, the authors conclude that the lack of pressure of the plates to the PMMA blocks for the SonicWeld RX system could not confound the test results, since, after all, fracture of the plates (instead of shear of the screws) occurred in all specimens. The use of PMMA instead of real bone was a conscious decision of the authors. Real bone could have different calcification levels which could result in different fracture patterns of the plates and screws. Subsequently, this could influence the results. PMMA blocks have the same mechanical characteristics as real bone and each block does have the same ‘quality’ level. Moreover, the difference between cancellous/cortical bone and PMMA

CHAPTER 3.2.2

0.05 -0.06 Stiffness Torsion

Resorb X 2.1 mm vs. SonicWeld Rx 2.1 mm

* = Significant

483.20

0.95 0.76

420.54 Stiffness

Resorb X 2.1 mm vs. SonicWeld Rx 2.1 mm*

Stiffness

Tensile

Side Bending

Resorb X 2.1 mm vs. SonicWeld Rx 2.1 mm*

64.05 45.31 Tensile

Resorb X 2.1 mm vs. SonicWeld Rx 2.1 mm*

Strength

Upper Bound

95% Confidence Interval

Test Table III. Comparison between osteofixation systems

* = according the specifications of the manufacturers.

Systems

Property

Lower Bound

1.1 mm 6.0 mm 26.0 mm 7.0 mm 2.1 mm 100 D(50%)L(50%) -Lactide Gebrüder Martin GmbH & Co. (Tuttlingen, Germany )

SonicWeld Rx

Sterile

1.1 mm 6.0 mm 26.0 mm 7.0 mm 2.1 mm 100 D(50%)L(50%) -Lactide Gebrüder Martin GmbH & Co. (Tuttlingen, Germany )

Resorb X

Sterile

Plate Plate Width* Thickness* Screw/pin Screw/pin Plate Diameter* Length* Length* Sterility Composition Manufacturer (city and state) Brand name

Table II. Characteristics of included biodegradable osteofixation systems

CHAPTER 3.2.2

DISCUSSION

CHAPTER 3.2.2

was not a major concern. Theoretically, the flow of polymers of the ultra-sound activated SonicWeld Rx pin into the cavities of the cancellous bone would enhance the pull out strength of the screws. However, none of the screws were pulled out during testing. Regarding the thermoplastic state of the biodegradable pin, we were concerned about the fusion or sticking of the biodegradable pin to the PMMA blocks. This could theoretically affect the test results. To prevent this, the boreholes were irrigated with saline before insertion of the pins. To check whether fusion or sticking had occurred, we checked whether the pin could be pulled out the PMMA blocks after the test. Despite not actually measuring the pull out strength of the pins, the authors noted that high forces were not required to do so. The SonicWeld Rx system is obviously an improvement in the search for a mechanically strong and stiff as well as a biodegradable osteofixation system. Moreover, usage of the device is relatively easy and comfortable. The application of SonicWeld Rx plates and pins is fast and easy. Nevertheless, the plates and screws are still bulky compared to the conventional titanium plates and screws. The question, though, is whether the promising in vitro results can be transferred to the in situ clinical situation. Future research about biodegradable osteofixation devices should therefore include the SonicWeld Rx system in randomized clinical trials in which a conventional titanium fixation device serves as the ´golden´ standard fixation device. Acknowledgements The gratuitously supply of the biodegradable plates and screws/pins through the manufacturer (Gebrüder Martin GmbH & Co.) was gratefully appreciated. The authors also would like to thank dr. H. Groen for his statistical assistance. Mr. J. de Jonge is acknowledged for the fabrication of the test set-ups.

CHAPTER 4

BIODEGRADABLE AND TITANIUM FIXATION SYSTEMS IN ORAL AND MAXILLOFACIAL SURGERY: A RANDOMIZED CONTROLLED TRIAL

G.J. BUIJS N.B. VAN BAKELEN J. JANSMA J.G.A.M. DE VISSCHER TH.J.M. HOPPENREIJS J.E. BERGSMA B. STEGENGA R.R.M. BOS

Submitted

Essential prerequisites for the bone healing of fractures and osteotomies include sufficient vascularization, anatomical reduction, and immobilization of bone segments (7;10). Up to the seventies, fractures and osteotomies were fixed with (stainless) steel wires supported by InterMaxillary Fixation (IMF) to achieve bone healing and restore occlusion. The use of IMF during the healing period of 6 weeks is very uncomfortable. Besides, it immobilizes the temporomandibular joints resulting in cartilage degeneration (140). The last four decades, immobilization of bone fragments can be obtained using metallic plates and screws without applying IMF (125;126). This allows patients to load functionally their masticatory system immediately following surgery. The currently available metal plating systems have the advantage of combining excellent mechanical and handling properties. A disadvantage of the use of metallic plates and screws is that they remain during life. This results in several potential adverse effects such as: (1) sensitivity to hot and cold stimuli (129), (2) palpability of the plates, (3) possible growth disturbance or mutagenic effects (37;41;43-45), and (4) interference with imaging or radio-therapeutic irradiation techniques (37;41;127). As a consequence, some authors remove the implants in a second operation following bone healing. This has been reported in 5 - 40% of the cases (32-34). Because of this apparent disadvantage, there is a continuous drive to explore the use of biodegradable fixation systems (4). These systems could reduce or even delete the problems associated with metallic systems (74). This would be highly desirable from the viewpoint of costeffectiveness, patient comfort, healthcare quality, and risk of complications due to plate removal. However, adverse tissue reactions to degradation products have been reported (66;67;100;114). Moreover, biodegradable systems are mechanically less favourable than metallic systems, which can result in insufficient bone healing. Many case reports and case series have been published reporting the clinical performance of a variety of commercially available biodegradable systems used for different indications. These studies show various outcome results (48;64;70;141-143). Only a few controlled trials have been published on this subject (2-4;144), which have previously been summarized and analyzed in a systematic review (122). The results were inconclusive, mainly because of the lack of sufficiently powered and appropriately designed trials and heterogeneity among the included studies. Given the lack of adequate evidence as well as the obvious advantages of using biodegradable plates and screws for the patient, and society, there is a need for well-designed randomized controlled trials of sufficient size. The aim of this study was to establish the effectiveness and safety of biodegradable plates and screws as an alternative to metallic ones. Therefore, we tested the null-hypothesis that the performance of the Inion CPS biodegradable system is inferior to the titanium system regarding bone healing following treatment of mandibular, maxillary (Le Fort I), and zygomatic fractures as well as after bi-lateral sagittal split (BSO) and/or Le Fort I osteotomies.

CHAPTER 4

INTRODUCTION Abstract: Background - Metallic plates and screws are used for immobilization of bone fragments in trauma and orthognathic surgery. Some authors advocate the removal of metallic plates and screws because of potential adverse reactions. A second operation to remove osteosynthesis following bone healing is reported in 5 - 40% of the cases. This is highly undesirable in terms of cost-effectiveness, patient comfort, healthcare quality and risk of complications. Biodegradable fixation systems could reduce or even delete the problems associated with metallic systems since removal is not necessary. Aim - The aim of this study was to establish the effectiveness and safety of biodegradable plates and screws as a potential alternative to metallic ones. Materials & Methods - This multi-centre randomized controlled trial was conducted from December 2006 to July 2009. Included were patients who underwent mandibularand Le Fort I osteotomies and those with fractures of the mandible, maxilla, and zygoma. The patients were assigned to a titanium control-group (KLS Martin) or to a biodegradable test-group (Inion CPS). The primary outcome measure was ‘bone healing 8 weeks after surgery’. Results - The Intention To Treat analysis (ITT) of 111 patients in the titanium group and 112 patients in the biodegradable group yielded a non-significant difference. In 25 patients (22%) who were included in the biodegradable group, the surgeon made the decision to switch to the titanium system per-operatively. Conclusion & discussion - Despite the ‘non inferior’ primary outcome result, the benefits of using biodegradable systems (less plate removal operations) should be demonstrated during a follow-up of minimally 5 years, especially when the large number of patients for whom it was per-operatively decided to switch from the biodegradable system to the conventional titanium system, are taken into account.

Patients This prospective study was conducted from December 2006 to July 2009. The source population consisted of patients who were treated at the departments of Oral and Maxillofacial Surgery (OMFS) of the: 1. University Medical Centre Groningen (UMCG) 2. Rijnstate Hospital Arnhem (RHA) 3. Amphia Hospital Breda (AHB) 4. Medical Centre Leeuwarden (MCL). Patients meeting the inclusion criteria were eligible for this study (Figure 1). All patients were informed regarding the treatment options prior to surgery and were required to provide informed consent in order to participate in the study. The surgeons recruited the participants and subsequently assigned them randomly to two treatment groups a day before (in case of osteotomies) or immediately prior to (in case of fractures) the operation. A statistician generated the randomization sequences using a computerized randomization Figure 1. In- and exclusion criteria Inclusion criteria: - patients scheduled for a Le Fort I fracture, and/or a solitary or multiple (maximum 2) mandibular fracture(s), and/or a zygoma fracture; - patients scheduled for a Le Fort I osteotomy, and/or a Bi-lateral Sagittal Split Osteotomy (BSO); - patients (also parents or responsible persons if necessary) who signed the informed consent form. Exclusion criteria: - patients who were younger than 18 years old (trauma), or patients who were younger than 14 years (osteotomies); - patients presented with heavily comminuted fractures of the facial skeleton; - patients who experienced compromised bone healing in the past; - patients who were pregnant; - patients who could/would not participate in a 1-year follow-up (reasons); - patients who would not agree with an at random assignment to one of the treatment groups, or one of the methods or treatment administered in the study; - patients who were diagnosed with a psychiatric disorder (diagnosed by a psychiatrist); - patients who experienced cleft lip and palate surgery in the past; - patients where fracture reduction and fixation was delayed for more than 7 days (after day of trauma); - patients of whom the general health and/or medication could affect bone healing, as determined by the oral and maxillofacial surgeon.

program. The randomization sequences were linked to a central telephone, which was available 24-hours a day to conceal the sequence until the interventions were assigned. Stratification to hospital was executed in order to detect hospital effects. The study was approved by the Medical Ethical Committee (MEC) of the UMCG, and approved for local workability by the MEC’s of the other centres. Interventions The patients were assigned to a titanium control-group (KLS Martin, Gebrüder Martin GmbH & Co. Tuttlingen, Germany) or to a biodegradable test-group (Inion CPS, Inion Ltd. Tampere, Finland). Neither prior to nor after surgery, the patients were aware of the system that had been used. All plates and screws were applied according to the instructions of the manufactures (with prescribed burs and taps). The screw holes were predrilled for both the titanium as for the biodegradable screws, and subsequently pre-tapped for the biodegradable screws. For fixation of mandibular osteotomies and fractures 2.5-mm biodegradable or 2.0mm titanium plates and screws were used, whereas 2.0-mm biodegradable or 1.5-mm titanium plates and screws were used for fixation of zygoma fractures, Le Fort I fractures, and Le Fort I osteotomies. Each participating OMF surgeon performed 2 ‘test-surgeries’ using the biodegradable system in order to acquire the slightly different application-skills, i.e., pre-tapping the screws and pre-heating the plates, and to get used to the different dimensions. These ‘test-surgeries’ were not included in the study. Outcome measures The primary outcome measure was ‘bone healing 8 weeks after surgery’, which was defined as follows: 1. absence of clinical mobility of the bone segments assessed using bi-manual traction on the distal and proximal bone segments; 2. absence of radiographic signs of disturbed bone healing assessed on an orthopantomogram (OPT; all indications), a lateral cephalogram (osteotomies), an occipito-mentalradiograph (zygoma fractures), and a fronto-suboccipital radiograph (mandible fracture). The following secondary outcome measures were assessed: 1. clinical: occlusion, palpability of plate/screw, wound dehiscence, and signs of inflammation; 2. radiographic: position of the bone segments (position of teeth, path of the mandibular canal, and contour of cortical structures); 3. patient-related (by self-evaluation): pain reported on a Visual Analogue Scale (VAS; ranging 1-100) and mandibular function evaluated by the mandibular function impairment questionnaire (MFIQ (145); ranging 17-85); 4. handling characteristics (plate adaptation, drilling/tapping, screw insertion, and wound closure recorded on a scale of 1-10). 5. cost-effectiveness: direct (hospital, surgeon, and time related) and indirect (discontinuing employment process) costs were reported on a questionnaire.

CHAPTER 4

MATERIALS & METHODS

Figure 2. Flow diagram of patient’s progress though the phases of RCT (Intention to treat analysis)

Assessed for eligibility (n= 832)

Statistical analysis. Hypothesis testing was conducted following the principles of non-inferiority analysis. Based on an expected percentage of bone healing of 95% using a titanium system and a maximum acceptable difference of 5% between the two groups with respect to the primary outcome measure, two groups of 109 patients were necessary to demonstrate non-inferiority with a power of 80% on a significance level of 5%. Taking patient loss during the follow-up into account, it was decided to include 115 patients in each group. The Statistical Package of Social Sciences (SPSS, version 16.0) was used to analyze the data. The means and standard deviations of normally distributed variables as well as dichotome variables were calculated and analyzed using the Independent-Samples T-test or the Fischers Exact-test. Skewed variables were either transformed to obtain normally distributed variables, or (if this could not be achieved) analyzed using non-parametric tests. No interim analyses were performed during the study period.

Patients randomized (n= 230)

Allocation

RESULTS Figure 2 represents the flow of 230 randomized patients during the phases of the study regarding the Intention-To-Treat (ITT)-analysis. The inclusion of the different centres (UMCG, RHA, AHB, and MCL) resulted in 103, 78, 44, and 5 patients, respectively. However, because of violating the study protocol, 7 patients had to be excluded from the analysis. Four other patients, who did not complete the follow-up, were considered ‘nonadherent’ to treatment (‘worst case scenario’). This resulted in the analysis of 111 patients in the titanium group and 112 patients in the biodegradable group. Table 1 shows the baseline data of the analyzed patients. Regarding the Per-Protocol (PP)-analysis, the 4 Table I. Baseline characteristics in titanium and biodegradable groups Baseline characteristics

Excluded (n= 604) Not meeting in- exclusion criteria (n= 105) Refused to participate (n= 499)

Biodegradable (n = 112)

Male (n)

Female (n)

Age (mean: sd in years)

31:11

30:12

Age (range in years)

14-60

14-56

Allocated to titanium group (n= 113)

Protocol violations (n = 2) - after randomisation it turned out patients have cleft lip and palate (n = 3); - after randomisation it turned out patient had a psychiatric disorder (n = 1); - randomized to the wrong centre (n = 1).

Protocol violations (n = 2) - after randomisation it turned out patient has cleft lip and palate (n = 1); - randomized to the wrong centre (n = 1).

Follow-up

Titanium (n = 111)

Abbreviations: n = number sd = standard deviation

Allocated to biodegradable group (n= 117)

Lost to follow-up 8-weeks (n = 3)

Lost to follow-up 8-weeks (n = 1)

Analyses Analyzed in biodegradable group (n = 112)

Analyzed in titanium group (n = 111)

CHAPTER 4

Post-operative interventions, such as wound irrigation with saline, use of antibiotics, abscess incision and drainage, or removal of plate/screws within 8 weeks were reported separately. The primary and the secondary outcome measures were evaluated 8 weeks following surgery by a colleague of the OMF surgeon who performed the surgery.

CHAPTER 4

above mentioned patients were excluded, because they did not complete the entire study. Additionally, patients were added to the titanium control group when it was decided peroperatively to switch to the titanium system (25 patients). This resulted in a PP-analysis of 135 patients in the titanium group and 84 patients in the biodegradable group. Inadequate bone healing of 2 patients in the biodegradable group was reported. One patient had a mobile maxilla one day after surgery, who was re-operated using the titanium system. The second patient had a mobile maxilla after 8-weeks, which eventually healed without intervention. Following the ITT-analysis, 5 patients of the biodegradable group (3 patients lost to follow-up and the 2 above-mentioned patients) and 1 patient of the titanium group (lost to follow-up) showed inadequate bone healing, resulting in a nonsignificant difference. In the PP-analysis 2 patients of the biodegradable group showed inadequate bone healing (table 2). The ITT-analysis showed significant differences with regard to dehiscence of the plate/screws, palpability of the plate/screws, and abscess formation. There were no significant differences with respect to incorrect occlusion and inflammatory reactions. There was no statistically significant difference between the 2 groups with regard to the position of the bone fragments 8-weeks after surgery, i.e. 1 patient in the titanium group and 6 patients in the biodegradable group. The self-evaluation of pain revealed VAS scores lower than 10 for both groups, whereas the MFIQ showed nearly equal scores for the mandibular function. The post-operative interventions, wound irrigation with saline, use of antibiotics, abscess incision and drainage, and removal of plate/screws after 8 weeks, did not significantly differ between the both groups. The handling characteristics revealed significant lower scores for the biodegradable system concerning plate adaptation, drilling/tapping, and screw insertion. Wound closure did not reveal a significant difference. The mean operation time did not differ between the 2 groups, despite the variation in handling characteristics. Regarding the cost-effectiveness, the direct costs were 1024 euro in the titanium group and 1311 euro in the biodegradable group, whereas the indirect costs were 2419 and 2481 euro respectively. These differences were not statistically significant. The results are summarized in Table 2. An ancillary analysis revealed that there was no centre effect with regard to bone healing. Analysis of the various surgeries did not differ significantly between the groups (table 3). In 25 patients who were included in the biodegradable group, the OMF surgeon made the decision to switch to the conventional titanium system per-operatively. The main reasons for switching were handling characteristics and material failure, including plate/screw fracture (n=2), non grip screws (n=8), inadequate position of bone segments after fixation (n=6), dimension of plate and screws (n=1), ‘unfavourable split’ (n=1), and inadequate stability after fixation (n=7). Figure 3 shows the distribution of switches during the study. The ‘unfavourable split’ occurred in a BSO-patient and was considered an adverse event.

Table II. Outcomes titanium versus biodegradable Titanium group (n)

Biodegradable group (n)

Significance (S/NS)

ITT analysis (inadequate bone healing)

PP analysis (inadequate bone healing)

Description Primary outcome measure*

Secondary outcome measures Clinical assessments

Non-correct occlusion

Palpability plate/screw

Dehiscence

Abscess formation

rubor

tumor

calor

dolor (local)

functio laesa

Inflammatory reactions

Radiographic assessment

Changed position bone segments Self-evaluation of patient Pain VAS; mean (sd)

6 (13)

8 (13)

MFIQ; mean (sd)

37 (17)

35 (14)

Irrigation with saline

Antibiotics

Abscess incision and drainage

Removal plate/screws after 8 weeks

Plate adaptation (mean;sd)

8.5;0.9

7.3;1.9

Drilling/tapping (mean;sd)

8.7;1.0

7.1;1.9

Screw insertion (mean;sd)

8.7;1.1

7.0;2.1

Wound closure (mean;sd)

8.7;1.0

8.3;1.7

Postoperative interventions

Handling characteristics

Cost-effectiveness

Direct costs

1024

1311

Indirect costs

2419

2481

2:12

2:20

Operation time (h:m) * Tested one-sided † Tested two-tailed

†

S Significant NS Non Significant

Operation

Titanium

Biodegradable

Total

BSO

142

Le Fort 1 osteotomy

Bi-maxillary osteotomy

Mandibular fracture

Le Fort 1 fracture

Zygomatic fracture

111

112

223

Figure 3. Scatter plot learning curve

Switch biodegradable to titanium

CHAPTER 4

Total

01-05-2007

01-11-2007

01-05-2008

Operation date

01-11-2008

01-05-2009

Both the ITT- and the PP-analysis revealed that biodegradable plates and screws did not perform inferiorly to titanium plates and screws regarding bone healing after 8 weeks for both maxillofacial fractures and osteotomies. This implies that the biodegradable system can be safely used without IMF for most indications used in this study (see below). Also concerning the majority of the secondary outcome measures the biodegradable system appeared to be not significantly different to the titanium system. In contrast, the handling characteristics showed a remarkable difference, between both systems whereby biodegradable plates and screws were more difficult in use as compared to titanium plates and screws. This is because biodegradable plates and screws are weaker and, more particularly, bulkier in terms of dimensions. The lack of confidence in a still ‘unknown and new’ biodegradable system, handling differences and having a sense of certainty and confidence regarding the conventional titanium system, may have contributed to the relatively high amount of switches. These should certainly be regarded as adverse events. The primary outcome measure, i.e. bone healing after 8 weeks, was chosen after several studies regarding the mechanical characteristics of biodegradable plates and screws (130;135;146). It has been concluded that these characteristics were less favourable as compared to titanium plates and screws. This may result in insufficient and delayed bone healing percentages. However, titanium plates and screws show high success rates of at least 95% according to the opinions of clinical experts as well as large patient series (32;33;147). Taking these results into account, it is a prerequisite to obtain ‘non inferior’ bone healing when using biodegradable plates and screws. Until now, there is no thorough scientific evidence that biodegradable plates and screws will result in more incomplete or delayed bone healing. It has been reported (144) to use IMF in the first 2 weeks after fixation with biodegradable plates and screws, especially in load bearing situations. In our opinion, this is undesirable. In the ITT analysis, 7 patients were excluded (figure 2). These 7 patients (1 patient had a psychiatric disorder, 4 had a cleft lip and palate deformity, and 2 were randomized to the wrong centre) did not meet the exclusion criteria. Inclusion of these results would obscure the intended indication whereas exclusion of these results leads to a better applicability and higher accuracy of the results of the study. The primary outcome measure was not stratified for indication as it could be expected that the bone segments would be healed after 8 weeks independent of the indication. The post-hoc analysis resulted in a non-significant result between the groups. However, the relatively low number of Le Fort I fractures impedes the eloquence of the results of the ITT-analysis for this indication. By contrast, the high number of inclusions of the other indications implies a good eloquence of the results of the ITT-analysis. The study was performed in 4 hospitals and different surgeons did the operations. This implies good generalizability. On the other hand, several surgeons could imply diminished power of the study as a result of a possible learning curve factor. However, it appeared that

CHAPTER 4

DISCUSSION

Table III. Numbers of various performed surgeries

CHAPTER 4

the switches of the biodegradable to the titanium system took place over the entire study (figure 3). Moreover, the switches were made by all participating surgeons and centres. It can therefore be expected that the performance of the Inion CPS biodegradable system in other hospitals will not be inferior to the conventional titanium system. In the materials and methods section it is stated that evaluation of outcome measures was planned to be) performed by a colleague of the OMF surgeon who performed the surgery. Despite the intended protocol, in too many cases it turned out to be practically unfeasible to perform the evaluation of the outcome measures by a different OMF surgeon than the OMF surgeon who performed the surgery. This phenomenon may have introduced observer bias. In summary, it is concluded that regarding bone healing after 8 weeks, the performance of the Inion CPS biodegradable system is not inferior compared to the titanium system regarding the treatment of mandibular-, and zygoma fractures as well as for BSO-, and Le Fort I osteotomies. However, despite the â&#x20AC;&#x2DC;non inferiorâ&#x20AC;&#x2122; primary outcome result, the benefits of using biodegradable systems (less plate removal operations) should be demonstrated during a follow-up of minimally 5 years, especially when the large number of patients for whom it was per-operatively decided to switch from the biodegradable system to the conventional titanium system, are taken into account. The presented results are part of a longer running follow-up study and the one year results will be published in the near future.

ACKNOWLEDGEMENT The authors thank the Stryker company for their support and the supply of the Inion CPS product.

CHAPTER 5

GENERAL DISCUSSION AND FUTURE PERSPECTIVES

Titanium plates and screws are currently regarded as the gold standard for fixation of bone fragments in the maxillofacial skeleton. As with any material, there are aspects that are undesirable and should be improved to meet the ideal characteristics for fixation. From the point of view of an ideal fixation system, there is a continuous drive to create a fixation system that disappears from the human body without any residues as soon as it has fulfilled its function, i.e. undisturbed healing of the bone segments. As stated in the introduction of this thesis, biodegradable plates and screws could be a suitable material as they dissolve in the human body. The known pros and cons of both titanium and biodegradable plates and screws are described in detail in the introduction. In this thesis, a systematic review was performed to investigate the clinical efficacy and safety of biodegradable plates and screws. Subsequently, in vitro studies were performed to establish the mechanical properties of biodegradable plates and screws. Finally, a clinical trial was performed in order to establish whether these plates and screws could be used safely and effectively to a largescale and fit into the current treatment protocols and guidelines in maxillofacial surgery. Clinical, patient-related, surgeon-related, and cost aspects were taken into account. Based on a systematic review of literature (122) regarding the clinical efficacy and safety of titanium and biodegradable plates and screws, a definitive conclusion regarding the fixation of fractured bone segments and osteotomies with respect to their long-term performance in maxillofacial surgery could not be drawn. Lack of sufficiently powered, high quality and appropriately reported (randomized) controlled clinical trials are the main reasons. Moreover, the application of biodegradable plates and screws for mandibular fractures and osteotomies without using IMF has not been thoroughly investigated. The mechanical properties of biodegradable plates and screws appeared to have less favourable strength and stiffness compared with titanium plates and screws (130;135;146). These lower strength and stiffness values apply for the functional unit characteristics, plate and screws together, as well as for the torsion characteristics of the screws. Despite the inferior mechanical characteristics, the above-mentioned review (122) presented uneventful clinical case series using biodegradable fixation devices. This raises the question as to whether the effectiveness and safety of biodegradable plates and screws will be at least non-inferior to the high success rates (more than 95%) of titanium plates and screws in large patient series. Adequately powered randomized controlled trials needed to be conducted to draw definitive conclusions regarding the effectiveness and safety of biodegradable plates and screws for bone healing in maxillofacial surgery. The manufacturers of biodegradable plates and screws increased the dimensions to compensate for the inferior mechanical characteristics. The dimensions of the LactoSorb

system are relatively bulky compared with the subtle dimensions of the Inion CPS and BioSorb FX biodegradable systems. It has been concluded that these bulky dimensions are responsible for the relatively good mechanical properties of the LactoSorb system (130;135). As the dimensions of biodegradable plates and screws are larger compared to titanium devices, it was not desirable to include the relatively bulky plates and screws of the LactoSorb system in the RCT. The manufacturers of the BioSorb FX system used a special self-reinforment principle to enhance the mechanical characteristics in order to keep the dimensions within acceptable limits. The application of biodegradable plates and screws is commonly limited to upper- and midface fractures and osteotomies. Most manufacturers discourage the use in the mandible unless in conjunction with 6 weeks of IMF. The use of IMF would be a step back in history. Inion Ltd. is the only exception and can be used to fixate fractures and osteotomies of the mandible according to the manufacturer. IMF should additionally support the fixation only in complex or comminuted cases. As the inclusion- and exclusion criteria of the RCT resulted in exclusion of these cases, and the regular mandibular fractures and osteotomies could be stabilized without using IMF, Inion CPS plates and screws were chosen to use in the RCT. Little data were available for the Inion CPS plates and screws as the material was relatively new onto the market. After contacting the manufacturer of the Inion CPS system, we received the proof of an article of Nieminen et. al. published later in 2008 (148). The authors investigated the tissue reactions and mechanical strength of the Inion CPS plates and screws during the course of degradation. The materials were implanted to the mandible and in the dorsal subcutis of 12 sheep. The animals were sacrificed at 6-156 weeks. In light microscopy, the in vivo implant material began to fragment at 52 weeks and could not be detected at 104 weeks. No significant foreign body reactions were seen in the mandibles. The dorsal subcutis disclosed mild reactions which were not of clinical significance. These findings suggest that Inion CPS plates can be used safely for fixation of the bony structures in the maxillofacial skeleton. Definitive proof of full degradation and resorption is still lacking, as it is for all biodegradable systems investigated in this thesis. In order to accomplish the main aim of this thesis, â&#x20AC;&#x2DC;to establish the effectiveness and safety of biodegradable plates and screws to fix bone segments in the maxillofacial skeleton as a potential alternative to metallic onesâ&#x20AC;&#x2122;, the clinical aspects were investigated in a randomized controlled clinical trial using the Inion CPS biodegradable fixation system (Buijs et. al, submitted). The Intention To Treat analysis (ITT-analysis) and the Per Protocol analysis (PP-analysis) yielded that Inion CPS biodegradable plates and screws did not perform inferiorly to titanium plates and screws regarding bone healing after 8 weeks for maxillofacial fractures (except for Le Fort I fractures) as well as osteotomies. This implies that the biodegradable system can be safely used without IMF, also for load bearing situations like bilateral sagittal spit osteotomies and non-comminuted mandibular fractures. Also regarding the secondary outcome measures, it can be concluded that there are no important differences between the two investigated systems.

CHAPTER 5

GENERAL DISCUSSION

The skeletal stability of the bone segments is an important variable which is evaluated in the RCT by assessing the dental occlusion and the positional change of the bone segments. During the 8-weeks follow-up the main focus was on bone healing (primary outcome measure). The skeletal stability will be evaluated after 1 year follow up. Skeletal structures may change especially during the first postoperative year (relapse; postoperative orthodontics). After 1 year the skeletal structures will be more reliable making complete effect size measurement of the skeletal stability possible. It is generally accepted that the strength and stiffness of different titanium plates and screws are comparable. This is also applicable for biocompatibility as is investigated in the study of Langford in 2002 (149). In this way, it can be concluded that the KLS Martin titanium system, which is used in the RCT, has a good generalizability for other titanium systems. Regarding the Inion CPS biodegradable system, the generalizability of the mechanical aspects is limited to the BioSorb FX, and LactoSorb. These systems represent comparable mechanical characteristics (135). The other biodegradable systems investigated in the study, performed significantly inferior. With respect to the biocompatibility, the generalizability of Inion CPS plates and screws is difficult as a result of the various copolymer compositions used to manufacture the different biodegradable plates and screws. Although many studies report promising results, ultimate biocompatibility and complete resorption has never been proven. It can be concluded that the results of the randomized controlled trial can be extrapolated to at least 2 of the investigated biodegradable plate and screw systems (BioSorb FX and LactoSorb). Based on the results of the RCT performed in this thesis, it is concluded that biodegradable

plates and screws do not perform inferior to titanium regarding a follow-up period of 8 weeks. The high percentage of switches is a threat to a widespread acceptation of biodegradable plates and screws in the current treatment protocols and guidelines in maxillofacial surgery. The follow-up period of 1 year will provide more clarity about the potential differences in plate removal operations and thus the potential gain in effectiveness in the treatment of fractures and osteotomies of the maxillofacial skeleton. The 1 year follow up results will also provide more information about the skeletal stability, biocompatibility, and resorption aspects of Inion CPS plates and screws. Further research is performed and will be published in the near future.

FUTURE PERSPECTIVES Despite the results of the RCT, some reservations remain regarding the use of biodegradable plates and screws in maxillofacial surgery. There may be alternatives that can contribute to finding the ideal fixation system. One such development is the welding technique incorporated in the Sonicweld Rx system (Gebrüder Martin GmbH & Co., Tuttlingen, Germany). A biodegradable pin is placed onto an ultra-sound activated sonic electrode, called a sonotrode, and inserted into the borehole. As a result of the added ultra-sound energy, the thermoplastic biodegradable pin will melt, resulting in a flow of biodegradable polymers into the cortical bone layer and the cavities of the underlying cancellous bone. At the same time the biodegradable plate and pinhead fuse. Due to the welding technique, the handling characteristics as well as the mechanical properties are greatly enhanced (146). These two aspects were the main reasons for the high amount of per-operative switches reported in the randomized clinical trial. Despite these promising results (146), the SonicWeld Rx system is considered not to be suitable for fixation of mandibular fractures and osteotomies according to the manufacturer (KLS Martin). The present co-polymer composition (50% L-lactide and 50% D-lactide) is not sufficient to fix mandibular fractures and osteotomies in a stable manner. Different co-polymer(s) (compositions) with improved mechanical characteristics could be used in conjunction with the welding technique to achieve strong and easy to apply biodegradable plate and screw systems. Important prerequisites, i.e. the biocompatibility and biodegradability of these polymers, should be taken into account since they are important potential advantages of biodegradable plates and screws. One should critically appraise the biocompatibility, biodegradability, and finally the resorption of these polymers as up till now there is no evidence regarding the complete resorption of biodegradable plate and screws to the electron microscopic level. Future of research of biodegradable plates and screws will be determined to a large extent by the above factors since the main rationale for using biodegradable plates and screws is their disappearance after fulfilling their function (bone healing).

CHAPTER 5

In contrast, the handling characteristics showed a remarkable difference, indicating that biodegradable plates and screws performed significantly less compared to titanium plates and screws. This is because biodegradable plates and screws are weaker and, more particularly, bulkier in terms of dimensions. These large dimensions remain a problem, especially in the small and subtle areas of the midface where thin bones are present. The large dimensions as well as the inferior mechanical characteristics are the main reasons for the high amount (22%) of peri-operative switches from biodegradable to titanium plates and screws. Besides the clinical aspects, the costs were also evaluated. It can be concluded that there is no significant difference between the Inion CPS biodegradable and the titanium plates and screws. The application of the biodegradable plates is slightly more expensive compared to titanium ones. However, productivity losses of people are the main costs. Following a post-operative period of 1 year, or perhaps even longer, one could draw definitive conclusions regarding the cost-effectiveness of the biodegradable plates and screws and whether the potential advantages of biodegradable plates and screws could be ‘confirmed’. Patient’s potential productivity gains could resolve the negative aspects of the per-operative switches of biodegradable plates and screws.

CHAPTER 6

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CHAPTER 7

SUMMARY

Chapter 2 comprises a systematic review of the available literature to determine the clinical efficacy and safety of biodegradable devices compared with titanium devices in oral and maxillofacial surgery. A highly sensitive search in the databases of MEDLINE (1966-2005), EMBASE (1989-2005), and CENTRAL (1800-2005) was conducted to identify eligible studies. The relevance of studies was evaluated by a first selection based on title and abstract. Eligible studies were independently evaluated by two assessors using a quality assessment scale. The procedure revealed four methodologically ‘acceptable’ articles. Owing to the different outcome measures used in the studies, it was impossible to perform a meta-analysis. Therefore, the major effects regarding the stability and morbidity of fracture fixation using titanium and biodegradable fixation systems were qualitatively described. Firm conclusions regarding the fixation of traumatically fractured bone segments cannot be drawn due to the lack of controlled clinical trials. Regarding the fixation of bone segments in orthognathic surgery, only a few controlled clinical studies are available. There does not appear to be a significant short-term difference between titanium and biodegradable fixation systems regarding stability and morbidity. However, definite conclusions, especially with respect to the long-term performance of biodegradable fixation devices used in maxillofacial surgery, cannot be drawn.

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Chapter 3 focuses on the mechanical characteristics of biodegradable versus titanium plates and screws. In chapter 3.1 the differences in maximum torque of 7 commercially available biodegradable and 2 commercially available titanium screw systems were investigated. Besides, the differences of maximum torque between ‘hand tight’ and break of the screws were investigated. Four oral and maxillofacial surgeons inserted 8 specimens of all 9 screw systems in polymethylmethacrylate (PMMA) plates. The surgeons were instructed to insert the screws as they would have done in the clinic (‘hand tight’). The data were recorded by a torque measurement meter. A PhD resident inserted 8 specimens of the same set of 9 screw systems until fracture occurred. The maximum applied torque was recorded likewise. The mean maximum torque of the 2 titanium screw systems was significantly higher than that of the 7 biodegradable screw systems. Besides, the mean maximum torque for ‘hand tight’ was significantly lower than for break regarding 2 biodegradable, and both titanium screw systems. Based on the results, we conclude that the 1.5- and 2.0 mm titanium screw systems still present the highest torque strength compared to the biodegradable screw systems. When there is an intention to use biodegradable screws, with regard to there mechanical characteristics, we recommend the use of 2.0 mm BioSorb FX, 2.0 mm LactoSorb or the 2.5 mm Inion CPS screws. In chapter 3.2.1 and 3.2.2 relevant mechanical data is presented in order to simplify the selection of an osteofixation system for situations requiring immobilization in oral and maxillofacial surgery. Seven biodegradable and 2 titanium osteofixation systems (chapter 3.2.1) and the SonicWeld Rx biodegradable osteofixation system (chapter 3.2.2) were investigated. The SonicWeld Rx system uses an ultra-sound activated sonic electrode to insert the biodegradable pin into the borehole. As a result of the added ultra-sound energy, the thermoplastic biodegradable pin will melt, resulting in a flow of biodegradable polymers into the cortical bone layer and the cavities of the cancellous bone. At the same time the biodegradable plate and pinhead fuse. The plates and screws were fixed to 2 polymethylmethacrylate (PMMA) blocks to simulate bone segments. The plates and screws were subjected to tensile, side bending, and torsion tests. During tensile tests, the strength of the osteofixation system was monitored. The stiffness was calculated for the tensile, side bending, and torsion tests. The results were that the two titanium systems (1.5 mm and 2.0 mm) presented significantly higher tensile strength and stiffness compared to the 7 biodegradable systems (2.0 mm, 2.1 mm, and 2.5 mm) presented in chapter 3.2.1. The 2.0 mm titanium system revealed significantly higher side bending and torsion stiffness than the other 7 systems. Regarding the SonicWeld Rx biodegradable plates and screws (chapter 3.2.2), the tensile strength and stiffness as well as the side bending stiffness of that system presented up to 11.5 times higher mean values than the conventional biodegradable Resorb X system. The torsion stiffness of both systems presents similar mean values and standard deviations. Based on the results of the current study, it can be concluded that the titanium osteofixation systems were (significantly) stronger and stiffer than the biodegradable systems. The BioSorb FX,

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Maxillofacial traumatology and orthognathic surgery are major fields of oral and maxillofacial surgery. Internal rigid fixation systems, i.e. plates and screws, are used for fixation and stabilization of osteotomized or fractured bone segments. Plates and screws are generally made of titanium and are currently regarded as the golden standard. However, titanium devices also have disadvantages. They interfere with radiotherapy and imaging techniques. Besides, titanium implants have been associated with complications such as growth restriction and brain damage, infection, and possible mutagenic effects. A second intervention to remove the implants implies additional surgical discomfort, risks, and associated socio-economical costs. Biodegradable osteofixation systems have the possibility to degrade, thus preventing the need for a second intervention. Another advantage of biodegradable devices is their radiolucency, implying good compatibility with radiotherapy and imaging techniques. Since the introduction of biodegradable devices in 1966, the development of their mechanical properties and degradation characteristics has been extensive. Numerous in vitro, animal, and clinical studies have been published with positive as well as negative results. Despite the supposed advantages of biodegradable osteofixation devices, these systems did not replace the titanium systems and are currently applied in only limited numbers. The mechanical properties are less favourable and ultimate resorption has not been proven. Another significant factor of the limited use is the resistance by surgeons to modify their conventional, well experienced, treatment techniques. The major drawback for general use of biodegradable devices is the lack of clinical evidence. The general aim of this thesis was to establish the effectiveness and safety of biodegradable plates and screws to fix bone segments in the maxillofacial skeleton as a potential alternative to metallic ones.

Chapter 4 comprises a randomized controlled trial regarding the effectiveness and safety of biodegradable plates and screws as a potential alternative to metallic ones. The multicentre RCT was conducted from December 2006 to July 2009. Included were patients who underwent mandibular- and Le Fort I osteotomies and those with fractures of the mandible, maxilla, or zygoma. The patients were assigned to a titanium control-group (KLS Martin) or to a biodegradable test-group (Inion CPS). The primary outcome measure was ‘bone healing 8 weeks after surgery’. The Intention To Treat analysis (ITT) of 111 patients in the titanium group and 112 patients in the biodegradable group yielded a non-significant difference. In 25 patients (22%) who were included in the biodegradable group, the surgeon made the decision to switch to the titanium system per-operatively. Concerning most of the secondary outcome measures, the biodegradable system appeared to be non-inferior to the titanium system. In contrast, the handling characteristics showed a remarkable difference between both systems whereby biodegradable plates and screws were more difficult in use as compared to titanium plates and screws. Despite the ‘non inferior’ primary outcome result, the benefits of using biodegradable systems (less plate removal operations) should be demonstrated during a follow-up of minimally 5 years, especially when the large number of patients for whom it was per-operatively decided to switch from the biodegradable system to the conventional titanium system, are taken into account.

CHAPTER 7

LactoSorb, and Inion CPS 2.5 mm systems have high mechanical device strength and stiffness compared to the investigated biodegradable osteofixation systems. In addition, the results presented in chapter 3.2.2 yielded that the SonicWeld Rx system is an improvement in the search for a mechanically strong and stiff biodegradable osteofixation system. Future research should be done in order to find out whether the promising in vitro results can be transferred to the in situ clinical situation.

The main research outcomes are discussed and general conclusions are drawn in chapter 5. Based on the results of the RCT performed in this thesis, it is concluded that biodegradable plates and screws do not perform inferior to titanium regarding a followup period of 8 weeks. The high percentage of per-operative switches from biodegradable to titanium is a threat to a widespread acceptation of biodegradable plates and screws in the current treatment protocols and guidelines in maxillofacial surgery. The follow-up period of 1 year is expected to provide more clarity about the potential differences in plate removal operations and thus the potential gain in effectiveness in the treatment of fractures and osteotomies of the maxillofacial skeleton. The 1 year follow up results will also provide more information about the skeletal stability, biocompatibility, and resorption aspects of Inion CPS plates and screws.

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DUTCH SUMMARY

Hoofdstuk 2 omvat een systematische review van de beschikbare literatuur om de effectiviteit en veiligheid van biodegradeerbare platen en schroeven in vergelijking met titanium platen en schroeven vast te stellen. Een uitgebreide zoekstrategie in de databases van MEDLINE (1966-2005), EMBASE (1989-2005) en CENTRAL (1800-2005) werd uitgevoerd om in aanmerking komende studies te identificeren. De relevantie van de studies werd geëvalueerd door een eerste selectie op basis van titel en samenvatting. In aanmerking komende studies werden onafhankelijk van elkaar beoordeeld door twee beoordelaars met behulp van een schaal waarop de kwaliteit van de studie kan worden getoetst. De procedure leverde vier methodologisch ‘aanvaardbare’ artikelen op. Vanwege de verschillende uitkomstmaten die waren gebruikt in de studies, was het onmogelijk om een meta-analyse uit te voeren. De belangrijkste effecten met betrekking tot de stabiliteit

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en de veiligheid van fractuurfixatie werden dan ook kwalitatief beschreven. Definitieve conclusies met betrekking tot de fixatie van gebroken botsegmenten konden niet worden getrokken als gevolg van het ontbreken van gecontroleerde klinische studies. Met betrekking tot de fixatie van botsegmenten bij orthognatische behandelingen, waren slechts een paar gecontroleerde klinische studies beschikbaar. Er leek op de korte termijn geen significant verschil te zijn tussen titanium en biodegradeerbare fixatie systemen met betrekking tot de stabiliteit en veiligheid. Echter, definitieve conclusies met betrekking tot de lange termijn prestaties van biodegradeerbare platen en schroeven konden niet worden getrokken. Hoofdstuk 3 richt zich op de mechanische eigenschappen van biodegradeerbare versus titanium platen en schroeven. In hoofdstuk 3.1 werden de verschillen onderzocht in het maximale draaimoment van 7 commercieel verkrijgbare biodegradeerbare en 2 commercieel verkrijgbare titanium schroeven. Bovendien werden de verschillen in het maximale draaimoment tussen ‘handvast’ en het breken van de schroef (‘breuk’) onderzocht. Vier kaakchirurgen draaiden 8 exemplaren van alle 9 verschillende schroeven in polymethylmethacrylaat (PMMA) platen. De chirurgen kregen de opdracht het aandraaien en plaatsen van de schroeven zo te doen als dat ze dat zouden doen in de kliniek (‘handvast’). De gegevens werden geregistreerd door de draaimoment-meter. Een promovendus schroefde eenzelfde set van 8 exemplaren van de 9 schroeven in de PMMA platen totdat breuk optrad. Het maximale draaimoment werd opgenomen en genoteerd. Het maximale draaimoment van de 2 verschillende titanium schroeven (1,5 mm en 2,0 mm) was significant hoger dan dat van de 7 biodegradeerbare schroeven (2,0 mm, 2,1 mm en 2,5 mm). Daarnaast kon worden vastgesteld dat het maximale draaimoment voor ‘handvast’ voor 2 biodegradeerbare alsook beide titanium schroeven, significant lager was dan voor ‘breuk’. Op basis van de resultaten concluderen we dat de 1,5- en 2,0 mm titanium schroeven het hoogste draaimoment vertonen. Wanneer er een voornemen is om biologisch afbreekbare schroeven te gebruiken, raden wij het gebruik van 2,0 mm BioSorb FX, 2,0 mm LactoSorb of de 2,5 mm Inion CPS schroeven aan. In hoofdstuk 3.2.1 en 3.2.2 worden relevante mechanische eigenschappen gepresenteerd met het oog op een goede selectie van platen en schroeven voor het immobiliseren van botsegmenten in de kaakchirurgie. Zeven biologisch afbreekbare en 2 titanium plaat- en schroef systemen, werden onderzocht in hoofdstuk 3.2.1, terwijl additioneel het SonicWeld Rx biologisch afbreekbaar plaat- en pin systeem in hoofdstuk 3.2.2 werd onderzocht. Het SonicWeld Rx systeem maakt gebruik van een ultra-geluid geactiveerde sonische elektrode voor het plaatsen van de biologisch afbreekbare pin in het boorgat. Als gevolg van de toegevoegde ultrasone energie, zal de thermoplastisch biologisch afbreekbare pin smelten. Dit resulteert in een stroom van plastische polymeren in de holten van het trabeculaire bot. Tegelijkertijd versmelten de biologisch afbreekbare plaat en kop van de pin. De platen en schroeven werden vastgezet op 2 polymethylmethacrylaat (PMMA) blokken welke botsegmenten simuleren. De platen en

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Maxillofaciale traumatologie en orthognathische chirurgie zijn belangrijke deelgebieden binnen de kaakchirurgie. Interne rigide fixatie systemen, dat wil zeggen platen en schroeven, worden gebruikt voor fixatie en stabilisatie van kaakfracturen of kaakverplaatsingen. Platen en schroeven zijn meestal gemaakt van titanium en worden op dit moment beschouwd als de gouden standaard. Titanium platen en schroeven hebben ook nadelen. Ze interfereren met radiotherapie en beeldvormende technieken. Verder zijn titanium platen en schroeven in verband gebracht met complicaties zoals groeiachterstand en hersenbeschadiging, infectie, en mogelijke mutagene effecten. Om deze nadelen weg te nemen worden de platen en schroeven in 5-40% van de gevallen verwijderd. Dit impliceert extra chirurgisch ongemak, risico’s en daarmee samenhangende sociaal-economische kosten. Biologisch afbreekbare platen en schroeven hebben de mogelijkheid om in het lichaam af te breken, waardoor de noodzaak van een tweede interventie zou worden voorkomen. Een ander voordeel van biodegradeerbare platen en schroeven is hun radiolucentie, wat een goede compatibiliteit met radiotherapie en beeldvormende technieken toelaat. Sinds de introductie van biologisch afbreekbare platen en schroeven in 1966, heeft de ontwikkeling van hun mechanische eigenschappen en degradatie karakteristieken een uitgebreide ontwikkeling doorgemaakt. Vele in vitro-, dier- en klinische studies zijn gepubliceerd met zowel positieve als negatieve resultaten. Ondanks de veronderstelde voordelen van biodegradeerbare platen en schroeven, hebben deze de titanium platen en schroeven (nog) niet vervangen. Biodegradeerbare platen en schroeven worden slechts in beperkte aantallen gebruikt. De mechanische eigenschappen zijn minder gunstig en de uiteindelijke (volledige) resorptie is niet bewezen. Een andere belangrijke factor van het beperkte gebruik is de weerstand van chirurgen om hun traditionele, zeer ervaren technieken en behandelwijze te wijzigen. Echter, het gebrek aan overtuigend klinisch wetenschappelijk bewijs is wellicht het belangrijkste aspect voor het summiere gebruik van biodegradeerbare platen en schroeven. Het doel van dit promotieonderzoek was om de effectiviteit en veiligheid van biodegradeerbare platen en schroeven vast te stellen bij het vastzetten van botsegmenten in het maxillofaciale skelet als een potentieel alternatief voor metalen platen en schroeven.

men rekening houdt met het grote aantal patiënten voor wie per-operatief besloten is om van de biologisch afbreekbare platen en schroeven over te schakelen naar de conventionele titanium platen en schroeven. De belangrijkste onderzoeksresultaten worden besproken en algemene conclusies worden getrokken in hoofdstuk 5. Gebaseerd op de resultaten van de RCT uitgevoerd in dit proefschrift wordt geconcludeerd dat biologisch afbreekbare platen en schroeven niet inferieur zijn aan titanium platen en schroeven met betrekking tot de botheling 8 weken na chirurgie. Het hoge percentage van de per-operatieve switches van biologisch afbreekbare platen en schroeven naar titanium platen en schroeven is echter wel een bedreiging voor een brede acceptatie en invoering in protocollen en richtlijnen in de kaakchirurgie. De follow-up periode van 1 jaar zal naar verwachting meer duidelijkheid over de mogelijke verschillen in de plaat verwijdering geven. En dus ook in en de eventuele winst in effectiviteit bij de behandeling van breuken en osteotomieën van het maxillofaciale skelet. De 1-jaars follow-up resultaten zullen ook meer informatie moeten geven over de skeletale stabiliteit, biocompatibiliteit en resorptie aspecten van Inion CPS platen en schroeven.

Hoofdstuk 4 omvat een gerandomiseerde gecontroleerde studie met betrekking tot de effectiviteit en veiligheid van biologisch afbreekbare platen en schroeven als een potentieel alternatief voor metalen platen en schroeven. De multi-center RCT werd uitgevoerd van december 2006 tot juli 2009. Patiënten bij wie een onderkaak- en bovenkaak osteotomie werd uitgevoerd, en mensen met fracturen van de onderkaak, bovenkaak, of het jukbeencomplex, werden geïncludeerd in de studie. De patiënten werden toegewezen aan een titanium controlegroep (KLS Martin) of een biologisch afbreekbare testgroep (Inion CPS). De primaire uitkomstmaat was ‘botgenezing 8 weken na chirurgie’. De ‘intention to treat-analyse’ (ITT) van 111 patiënten in de titanium groep en 112 patiënten in de biologisch afbreekbare groep leverde een niet-significant verschil op. Bij 25 patiënten (22%) die werden geïncludeerd in de biologisch afbreekbare studiegroep, nam de chirurg per-operatief de beslissing om over te schakelen naar het titanium systeem. Met betrekking tot de meeste van de secundaire uitkomstmaten, bleek dat het biologisch afbreekbare systeem niet inferieur was aan het titanium systeem. In tegenstelling tot bovengenoemde, bleek dat de handelingeigenschappen een opvallend verschil vertoonde tussen beide systemen. De biologisch afbreekbare platen en schroeven waren moeilijker in het gebruik in vergelijking met titanium platen en schroeven. Ondanks de ‘niet inferieure’ resultaten aangaande de primaire uitkomstmaat, moeten de voordelen van het gebruik van biologisch afbreekbare systemen (minder plaat verwijdering) worden bevestigd gedurende een follow-up van minimaal 5 jaar. Dit geldt voornamelijk wanneer

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schroeven werden onderworpen aan trek-, zijdelings buigen-, en torsie- tests. Tijdens trekproeven werd de sterkte gemeten. De stijfheid werd berekend voor de trek-, zijdelings buigen- en torsie- testen. De resultaten waren dat de twee titanium systemen (1,5 mm en 2,0 mm) significant hogere treksterktes en stijfheid presenteerden ten opzichte van de 7 biologisch afbreekbare systemen (2,0 mm, 2,1 mm en 2,5 mm). Het 2,0 mm titanium systeem presenteerde significant hogere zijdelingse buigen torsiestijfheid dan de andere 7-systemen (hoofdstuk 3.2.1). Met betrekking tot de SonicWeld Rx biologisch afbreekbare platen en pinnen (hoofdstuk 3.2.2), presenteerde de treksterkte en stijfheid, alsmede de zijdelingse buigstijfheid van dat systeem tot 11,5 maal hogere waarden dan de conventionele biologisch afbreekbare Resorb X platen en schroeven. De torsiestijfheid van beide systemen presenteerde vergelijkbare waarden. Gebaseerd op de resultaten kon worden geconcludeerd dat de titanium platen en schroeven sterker en stijver zijn dan de biologisch afbreekbare systemen. De BioSorb FX, LactoSorb, Inion CPS 2,5 mmplaten en schroeven hebben een hoge mechanische sterkte en stijfheid in vergelijking met de andere onderzochte biologisch afbreekbare platen en schroeven. Daarnaast lieten de resultaten, gepresenteerd in hoofdstuk 3.2.2, zien dat de SonicWeld Rx platen en pinnen een sterke verbetering betroffen in het zoeken naar een mechanisch sterk en stijf biologisch afbreekbaar fixatie systeem. Toekomstig onderzoek moet worden uitgevoerd om uit te vinden of de veelbelovende in vitro resultaten kunnen worden vertaald naar de in situ klinische situatie.

DANKWOORD

Geachte prof. de Bont, veel dank voor het feit dat ik mocht beginnen aan dit promotietraject alsook de vrijheid die u mij heeft gegeven in het afronden hiervan.

Veel mensen hebben geholpen om dit proefschrift tot een goed einde te brengen. Allereerst wil ik de patiënten bedanken die hebben gekozen om deel te nemen aan de grootste en enige patiënten studie van dit proefschrift. Iedereen hartelijk dank hiervoor!

Geachte drs. van der Houwen, beste Ward, samen hebben we vele uren achter de computer en de trekbank doorgebracht om de mechanische testen te bedenken, te testen en uit te voeren. Het was altijd gezellig en inspirerend. In het bijzonder je ‘net iets andere’ kijk op dingen en zaken in de maatschappij heb ik altijd erg leuk gevonden! Voor mij is het proefschrift nu afgerond; ik hoop dat je snel zult volgen!

Geachte prof. dr. Bos, enthousiasmerende 1ste promotor, best Ruud, altijd druk, maar toch ook altijd tijd! Je ongeëvenaarde aanstekelijke enthousiasme heeft ervoor gezorgd dat ik je heb gevraagd begeleider te worden voor mijn scriptie. Dit heeft uiteindelijk de basis gevormd voor dit proefschrift. Mede door al je contacten op het gebied van de biodegradeerbare materialen alsook de bewaker van de grote lijnen heeft dit proefschrift tot een goed einde kunnen komen. Naast het onderzoek was je ook ‘bewaker van een ontspannen sfeer’ en had je altijd interesse in zaken buiten het onderzoek. Hartelijk dank daarvoor! Geachte prof. dr. Stegenga, scherpzinnige 2e promotor, beste Boudewijn, onze vele onderzoeksbesprekingen waren altijd bijzonder leerzaam. Soms ging ik weg met het gevoel dat er honderden beren op de weg waren bijgekomen en, soms ook met een gevoel van ‘yes’ we hebben weer stappen in de goede richting gezet. Je hebt me geleerd kritisch te zijn, oplossingsgericht te denken, en alles in hapklare brokken te verwerken. De keren dat de brokken in m’n keel bleven hangen, kon ik altijd bij je terecht. Veel dank voor dit alles, ik heb veel van je geleerd! Geachte prof. dr. Verkerke, beste 3e promotor, beste Bart, dank voor de samenwerking en de kritische commentaren ‘vanuit een andere invalshoek’ welke de 3 artikelen uit hoofdstuk 3 voor een belangrijk deel hebben vormgegeven. Geachte dr. Jansma, beste co-promotor, beste Johan, je hebt verreweg de meeste patiënten met oplosbare platen en schroeven behandeld. Je hebt daarmee een belangrijke bijdrage geleverd aan het tot stand komen van de RCT. Je praktische en klinische blik hebben bovendien voor waardevolle open aanmerkingen gezorgd bij het schrijven van het artikel van de RCT alsook de afronding van mijn proefschrift.

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Geachte leden van de promotie commissie, geachte prof. dr. de Lange en geachte prof. dr. Tuinzing, ik ben u zeer erkentelijk voor de snelle en nauwgezette beoordeling van het manuscript. Dear member of the appraisal committee, dear prof. Gerlach, thanks for the fast and the accurate appraisal of the manuscript.

Geachte dr. de Visscher, dr. Hoppenreijs, dr. Brouns, dr. Fennis, dr. Bergsma, dr. Gooris en de secretariaten van bovengenoemde heren, beste Jan, Theo, John, Jeroen, Eelco en Peter. Veel dank voor het uitvoeren van de operaties bij de patiënten en het invullen en opsturen van de formulieren. Al jullie inspanningen hebben geleid tot de grootste gerandomiseerde klinische studie naar osteotomieen en fracturen in het aangezicht van dit moment. Drs. N.B. van Bakelen, beste Nico, we leerden elkaar kennen op het introductiekamp van Panacea, jij ging geneeskunde doen en ik tandheelkunde. Gelukkig zijn we elkaar niet uit het oog verloren. We werden vrienden, huisgenoten en uiteindelijk ook collega promovendus. Ik ben zeer blij met de manier waarop jij ‘mijn’ promotieonderzoek hebt opgepakt. De manier waarop jij dat hebt vormgegeven vind ik bewonderenswaardig. Je nauwgezette manier van werken en je ongeëvenaarde inzet kenmerken je als collega en goede vriend en zullen je helpen ‘jouw’ proefschrift tot een goed einde te brengen. Bedankt dat je mijn paranimf wilt zijn. Drs. H.J.W.E. de Lange, beste Henk-Jan, onze passie voor de tandheelkunde heeft ons niet alleen vele levendige discussies opgeleverd, maar ook een bijzondere vriendschap. De gesprekken en discussies doorspekt met humor en metaforen zijn altijd erg aanstekelijk. Je onophoudelijke interesse in mijn onderzoek en in mijn persoon heb ik altijd als zeer waardevol ervaren. Ik hoop daar nog lang van te mogen genieten. Bedankt dat je mijn paranimf wilt zijn. Geacht secretariaat, beste Karin, Lisa en Nienke, dank voor jullie plezierige koffiemomenten en gezelligheid. Als er taart was wisten jullie mij gelukkig als een van de eerste te vinden!

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DANKWOORD

Eindelijk is het zover! Begonnen aan een promotietraject met als doel kaakchirurg te worden. Enkele jaren later blijkt dat er voor mij bijzonder grote uitdagingen liggen binnen de tandheelkunde. Er waren reeds drie artikelen gepubliceerd, en het vierde artikel was geaccepteerd. Alhoewel de follow-up van het vijfde artikel 8 weken betrof, duurde de daadwerkelijke afronding hiervan, nog vele weken langer. Na 7 jaren is het proefschrift dan af. Tijd voor nieuwe hoofdstukken binnen de tandheelkunde, sociale activiteiten, hobby’s, vrienden en familie. Maar eerst nog de afronding op de Broerstraat voordat dit hoofdstuk gesloten kan worden.

Medewerkers en kaakchirurgen in opleiding van de afdelingen Kaakchirurgie in het UMCG, het Amphia ziekenhuis Breda, het Medisch Centrum Leeuwarden en het Rijnstate Ziekenhuis Arnhem en ieder ander niet met naam en toenaam genoemd die heeft geholpen de RCT in hoofdstuk 4 tot een goed einde te brengen, hartelijk dank hiervoor. Alle mede-onderzoekers van de afdeling Kaakchirurgie op de derde verdieping. Hartelijk dank voor de belangstelling en interesse de afgelopen jaren.

Broertjes, lieve Janne, lieve Jauke, de afgelopen tijd hebben we weinig tijd gehad om samen leuke dingen te doen. Toch hebben jullie altijd belangstelling getoond en tijdens de familie aangelegenheden hebben we veel gelachen. Nu de drukke periode wat verminderd is, kunnen we dit weer meer gaan oppakken.

DANKWOORD

Lieve vrienden; Jeroen en Anke, Klaske en Pieter, Wietse en Annemarie, Marieke, Alies, Maurits, Leony, Christiaan, Marco, Stephan, Eric en Derk Jan, dank voor jullie warme belangstelling voor mijn onderzoek en de gezelligheid en biertjes in de kroeg en daarbuiten welke voor de nodige afleiding hebben gezorgd.

Lieve pap en mam, jullie hebben me altijd gesteund in wat voor opzicht dan ook. Nooit hebben jullie me gestuurd in dingen; jullie hebben me altijd vrijgelaten om mij mijn eigen keuzes te laten maken. Maar, jullie gaven wel jullie visie en ideeën op de keuzes die ik maakte en de manier waarop ik tegen dingen aankeek. Nooit heb ik daarbij het gevoel gehad daarbij belemmerd te worden, maar juist heeft mij dat het gevoel gegeven van ‘altijd bij jullie terecht kunnen’. Jullie zijn er altijd voor me! Lieve Kirs, jij bent degene die het proces van promoveren van dichtbij hebt meegemaakt. Regelmatig kwam ik met stukken naar je toe met de vraag of je naar het Engels wilde kijken. Gelukkig wilde je altijd tijd vrijmaken om me hierbij te helpen. Gelukkig hielp je me ook bij het zien dat promoveren en werken als tandarts niet de enige bezigheden zijn die optimale aandacht verdienen. Ironisch genoeg ben je nu zelf ook een promotieonderzoek begonnen en ga je ook drukke tijden tegemoet. Je hebt me geholpen me te ontspannen op de momenten dat dit nodig was. Met het afronden van dit proefschrift zal ik daar ongetwijfeld meer tijd voor krijgen. En, zal ik zorgen dat jij ook aan je ontspanning komt. Elke dag geniet ik van jouw aanwezigheid, je grappen en je mooie verschijning. Ik hoop dat we samen nog veel mogen reizen en genieten van elkaar. I love you!

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CURRICULUM VITAE Jappe Buijs was born on November 18th 1980 in Purmerend, the Netherlands. After finishing secondary school in 1999 at the ‘Baudartius College’ in Zutphen, he studied Dentistry at the University of Groningen. During his study, in cooperation with other faculty students, he founded the ‘dental faculty association Archigenes’ and took place in the first board. He obtained his qualification as a dentist in 2004. Subsequently he started his PhD research project. In January 1st 2008 he became partner in the private practice ‘de Boer Tandartsen’ in Groningen. Jappe is living together with Kirsten Slagter, dentist, PhD-resident.

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