December 2023
What Is the Role of Platelet-Derived Biologics? Editorial Summary This article explores the surgical strategy of platelet-derived orthobiologics, providing an overview of the benefits of their use and a consideration of the future of these products.
Introduction
O Prof Anand Pillai Consultant Orthopaedic Foot & Ankle and Adult Reconstruction Surgeon Manchester, United Kingdom
rthobiologics therapies have gained considerable interest in recent years. They are increasingly becoming popular for treatment of a variety of musculoskeletal pathologies. The term ‘biologic’ refers to a naturally occurring substance with the ability to heal, and ‘ortho’ refers to its application in musculoskeletal tissue. They are different from ‘biologic’ drugs commonly used now for treatment of rheumatological conditions. A wide array of orthobiologics are available but the broad categories of preparations include, but are not limited to: autologous blood products, cell-based therapies, and growth factors. In this article, various autologous blood products and their roles are discussed.1 Autologous blood products refers to any preparation derived from a patient’s whole blood. These include a range of products that can be further categorised into platelet-rich plasma (PRP), platelet poor-plasma (PPP) and autologous anti-inflammatory preparations (AAIs).2 Figure 1: Steps in preparation of PRP and PPP.
Dr Vish Kumar Consultant Orthopaedic Foot and Ankle Surgeon at Wye Valley NHS Trust & Spire Banks Hospital Worcester, United Kingdom
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As ‘natural’ treatments, these products are an attractive option for both patients and clinicians as they eliminate concerns about immunogenic reactions and disease transmission. Platelet-rich plasma is a volume of plasma fraction of autologous blood having platelet concentrations above baseline where platelet count is usually 5 times higher than that of blood. PRP was first used to aid wound healing in 1987 after cardiac bypass surgery. It was first used in orthopaedics in 2003 for treatment of recalcitrant tennis elbow. PRP can be prepared in the laboratory, in the operating theatre or the clinic, from venous blood collected immediately before treatment. There are 3 techniques for PRP preparation: the gravitational platelet sequestration (GPS) technique, standard cell separators, and autologous selective filtration technology, also referred to as plateletpheresis. A small amount of PRP can be obtained in minutes using the GPS technique which is a table-top centrifuge system. For example, 5 ml of PRP volume can be prepared following a 12 minute spin at 3200 rpm using a GPS system.
What Is the Role of Platelet-Derived Biologics?
“Once the PRP is activated, its advocates suggest benefits including restoration of bone and soft tissue, improved wound healing, and a reduction in post-operative infection and blood loss.”
An anticoagulant such as citrate dextrose (ACD) is added where citrate binds calcium and prevents coagulation, whereas dextrose supports platelet metabolism and viability. PRP is stable in the anticoagulated state for 8 hours or longer allowing the blood to be drawn before the operation and used as needed during long surgical procedures. Once PRP is prepared, it must be activated for platelets to release its granules bioactive contents. This is usually accomplished by adding a small amount of topical bovine thrombin and 10% calcium chloride to the PRP.2 Once the PRP is activated, its advocates suggest benefits including restoration of bone and soft tissue, improved wound healing, and a reduction in post-operative infection and blood loss. There has been several publications on the use of PRP for clinical applications in plastic surgery, oral surgery, trauma and orthopaedic surgery, spinal fusion surgery, heart bypass surgery and in the treatment of chronic skin and soft-tissue ulcers.4,5 PRP preparations can be further subdivided into leucocyte-poor preparations (LP-PRP; defined as having a leucocyte concentration below baseline) and leucocyte rich preparations (LR-PRP; defined as having a leucocyte concentration above baseline.
Autologous Anti-inflammatories Preparations (AAIs) With an increasing appreciation that many of the anti-inflammatory factors within blood arise from leucocytes rather than platelets, strategies focussing on concentrating leucocytes or the anti-inflammatory factors they release have been developed. These include platelet-poor plasma (PPP) and AAIs. AAI formulations include Autologous Protein Solution (APS) (nStride) and Autologousconditioned serum ACS (known as Orthokine
in Europe and Regenokine in the US). APS is an AAI that has supraphysiological concentrations of anti-inflammatory factor ILr. APS is produced by obtaining LR-PRP, which is then filtered through polyacrylamide beads producing a high concentration of anti-inflammatory cytokines while ensuring low levels of pro-inflammatory contents. ACS is another AAI which is a cell free serum containing anti-inflammatory factors released from activated leucocytes. ACS is obtained by drawing whole blood and incubating this with chromium sulphate to stimulate the synthesis of interleukin-1 (IL-1) receptor antagonists and other anti-inflammatory cytokines. This then undergoes filtration and centrifugation prior to intra-articular injections to treat osteoarthritic conditions such as knee OA.1
Biological Properties and Activities of PRP Platelets are the smallest of the blood cells, approximately 2 μm in diameter. Theirα granules contain more than 30 bioactive proteins such as Platelet Derived Growth factor (PDGF), Transforming Growth Factors-Beta (TGF-B), Vascular Endothelial Growth Factors (VEGF), among others. These proteins have a fundamental role in haemostasis and tissue healing. The biological properties of PRP are based on the production and release of these multiple growth and differentiation factors when the platelets are activated. Platelets actively begin secreting these proteins within 10 minutes of clotting. Healing of both soft and hard tissue is mediated by a complex array of intra- and extra- cellular events that are regulated by these signaling proteins.5
Safety Profile of PRP PRP preparations are generally safe. However, activation of PRP requires bovine thrombin preparations which has some concerns related to coagulopathies, especially when used in large
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What Is the Role of Platelet-Derived Biologics? amounts. Table 1: Broad categories of Autologous blood products. Autologous blood products
Platelet rich plasma (PRP)
Autologous antiinflammatories (AAIs)
PRP subdivisions
Commercially available separator devices
Leucocyte poorPRP (LP-PRP)
ACP, Arthrex A-PRP, Regenlab Cascade, MTF clearPRP, Harvest PurePRP, EmCyte Endoret (PGRF0, BTI
Leucocyte richPRP (LR-PRP)
GPSIII, ZimmerBiomet Angel, Arthrex GenesisCS, EmCyte Magellan, Arteriocyte, SMART PReP, Harvest
Autologous Protein Solution (APS)
nStride, ZimmerBiomet
Autologous Conditioned Serum (ACS)
Orthokine, Orthogen
In the UK, PRP is classed as an unlicensed human medicine. Therefore, it is subject to human medicines legislation. Recently, there have been some concerns in relation to its unregulated widespread use, so much so that it has come under scrutiny by some professional bodies. The Royal College of Podiatry (RCPod) is instructing its members to stop providing platelet-rich plasma (PRP) therapy to patients with immediate effect; the RCPod is instructing any members who undertake PRP injections to suspend their use while an urgent review of information from the Medical Healthcare Regulatory Authority (MHRA) takes place.6 It is recommended any clinician offering PRP therapy should do so within a clinical governance framework.
Global Market of PRP Despite the lack of sound evidence use of PRP is increasing. The global platelet rich plasma (PRP) market size was valued at USD 627.9 million in 2022 and is expected to grow at a compound annual growth rate of 15% from 2023 to 2030. Platelet-rich plasma usage is witnessing growth owing to the increasing participation in sporting events leading to increasing cases of sports injuries, and an upsurge in cosmetic surgery.
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Increasing research applications of platelet rich plasma (PRP) are also fuelling the industry growth. The growth of PRP treatment in the upcoming years may involve treating the large geriatric population, and in dental health. For instance, in 2020, according to the American Society of Plastic Surgeons, a 25% rise in the use of PRP in cosmetics was observed in the last 4 years.7
Conclusion Orthobiologics and regenerative therapies, particularly PRP, represents an exciting field with multiple potential uses. However, many products with different trade names and descriptions continue to be introduced making the terminology and nomenclature of these therapies ambiguous and difficult to follow. More research trials with linked clinical registries and biospecimen repositories are needed to standardize and substantiate its continued future use.
References 1. Toland GE, Makaram NS, Atzmon R et al. Orthobiologics in the knee. Orthopaedics and Trauma 37:3, 2023. 2. Murray IR SM, De Bari C, McCaskie AW. Orthobiologics: scientific background. J Trauma Orthop 2022;10:48-9As ‘Natural’ treatments, attractive option for both patients and Surgeons/ Clinicians 3. J Alsousou , M Thompson, P Hulley, A Noble, K Willett. The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature. J Bone Joint Surg Br. 2009 Aug; 91(8):987-96. 4. Kumar V, Millar T, Murphy PN, Clough T. The treatment of intractable plantar fasciitis with platelet-rich plasma injection. Foot (Edinb). 2013 Jun-Sep; 23(2-3):74-7. 5. Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: a review of biology and applications in plastic surgery. Plast Reconstr Surg. 2006 Nov;118(6):147e-159e. 6. RCPod tells its members to stop providing PRP injections. Royal College of Podiatry. Available at: https://rcpod.org.uk/news/rcpod-tells-its-members-to-stop-providing-prpinjections. [Accessed on 17th June 2023]. 7. Platelet Rich Plasma (PRP) Market Size, Share & Trends Analysis Report By Type (Pure, Leukocyte Rich), By Application (Orthopedics, Sports Medicine, Cosmetic Surgery), By End-use, By Region, And Segment Forecasts, 2023 - 2030. Grand View Research. Available at: https://www.grandviewresearch.com/industry-analysis/platelet-rich-plasma-prp-market. [Accessed on 16 June 2023].