Intra-articular platelet-rich plasma for the treatment of osteoarthritis

Platelet-rich plasma (PRP) is an autologous blood derivative that has been used in different medical fields, ranging from dermatology to ophthalmology and orthopaedic surgery, with the aim of stimulating tissue healing through the local administration of a milieu of platelet-derived growth factors and other bioactive molecules (1). In the orthopaedic practice its main application is in sports medicine (2,3) and in the treatment of degenerative disorders, in particular osteoarthritis (OA) (4). Due to its intrinsic features, PRP is believed to play a beneficial role in joint tissue homeostasis, exerting a positive modulation on all the articular tissues involved in the OA degenerative process, i.e., cartilage, menisci, and synovia (5).

The most common therapeutic approach for PRP application in joint OA consists in intra-articular injections, which can be safely performed in an outpatient setting. PRP intra-articular injection has soon encountered a large success among clinicians, mainly due to the autologous nature of this blood-derived product and due to the attractive perspective of providing a direct stimulus to tissue healing. More than a decade has passed from the very first experiences with intra-articular platelet concentrate (6) but, despite initial enthusiasm and encouraging preliminary results, there is still lack of sounding evidence to recommend it as a first line treatment for the conservative management of OA. The commercial success of PRP has not been backed up by a robust evidence to fully endorse it: in fact, the promising clinical outcomes reported by preliminary case series have not been completely confirmed by high level randomized controlled trials. Just a few double blinded randomised controlled clinical trials (RCTs) are currently available and the overall findings do not allow to assess a clear superiority of PRP over other more traditional approaches. While Patel et al. (7) were able to demonstrate that a single PRP injection could provide superior clinical outcome compared to saline solution, Filardo et al. (8) failed to document any true, substantial advantage of this blood-derivative compared to viscosupplementation. In particular, the authors could not find any significant inter-group difference at any follow-up evaluation in their trial, which included the strongest study design with the largest cohort of patients currently available in literature. Similar findings were also reported by Battaglia et al. (9), who compared PRP to HA in hip OA without showing any superior clinical benefit exerted by growth factors administration.

While a clear superiority compared to other treatments remains to be proven and a powerful placebo effect has been ascribed to PRP (10), its effectiveness is supported by the available literature, with overall positive outcomes in terms of symptomatic relief and functional recovery over time. Single blinded randomized or comparative trials have highlighted better results for PRP compared to saline or HA (11-13).

The main reason beyond these controversial findings, as well as the still inconclusive evidence to support the use of PRP injections in the clinical practice may be due to the great inter-product variability, which is currently the most debated issue in the field of PRP research. From the very beginning of PRP clinical application, several products have been developed and tested, characterized by different preparation methods (blood centrifugation or filtration), different platelet concentration rate, cellular content, activation strategies, storage modalities and also applicative protocols (14,15). Furthermore, PRP has been applied to treat different phases of articular degeneration, ranging from simple chondropathy to severe OA, and different responses may be ascribed to different disease stages. A superior benefit from PRP application has been hypothesized in lower degrees of cartilage degeneration but the relatively small number of patients included in the current trials has prevented any definitive sub-group analysis. The number of variables to consider is so high that it has been yet impossible to identify the best formulation and therapeutic strategy to fully exploit the potential of PRP and its many biological actions. Despite many attempts to classify different PRP products (16,17), the clinical relevancy of those classifications is questionable, and they are mainly used for research purpose to favour study comparison rather than for guiding clinicians to opt for a particular PRP formulation to address a specific clinical need.

In light of the rising interest towards the application of biologics in the orthopaedic practice, several companies have launched their proprietary formulations on the market and several authors have proposed their particular therapeutic protocols (differing in terms of number of injections and time interval), claiming hypothetical superiority in terms of quality and clinical benefit. In vitro and animal studies have been performed in the attempt to shed some light on this controversial field, but even in this case findings have not always been univocal. The paradigmatic example is the role of leukocytes, which is among the most discussed aspects concerning PRP formulation in terms of clinical implications. The presence of leukocytes has been deemed to be detrimental and impair the overall effects of PRP due to the release of metalloproteinases and other lytic enzymes that could interfere with growth factors action and stimulate an early inflammatory response within the joint environment (18,19). Based on the data coming from some in-vitro trials (20,21), clinicians argued that leukocyte-poor PRP should be preferred for intra-articular administration. However, the only available clinical trial that compared leukocyte-rich and leukocyte-poor PRP showed no difference in the clinical scores between the two biological approaches, revealing just slightly higher post-injective pain and swelling reaction in the leukocyte-rich PRP group (22). More recently, a systematic review analyzed the adverse events following PRP injection and found a similar safety profile between the different products, suggesting that leukocytes may not be crucial in terms of side effects and overall clinical benefit (23). In light of these recent findings, the role of leukocytes still needs to be fully understood, also taking into account the different leukocytes sub-populations that could exert specific and very different actions in modulating joint homeostasis (24). Therefore, the hunting for the “bad”, the “good” and the “ugly” in PRP formulations is still ongoing, and the increasing pre-clinical efforts leave still many unanswered questions. The in-vitro setting cannot perfectly mimic the much more complex in-vivo scenario, therefore the evidence coming from pre-clinical trials may not be completely mirrored when going into human application, which supports the need for more clinical comparative trials.

PRP technology is still under development and will likely undergo optimization in the future through the identification of factors, related both to the product and to the patient, leading to beneficial effects while avoiding any impairment of joint tissue homeostasis (6). There is still a wide margin to improve this biological treatment approach, and further research efforts are needed to fully exploit the potential of PRP for the treatment of OA.

Acknowledgements

None.

Footnote

Conflicts of Interest: B Di Matteo has nothing to disclose; G Filardo is consultant for CartiHeal (2009) Ltd (Israel) and EON Medica (Italy), and he received institutional support from Finceramica SpA, Italy, Fidia SpA, Italy IGEA Clinical Biophysics (Italy), BIOMET (USA), and Kensey Nash (USA); E Kon is consultant for CartiHeal (2009) Ltd. (Israel) and has stocks of CartiHeal (2009) Ltd (Israel), and she received institutional support from Finceramica SpA (Italy), Fidia SpA (Italy), IGEA Clinical Biophysics (Italy), BIOMET (USA), and Kensey Nash (USA).

References

1. Boswell SG, Cole BJ, Sundman EA, et al. Platelet-rich plasma: a milieu of bioactive factors. Arthroscopy 2012;28:429-39. [PubMed]
2. Andriolo L, Di Matteo B, Kon E, et al. PRP augmentation for ACL reconstruction. Biomed Res Int 2015;2015:371746.
3. Di Matteo B, Filardo G, Kon E, et al. Platelet-rich plasma: evidence for the treatment of patellar and Achilles tendinopathy--a systematic review. Musculoskelet Surg 2015;99:1-9. [PubMed]
4. Meheux CJ, McCulloch PC, Lintner DM, et al. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthroscopy 2015. [Epub ahead of print]. [PubMed]
5. Filardo G, Kon E, Roffi A, et al. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc 2015;23:2459-74. [PubMed]
6. Kon E, Filardo G, Di Matteo B, et al. PRP for the treatment of cartilage pathology. Open Orthop J 2013;7:120-8. [PubMed]
7. Patel S, Dhillon MS, Aggarwal S, et al. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med 2013;41:356-64. [PubMed]
8. Filardo G, Di Matteo B, Di Martino A, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med 2015;43:1575-82. [PubMed]
9. Battaglia M, Guaraldi F, Vannini F, et al. Efficacy of ultrasound-guided intra-articular injections of platelet-rich plasma versus hyaluronic acid for hip osteoarthritis. Orthopedics 2013;36:e1501-8.
10. Filardo G, Kon E. PRP: product rich in placebo? Knee Surg Sports Traumatol Arthrosc 2015. [Epub ahead of print]. [PubMed]
11. Cerza F, Carnì S, Carcangiu A, et al. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med 2012;40:2822-7. [PubMed]
12. Vaquerizo V, Plasencia MÁ, Arribas I, et al. Comparison of intra-articular injections of plasma rich in growth factors (PRGF-Endoret) versus Durolane hyaluronic acid in the treatment of patients with symptomatic osteoarthritis: a randomized controlled trial. Arthroscopy 2013;29:1635-43. [PubMed]
13. Spaková T, Rosocha J, Lacko M, et al. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil 2012;91:411-7. [PubMed]
14. Tschon M, Fini M, Giardino R, et al. Lights and shadows concerning platelet products for musculoskeletal regeneration. Front Biosci (Elite Ed) 2011;3:96-107. [PubMed]
15. Roffi A, Filardo G, Assirelli E, et al. Does platelet-rich plasma freeze-thawing influence growth factor release and their effects on chondrocytes and synoviocytes? Biomed Res Int 2014;2014:692913.
16. DeLong JM, Russell RP, Mazzocca AD, et al. Platelet-rich plasma: the PAW classification system. Arthroscopy 2012;28:998-1009. [PubMed]
17. Mautner K, Malanga GA, Smith J, et al. A call for a standard classification system for future biologic research: the rationale for new PRP nomenclature. PM R 2015;7:S53-9. [PubMed]
18. Assirelli E, Filardo G, Mariani E, et al. Effect of two different preparations of platelet-rich plasma on synoviocytes. Knee Surg Sports Traumatol Arthrosc 2015;23:2690-703. [PubMed]
19. Braun HJ, Kim HJ, Chu CR, et al. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med 2014;42:1204-10. [PubMed]
20. Cavallo C, Filardo G, Mariani E, et al. Comparison of platelet-rich plasma formulations for cartilage healing: an in vitro study. J Bone Joint Surg Am 2014;96:423-9. [PubMed]
21. Sundman EA, Cole BJ, Fortier LA, et al. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med 2011;39:2135-40. [PubMed]
22. Filardo G, Kon E, Pereira Ruiz MT, et al. Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single-versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc 2012;20:2082-91. [PubMed]
23. Riboh JC, Saltzman BM, Yanke AB, et al. Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis. Am J Sports Med 2015. [Epub ahead of print]. [PubMed]
24. Mariani E, Canella V, Berlingeri A, et al. Leukocyte presence does not increase microbicidal activity of Platelet-rich Plasma in vitro. BMC Microbiol 2015;15:149. [PubMed]