The Role Of Biologics in Sports Medicine

By: Matthew Lucero, ATC, LAT, Assistant Athletic Trainer, Texas Rangers, Keith Meister, MD, TMI Sports Medicine, and Rathna Nuti, MD, TMI Sports Medicine

In recent years, regenerative medicine has grown in popularity with professional athletes to treat both sports-related injuries and theoretically enhance off-season recovery with common biologics, such as platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Theoretically, biologics offer enhanced potential to fully restore damaged tissues by enhancing the healing process and provide a less-invasive and more holistic alternative to surgery.^{1, 2} This potentially allows for expedited recovery time while sustaining athletic performance. In spite of its growing popularity, there is still a significant need for rigorous investigation of the application and efficacy of both PRP and MSCs in sports medicine.³  

Platelet-Rich Plasma

PRP refers to autologous blood that has been centrifuged to produce a higher-than-average concentration of platelets. The theory is that PRP concentrates cytokines and growth factors to promote tissue healing.^2-4 Typically 30-60 ccs of blood are obtained through venipuncture. Upon capture, the blood is centrifuged to separate out the platelet concentrate. The activated platelets are then injected back into the individual’s joint or specific area of tissue damage, with or without a clotting activator (thrombin), to enhance a healing response.

Injectable Composition. A number of studies have attempted to but have yet to determine the optimal concentration of platelets.² Additionally, the concentration of cytokines and growth factors released fluctuates and depends upon platelet recovery methods, amount of whole blood used, platelet activation, final volume of platelets and other variables. Along with cytokines and growth factors, white blood cell concentration becomes controlled creating leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP) concentrates. At this time, no randomized or prospective clinical studies have been performed to compare outcomes between LR-PRP versus LP-PRP.⁴

Clinical Use. PRP use has been studied in various musculoskeletal (MSK) injuries to bone, tendon, muscle and ligaments. Several systematic reviews and meta-analyses have found improved functional outcome scores with LP-PRP for the treatment of knee osteoarthritis (OA).^{3, 4} Furthermore, there has been suggested significant improvements in clinical outcomes in patients with lateral epicondylitis and rotator cuff injuries, but results of good scientific studies in the treatment of other tendinopathies are lacking.^4-6 Theoretically, there are increasing arguments for using PRP in tendinopathy based on its tendo-inductive factors.⁷ At this time, further studies are required to conclusively determine the efficacy and role of PRP therapy in muscle and ligamentous injuries.^4-6 In general, more high-quality studies are necessary before widespread clinical recommendations can be implemented.

Regenokine. This alternative therapy was developed in Germany. Autologous venous blood is obtained, centrifuged and incubated (heated). The incubation process stimulates the release of IL-1 receptor antagonist. IL-1 modulates inflammation in the body. The released chemical blocks the receptor to decrease inflammation. It has 100 times the concentration of that in normal PRP preparation and may have a higher level of potency.

Unlike PRP, Regenokine preparation has no cells. Additionally, unlike PRP, which is a single or even a second injection given weeks apart, Regenokine is a series of 5 to 6 injections into the joint/tendon given on 5 to 6 consecutive days. Although a broad worldwide use has taken hold, and anecdotally there has been a very positive response in many professional sporting circles, studies of true efficacy have still yet to be presented.¹²  

Additional Considerations. In the United States, many insurance plans do not cover PRP therapy due to insufficient data supporting its use in MSK injuries.⁵ Furthermore, PRP products are not subjected to oversight like prescription drugs, which leads to a lack of standardization and quality control.⁵ However, PRP injections are relatively benign and are not classified as performance enhancing.⁵ After a short ban in 2010, the World Anti-Doping Agency (WADA) removed this in 2011 due to lack of substantial evidence.

Mesenchymal Stem Cells

MSCs are precursor cells that provide replacement units for normal cell turnover and are defined by International Society for Cell Therapy Mesenchymal Stem Cells as having the capacity for differentiation to osteoblasts, adipocytes and chondroblasts in vivo.^{1, 8}

Cell Sources. MSCs can be derived from either embryonic cells (human embryo or more commonly amniotic fluid) or adult tissue.⁹ Embryonic stem cells have the ability to proliferate indefinitely in vitro without loss of differentiation, but there have been reports in the literature over concerns in its potential for oncologic transformation.¹ Adult stem cells are considered to be less complicated by political and ethical ramifications.¹ Adult cells can be isolated from adipose tissue, peripheral blood, periosteum, synovium, pericytes, blood, bone marrow, skeletal muscle, umbilical cord and dental pulp.^1,8 Fat and bone marrow are the most commonly sourced in adults.

Clinical Use. Studies have shown variable results in utilizing MSCs as therapeutic modality for various MSK conditions. Currently, studies show improvement in cartilage architecture and function, as well as meniscus volume in knee OA when injecting MSCs.⁹ However, many of the current studies in the treatment of knee OA are heavily biased and still lack long-term risk assessment.¹⁰ Recommendations presently stand for clinicians to refrain from using MSCs in patients with knee OA, but if utilized, extensive monitoring is required.¹⁰ A few trials have been conducted to investigate the role of MSCs in tendon disorders. Although improved healing was noted, these investigations were of poor quality, had high risk of bias and safety was inadequately reported.¹¹ Therefore, the use of MSCs for tendon disorders in clinical practice is not suitable outside of an appropriate ethics-approved clinical trial.¹¹

Controversies over use of MSCs prevail since professional athletes in the National Football League and Major League Baseball have traveled abroad to receive cell-based therapeutic procedures for a variety of sports-related injuries.¹ Unmonitored practice concerns arise with regard to risk exposure to an unproven therapy, as well as concomitant exposure to adjuvants of currently banned substances, such as human growth hormone (HGH).¹

Overall, biologics have a potential role in providing promising therapeutic options for sports injuries. However, high-quality studies and clear delineation of safety profiles are severely lacking in order to fully endorse in clinical practice.

References

1. Ajibade, D.A., et al., Emerging Applications of Stem Cell and Regenerative Medicine to Sports Injuries. Orthop J Sports Med, 2014. 2(2): p. 1-7.
2. Kraeutler, M.J., et al., Biologic Options for Articular Cartilage Wear (Platelet-Rich Plasma, Stem Cells, Bone Marrow Aspirate Concentrate). Clin Sports Med, 2017. 36(3): p. 457-468.
3. Gobbi, A. and M. Fishman, Platelet-rich Plasma and Bone Marrow-derived Mesenchymal Stem Cells in Sports Medicine. Sports Med Arthrosc, 2016. 24(2): p. 69-73.
4. Williams, P.N., et al., Platelet-rich plasma and other cellular strategies in orthopedic surgery. Curr Rev Musculoskelet Med, 2015. 8(1): p. 32-39.
5. Navani, A., G. Li, and J. Chrystal, Platelet Rich Plasma in Musculoskeletal Pathology: A Necessary Rescue or a Lost Cause? Pain Physician, 2017. 20(3): p. 345-356.
6. Chen, X., et al., The Efficacy of Platelet-Rich Plasma on Tendon and Ligament Healing: A Systematic Review and Meta-analysis With Bias Assessment. Am J Sports Med, 2017: p. 1-13.
7. Andia, I., J.I. Martin, and N. Maffulli, Advances With Platelet Rich Plasma Therapies For Tendon Regeneration. Expert Opin Biol Ther, 2018.
8. Gupta, P.K., et al., Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell Res Ther, 2012. 3(4): p. 25.
9. Hogan, M.V., et al., The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions. Arthroscopy, 2015. 31(5): p. 1017-21.
10. Pas, H.I., et al., Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med, 2017. 51(15): p. 1125-1133.
11. Pas, H., et al., No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med, 2017. 51(13): p. 996-1002.
12. Waslewski, G. Personal communication. 2017.