Biologic Therapies for Tendon and Muscle Injury

Introduction: Biologic therapies, often referred to as "biologics," represent a fascinating frontier in regenerative medicine, offering new hope for the treatment of a wide range of musculoskeletal conditions. In this article, we embark on an exciting journey through the world of biologic therapies for tendon and muscle injuries, exploring their mechanisms, clinical applications, and the evolving landscape of evidence supporting their use. These therapies have gained remarkable momentum and are poised to revolutionize the field of regenerative medicine.

Terminology and Background: The term "biologic therapies" encapsulates innovative treatments that go beyond traditional pharmacological approaches, focusing on the use of substances such as cells and tissues. Within musculoskeletal medicine, these therapies can be broadly categorized into two inspiring groups: blood-derived therapies and cellular therapies.

1. Blood-Derived Therapies: These encompass treatments like autologous whole blood (ABI) and platelet-rich plasma (PRP). PRP, in particular, stands out as it harnesses the power of platelets, which release a myriad of growth and inflammatory factors, promising accelerated tissue healing.

2. Cellular Therapies: This category opens up a world of possibilities by introducing various cells directly into the affected tissue. The roster includes mesenchymal stem or stromal cells (MSCs), autologous tenocytes, and dermal fibroblasts, each carrying the potential to trigger remarkable regenerative processes.

The Expanding Popularity: Over the past decade, we've witnessed an exhilarating surge in clinics offering biologic therapies for muscle and tendon injuries. This growth can be attributed to several factors, including the dearth of established treatments for these conditions, the simplicity of administration, and the enthusiastic marketing efforts of biotechnology companies. While regulations are beginning to take shape, the journey ahead holds the promise of a more widespread availability of these treatments.

Proposed Mechanisms and Production of Biologic Therapies: Blood-derived therapies like PRP draw their strength from the activation of platelets, which release a diverse array of growth and inflammatory factors. What's truly exciting is the varying platelet concentrations in PRP, opening up possibilities for tailoring treatments to individual needs. Cellular therapies, led by MSCs, offer an enchanting prospect of direct incorporation into injured tissue, driven by local signals. These cells can be harvested from sources like bone marrow or adipose tissue and undergo a fascinating multi-stage manufacturing process.

Indications and Contraindications for Biologic Therapies: The horizon for biologic therapies appears limitless, with proponents advocating for their application in an extensive range of clinical scenarios. PRP is already making strides in conditions like osteoarthritis and tendinopathy, while MSCs continue to captivate researchers. Contraindications are indeed important to consider, with patient-specific factors like allergies, malignancies, infections, and medication use guiding the treatment path. Additionally, the intriguing realm of doping in sports introduces its own set of guidelines when contemplating biologic therapies.

Biologic Therapies for Tendon and Muscle Injuries: Tendon injuries, particularly the challenging degenerative overuse tendon injuries, pose exciting opportunities for exploration. Studies on the efficacy of PRP and ABI may yield contradictory results, yet the journey of discovery is filled with promise. For muscle injuries, the emerging evidence suggests that PRP may lead to quicker returns to sport, hinting at a brighter future for athletes. Meanwhile, the world of MSCs remains full of potential, with ongoing research poised to reveal their true capabilities.

Safety and the Quest for Proven Effectiveness: One paramount takeaway is that biologic therapies, including PRP and MSCs, appear to be remarkably safe, carrying minimal risks and adverse effects. What truly ignites our enthusiasm is the potential of these therapies to unlock new frontiers of healing. While the evidence hints at their safety, the journey to fully realizing their efficacy is still underway. The promising findings, albeit with methodological challenges, make us eager to uncover their full potential.

In summary, biologic therapies stand as beacons of hope for the treatment of tendon and muscle injuries, heralding a new era in regenerative medicine. The path forward is filled with promise and excitement. While we currently recommend these therapies within well-designed clinical trials, the prospect of further research and exploration promises to unlock their full potential, offering a brighter future for patients and athletes alike.

REFERENCES

1. Munsie M, Pera M. Regulatory loophole enables unproven autologous cell therapies to thrive in Australia. Stem Cells Dev 2014; 23 Suppl 1:34.

2. Rubin R. Unproven but Profitable: The Boom in US Stem Cell Clinics. JAMA 2018; 320:1421.

3. Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstr Surg 2004; 114:1502.

4. Fitzpatrick J, Bulsara M, Zheng MH. The Effectiveness of Platelet-Rich Plasma in the Treatment of Tendinopathy. Am J Sports Med 2017; 45:226.

5. Yerlikaya M, Talay Çaliş H, Tomruk Sütbeyaz S, et al. Comparison of Effects of Leukocyte-Rich and Leukocyte-Poor Platelet-Rich Plasma on Pain and Functionality in Patients With Lateral Epicondylitis. Arch Rheumatol 2018; 33:73.

6. Robins RJ. Platelet Rich Plasma: Current Indications and Use In Orthopaedic Care. Medical Research Archives 2017; 5.

7. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8:315.

8. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 2007; 9:204.

9. Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2005; 2:8.

10. Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 2012; 7:e47559.

11. Peeters CM, Leijs MJ, Reijman M, et al. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthritis Cartilage 2013; 21:1465.

12. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 2011; 9:12.

13. Jurgens WJ, Oedayrajsingh-Varma MJ, Helder MN, et al. Effect of tissue-harvesting site on yield of stem cells derived from adipose tissue: implications for cell-based therapies. Cell Tissue Res 2008; 332:415.

14. Imam MA, Holton J, Horriat S, et al. A systematic review of the concept and clinical applications of bone marrow aspirate concentrate in tendon pathology. SICOT J 2017; 3:58.

15. Lee JI, Lee S, Han Y, Balolong E Jr. Labeling Cells Correctly as Stromal Vascular Fraction Matters. Arthroscopy 2017; 33:1438.

16. Hsu WK, Mishra A, Rodeo SR, et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J Am Acad Orthop Surg 2013; 21:739.

17. Bausset O, Magalon J, Giraudo L, et al. Impact of local anaesthetics and needle calibres used for painless PRP injections on platelet functionality. Muscles Ligaments Tendons J 2014; 4:18.

18. Lucchinetti E, Awad AE, Rahman M, et al. Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing. Anesthesiology 2012; 116:841.

19. Schippinger G, Prüller F, Divjak M, et al. Autologous Platelet-Rich Plasma Preparations: Influence of Nonsteroidal Anti-inflammatory Drugs on Platelet Function. Orthop J Sports Med 2015; 3:2325967115588896.

20. The Prohibited List. World Anti-Doping Agency. Available at: https://www.wada-ama.org/en/prohibited-list (Accessed on November 01, 2022).

21. Cook JL, Purdam C. Is compressive load a factor in the development of tendinopathy? Br J Sports Med 2012; 46:163.

22. Docking SI, Cook J, Chen S, et al. Identification and differentiation of gluteus medius tendon pathology using ultrasound and magnetic resonance imaging. Musculoskelet Sci Pract 2019; 41:1.

23. Cook JL, Purdam CR. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br J Sports Med 2009; 43:409.

24. Cook JL, Rio E, Purdam CR, Docking SI. Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research? Br J Sports Med 2016; 50:1187.

25. Kannus P, Józsa L. Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am 1991; 73:1507.

26. Moraes VY, Lenza M, Tamaoki MJ, et al. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev 2013; :CD010071.

27. Krogh TP, Ellingsen T, Christensen R, et al. Ultrasound-Guided Injection Therapy of Achilles Tendinopathy With Platelet-Rich Plasma or Saline: A Randomized, Blinded, Placebo-Controlled Trial. Am J Sports Med 2016; 44:1990.

28. Davenport KL, Campos JS, Nguyen J, et al. Ultrasound-Guided Intratendinous Injections With Platelet-Rich Plasma or Autologous Whole Blood for Treatment of Proximal Hamstring Tendinopathy: A Double-Blind Randomized Controlled Trial. J Ultrasound Med 2015; 34:1455.

29. Pearson J, Rowlands D, Highet R. Autologous blood injection to treat achilles tendinopathy? A randomized controlled trial. J Sport Rehabil 2012; 21:218.

30. Wolf JM, Ozer K, Scott F, et al. Comparison of autologous blood, corticosteroid, and saline injection in the treatment of lateral epicondylitis: a prospective, randomized, controlled multicenter study. J Hand Surg Am 2011; 36:1269.

31. Kazemi M, Azma K, Tavana B, et al. Autologous blood versus corticosteroid local injection in the short-term treatment of lateral elbow tendinopathy: a randomized clinical trial of efficacy. Am J Phys Med Rehabil 2010; 89:660.

32. Arik HO, Kose O, Guler F, et al. Injection of autologous blood versus corticosteroid for lateral epicondylitis: a randomised controlled study. J Orthop Surg (Hong Kong) 2014; 22:333.

33. Boesen AP, Hansen R, Boesen MI, et al. Effect of High-Volume Injection, Platelet-Rich Plasma, and Sham Treatment in Chronic Midportion Achilles Tendinopathy: A Randomized Double-Blinded Prospective Study. Am J Sports Med 2017; 45:2034.

34. Creaney L, Wallace A, Curtis M, Connell D. Growth factor-based therapies provide additional benefit beyond physical therapy in resistant elbow tendinopathy: a prospective, single-blind, randomised trial of autologous blood injections versus platelet-rich plasma injections. Br J Sports Med 2011; 45:966.

35. de Jonge S, de Vos RJ, Weir A, et al. One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial. Am J Sports Med 2011; 39:1623.

36. Thanasas C, Papadimitriou G, Charalambidis C, et al. Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. Am J Sports Med 2011; 39:2130.

37. Ozturan KE, Yucel I, Cakici H, et al. Autologous blood and corticosteroid injection and extracoporeal shock wave therapy in the treatment of lateral epicondylitis. Orthopedics 2010; 33:84.

38. Dragoo JL, Wasterlain AS, Braun HJ, Nead KT. Platelet-rich plasma as a treatment for patellar tendinopathy: a double-blind, randomized controlled trial. Am J Sports Med 2014; 42:610.

39. Kesikburun S, Tan AK, Yilmaz B, et al. Platelet-rich plasma injections in the treatment of chronic rotator cuff tendinopathy: a randomized controlled trial with 1-year follow-up. Am J Sports Med 2013; 41:2609.

40. Mishra AK, Skrepnik NV, Edwards SG, et al. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med 2014; 42:463.

41. Gautam VK, Verma S, Batra S, et al. Platelet-rich plasma versus corticosteroid injection for recalcitrant lateral epicondylitis: clinical and ultrasonographic evaluation. J Orthop Surg (Hong Kong) 2015; 23:1.

42. Krogh TP, Fredberg U, Stengaard-Pedersen K, et al. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med 2013; 41:625.

43. Keene DJ, Alsousou J, Harrison P, et al. Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial. BMJ 2019; 367:l6132.

44. Boesen AP, Boesen MI, Hansen R, et al. Effect of Platelet-Rich Plasma on Nonsurgically Treated Acute Achilles Tendon Ruptures: A Randomized, Double-Blinded Prospective Study. Am J Sports Med 2020; 48:2268.

45. Scott A, LaPrade RF, Harmon KG, et al. Platelet-Rich Plasma for Patellar Tendinopathy: A Randomized Controlled Trial of Leukocyte-Rich PRP or Leukocyte-Poor PRP Versus Saline. Am J Sports Med 2019; 47:1654.

46. Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo and therapeutic efficacy. JAMA 2008; 299:1016.

47. Howick J, Friedemann C, Tsakok M, et al. Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One 2013; 8:e62599.

48. Warth RJ, Dornan GJ, James EW, et al. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy 2015; 31:306.

49. Saltzman BM, Jain A, Campbell KA, et al. Does the Use of Platelet-Rich Plasma at the Time of Surgery Improve Clinical Outcomes in Arthroscopic Rotator Cuff Repair When Compared With Control Cohorts? A Systematic Review of Meta-analyses. Arthroscopy 2016; 32:906.

50. Chen X, Jones IA, Togashi R, et al. Use of Platelet-Rich Plasma for the Improvement of Pain and Function in Rotator Cuff Tears: A Systematic Review and Meta-analysis With Bias Assessment. Am J Sports Med 2020; 48:2028.

51. Rodeo SA, Delos D, Williams RJ, et al. The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med 2012; 40:1234.

52. Zumstein MA, Rumian A, Thélu CÉ, et al. SECEC Research Grant 2008 II: Use of platelet- and leucocyte-rich fibrin (L-PRF) does not affect late rotator cuff tendon healing: a prospective randomized controlled study. J Shoulder Elbow Surg 2016; 25:2.

53. Wang A, McCann P, Colliver J, et al. Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial. Am J Sports Med 2015; 43:1430.

54. Flury M, Rickenbacher D, Schwyzer HK, et al. Does Pure Platelet-Rich Plasma Affect Postoperative Clinical Outcomes After Arthroscopic Rotator Cuff Repair? A Randomized Controlled Trial. Am J Sports Med 2016; 44:2136.

55. Pandey V, Bandi A, Madi S, et al. Does application of moderately concentrated platelet-rich plasma improve clinical and structural outcome after arthroscopic repair of medium-sized to large rotator cuff tear? A randomized controlled trial. J Shoulder Elbow Surg 2016; 25:1312.

56. Zou J, Mo X, Shi Z, et al. A Prospective Study of Platelet-Rich Plasma as Biological Augmentation for Acute Achilles Tendon Rupture Repair. Biomed Res Int 2016; 2016:9364170.

57. Jo CH, Shin JS, Shin WH, et al. Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. Am J Sports Med 2015; 43:2102.

58. Ebert JR, Wang A, Smith A, et al. A Midterm Evaluation of Postoperative Platelet-Rich Plasma Injections on Arthroscopic Supraspinatus Repair: A Randomized Controlled Trial. Am J Sports Med 2017; 45:2965.

59. Malavolta EA, Gracitelli ME, Ferreira Neto AA, et al. Platelet-rich plasma in rotator cuff repair: a prospective randomized study. Am J Sports Med 2014; 42:2446.

60. Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med 2011; 39:258.

61. De Carli A, Lanzetti RM, Ciompi A, et al. Can platelet-rich plasma have a role in Achilles tendon surgical repair? Knee Surg Sports Traumatol Arthrosc 2016; 24:2231.

62. Schepull T, Kvist J, Norrman H, et al. Autologous platelets have no effect on the healing of human achilles tendon ruptures: a randomized single-blind study. Am J Sports Med 2011; 39:38.

63. Randelli P, Arrigoni P, Ragone V, et al. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg 2011; 20:518.

64. Godwin EE, Young NJ, Dudhia J, et al. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J 2012; 44:25.

65. Pas HIMFL, Moen MH, Haisma HJ, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med 2017; 51:996.

66. Hölmich P, Uhrskou P, Ulnits L, et al. Effectiveness of active physical training as treatment for long-standing adductor-related groin pain in athletes: randomised trial. Lancet 1999; 353:439.

67. Sheth U, Dwyer T, Smith I, et al. Does Platelet-Rich Plasma Lead to Earlier Return to Sport When Compared With Conservative Treatment in Acute Muscle Injuries? A Systematic Review and Meta-analysis. Arthroscopy 2018; 34:281.

68. Rossi LA, Molina Rómoli AR, Bertona Altieri BA, et al. Does platelet-rich plasma decrease time to return to sports in acute muscle tear? A randomized controlled trial. Knee Surg Sports Traumatol Arthrosc 2017; 25:3319.

69. Reurink G, Goudswaard GJ, Moen MH, et al. Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch Hamstring Injection Therapy study. Br J Sports Med 2015; 49:1206.

70. Li Y, Huard J. Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. Am J Pathol 2002; 161:895.

71. Ghosh AK. Factors involved in the regulation of type I collagen gene expression: implication in fibrosis. Exp Biol Med (Maywood) 2002; 227:301.

72. Maclean S, Khan WS, Malik AA, et al. The potential of stem cells in the treatment of skeletal muscle injury and disease. Stem Cells Int 2012; 2012:282348.

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