Hospital for Special Surgery Consensus Statement on Regenerative Medicine Treatmentss
“Biologic therapies” encompass techniques such as the injection of platelet rich plasma (PRP), the collection and injection of autologous progenitor cells derived from bone marrow or fat tissue, and the use of allogenic cells from other sources such as placenta. The underlying rationale for use of these techniques is the potential to improve symptoms and to possibly augment healing of tissues that have relatively poor intrinsic healing ability such as cartilage, tendon, ligament, bone, muscle, and meniscus. Basic science data suggests strong potential for these approaches to improve tissue healing, but there is currently very limited clinical data to support use of these techniques for treatment of musculoskeletal conditions. A large number of unproven therapies are being marketed directly to consumers, with unsubstantiated claims of efficacy and lack of information about risks, product manufacturing, and realistic expectations of outcomes.
Platelet Rich Plasma (PRP)
PRP is produced from a small sample of the patient’s blood. The blood is centrifuged (“spun down”) to isolate and concentrate the platelets in blood. The platelets and the fluid portion of blood (“plasma”) contain a number of proteins that can potentially decrease inflammation and improve pain and tissue healing. PRP has been used for many soft tissue injuries, including ligament, tendon, meniscus, cartilage, and muscle. However, at this time there is only data to support the use of specific PRP formulations for: 1) symptoms of osteoarthritis of the knee, and 2) chronic tendinitis of the patellar tendon (“ jumpers knee”) and elbow extensor tendons (“tennis elbow”). PRP is generally safe since it is derived from the patient’s own blood. The major limitation at this time is the significant unpredictability in outcomes, due in large part to the wide variability in different PRP formulations and lack of information about the optimal PRP formulation (for example, leukocyte rich vs leukocyte poor PRP) for different conditions. Further information is required to define the specific type of PRP that will be most effective for a specific condition or injury. Indiscriminate use of the same type of PRP for widely different injuries and conditions has contributed to the unpredictable and variable outcomes. Additionally, the lack of strong clinical data supporting efficacy of PRP is the reason that most medical insurance companies do not cover the cost of PRP therapy.
There is much hype about “stem cells” for healing and regeneration of numerous different tissues. Stem cells are defined by the ability to undergo self-renewal, and to regenerate other types of cells and tissues. There are stem cells in many tissues, including bone marrow and fat. However, the number of stem cells by formal criteria is very small - only approximately 1 in 10,000. Current evidence suggests that the best way to use stem cells from bone marrow or fat is to isolate the cells in the laboratory and then culture the cells to increase their number without altering their differentiation. Although permitted in some other countries, such “manipulation” is not currently allowed by the FDA in the United States. Uncultured cells as currently used in the U.S. should NOT be equated with cultured cells. The “stem cell” preparations offered at numerous clinics in the U.S. contain very few true stem cells by formal criteria.
There is some very limited data to suggest that cells derived from bone marrow, fat, placenta, or amniotic tissue may improve symptoms from osteoarthritis of the knee. This effect may be due to the production of anti-inflammatory chemicals by the cells. However, there is essentially no data to suggest that these uncultured cell populations can lead to any tissue regeneration. Many of the marketing claims made about the efficacy of stem cell therapy are based on data using cultured cells, and current data on currently-available cell preparations in the U.S. strongly suggests that this is false and misleading.
There is no doubt that cell-based therapies have tremendous potential for treatment of numerous injuries and diseases. However, much more research is required to identify the optimal cell types, cell processing techniques, cell dosing schedules, methods to localize and retain the cells at the desired site after injection, and post-injection protocols. Also needed are standards that define the criteria used to characterize cell populations, along with uniform reporting of those criteria in publications.
The Current Regulatory Environment for Regenerative Medicine
The widespread use of inappropriate direct-to-consumer marketing of unproven cellular therapies has recently led to increased scrutiny from the United States FDA. New guidelines have been published by the FDA that are aimed at curtailing the inappropriate marketing and use of cell-based therapies, blood based derivatives, and other “regenerative medicine” approaches in the US. Unsubstantiated claims of efficacy and/or using cell and blood processing techniques that go beyond the “minimal manipulation” allowed by the FDA has led to official warning letters and even closure of some “stem cell” and “regenerative medicine” centers. At the same time, these new FDA regulations will also help accelerate the approval pathway for legitimate therapies after appropriate clinical trials.
What We Are Doing at HSS in the Area of Regenerative Medicine
As a world leader in the care of musculoskeletal injuries and diseases, HSS clinicians and scientists are actively engaged in both basic science and clinical studies to further our understanding of regenerative medicine approaches, such as PRP and cell-based therapies. We recognize the tremendous potential of these treatment options for numerous difficult to treat conditions, such as osteoarthritis, chronic tendinitis, degenerative disc disease in the spine, delayed or failed healing of difficult fractures, cartilage repair and regeneration, muscle strain injuries in athletes, and healing following ligament or meniscus repair. Given our extensive experience with managing these conditions and studying the underlying scientific issues, we fully understand the potential and limitations of current regenerative medicine approaches.
At The Hospital for Special Surgery we are committed to exploring, studying, and reporting the use of regenerative medicine approaches in a responsible and rigorous fashion. Recognizing that many patients can gain relief with these generally safe therapies, we aim to use these treatments in the appropriate clinical situations. However, more than simply using these therapies, we are committed to furthering the science and understanding of regenerative medicine approaches. To do so, we aim to enroll all patients treated with these therapies in a clinical registry so that we may carefully follow outcomes. We also are studying the composition and biologic activity of samples of the specific formulations given to each individual patient, so that we can further define the relationship between the material administered to the patient and their ultimate clinical outcome. We believe that responsible use of regenerative medicine treatments is the best way to both provide cutting edge care for our patients and to also contribute to the knowledge base in order to advance this rapidly developing field.
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Editorial views on regenerative medicine in musculoskeletal disease:
- Bauer TW. Stem Cell Therapy for Knee Pain-What Exactly Are We Injecting, and Why? J Bone Joint Surg Am. 2016 Sep 21;98(18):1509-10. doi: 10.2106/JBJS.16.00872. PubMed PMID: 27655977.
- Rodeo SA. Biologic Approaches in Sports Medicine: Potential, Perils, and Paths Forward. American J Sports Med. 2016 Jul;44(7):1657-9. doi: 10.1177/0363546516655130.PubMed PMID: 27371674.
- Rodeo SA. Moving Toward Responsible Use of Biologics in Sports Medicine. American J Sports Med. 2018 Jul;46(8):1797-1799. doi: 10.1177/0363546518782182. PubMed PMID: 29953295.
- Rodeo SA. Cell therapy in orthopaedics: where are we in 2019? Bone Joint J. 2019 Apr;101-B(4):361-364. doi: 10.1302/0301-620X.101B4.BJJ-2019-0013.R1. Review. PubMed PMID: 30929493.
PRP for knee arthritis:
- Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled Trials. Arthroscopy. 2017 Mar;33(3):659-670.e1. doi:10.1016/j.arthro.2016.09.024. Epub 2016 Dec 22. Review. PubMed PMID: 28012636.
- Laudy AB, Bakker EW, Rekers M, Moen MH. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015 May;49(10):657-72. doi: 10.1136/bjsports-2014-094036. Epub 2014 Nov 21. Review. PubMed PMID: 25416198.
PRP for patellar tendonitis (“jumper’s knee”):
- Dupley L, Charalambous CP. Platelet-Rich Plasma Injections as a Treatment for Refractory Patellar Tendinosis: A Meta-Analysis of Randomised Trials. Knee Surg Relat Res. 2017 Sep 1;29(3):165-171. doi: 10.5792/ksrr.16.055. Review. PubMed PMID: 28854761; PubMed Central PMCID: PMC5596405.
- Andriolo L, Altamura SA, Reale D, Candrian C, Zaffagnini S, Filardo G. Nonsurgical Treatments of Patellar Tendinopathy: Multiple Injections of Platelet-Rich Plasma Are a Suitable Option: A Systematic Review and Meta-analysis. Am J Sports Med. 2018 Mar 1:363546518759674. doi:10.1177/0363546518759674. [Epub ahead of print] PubMed PMID: 29601207.
PRP for lateral epicondylitis (“tennis elbow”):
- Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39(6):1200-1208.
- Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a doubleblind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med. 2010; 38(2):255-262.
- Fitzpatrick J, Bulsara M, Zheng MH. The Effectiveness of Platelet-Rich Plasma in the Treatment of Tendinopathy: A Meta-analysis of Randomized Controlled Clinical Trials. Am J Sports Med. 2017 Jan;45(1):226-233. doi:10.1177/0363546516643716. Epub 2016 Jul 21. PubMed PMID: 27268111.
Number of stem cells in bone marrow:
- Jones EA, Kinsey SE, English A, Jones RA, Straszynski L, Meredith DM, Markham AF, Jack A, Emery P, McGonagle D. Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. Arthritis Rheum. 2002 Dec;46(12):3349-60. PubMed PMID: 12483742.
- Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000 Aug;28(8):875-84. Review. PubMed PMID: 10989188.
Need for standardization in reporting:
- Chahla J, Cinque ME, Piuzzi NS, Mannava S, Geeslin AG, Murray IR, Dornan GJ, Muschler GF, LaPrade RF. A Call for Standardization in Platelet-Rich Plasma Preparation Protocols and Composition Reporting: A Systematic Review of the Clinical Orthopaedic Literature. J Bone Joint Surg Am. 2017 Oct 18;99(20):1769-1779. doi: 10.2106/JBJS.16.01374. Review. PubMed PMID: 29040132.
- Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF. Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): Platelet-Rich Plasma and Mesenchymal Stem Cells. J Bone Joint Surg Am. 2017 May 17;99(10):809-819. doi: 10.2106/JBJS.16.00793. PubMed PMID: 28509821.
- Piuzzi NS, Mantripragada VP, Kwee E, Sumski A, Selvam S, Boehm C, Muschler GF. Bone Marrow-Derived Cellular Therapies in Orthopaedics: Part II: Recommendations for Reporting the Quality of Bone Marrow-Derived Cell Populations. JBJS Rev. 2018 Nov;6(11):e5. doi: 10.2106/JBJS.RVW.18.00008. PubMed PMID: 30461436.