Article Text

Download PDFPDF

Highlights from the American Medical Society for Sports Medicine position statement on responsible use of regenerative medicine and orthobiologics in sports medicine
  1. Shane A Shapiro1,
  2. Jonathan T Finnoff2,3,
  3. Tariq M Awan4,
  4. Joanne P Borg-Stein5,
  5. Kimberly G Harmon6,
  6. Daniel C Herman7,
  7. Gerard Malanga8,9,
  8. Zubin Master10,
  9. Kenneth Mautner11
  1. 1 Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, Florida, USA
  2. 2 Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota, USA
  3. 3 United States Olympic and Paralympic Committee, Colorado Springs, Colorado, USA
  4. 4 Family Medicine and Sports Medicine, AdventHealth, Orlando, Florida, USA
  5. 5 Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, USA
  6. 6 Family Medicine, University of Washington School of Medicine, Seattle, Washington, USA
  7. 7 Department of Physical Medicine and Rehabilitation, University of California at Davis, Sacramento, California, USA
  8. 8 Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
  9. 9 NJ Regenerative Insttitue, Cedar Knolls, New Jersey, USA
  10. 10 Biomedical Ethics Research Program and Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA
  11. 11 Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
  1. Correspondence to Dr Shane A Shapiro, Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA; shapiro.shane{at}mayo.edu

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Musculoskeletal conditions including osteoarthritis and chronic tendinopathies are leading causes of pain and disability worldwide. The emergence of novel regenerative therapies, referred to as orthobiologics, has led to promising interventions which may reduce pain and improve function. Orthobiologics are biological substances intended to enhance healing and alter the natural course of orthopaedic disease.1 2 Despite growing experience, the field remains under-researched with inconsistent evidence; yet increasing enthusiasm has permitted overexuberant, sometimes inappropriate use with proliferation of misinformation among both providers and patients.

An American Medical Society for Sports Medicine (AMSSM) position statement was developed to help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine in their practice.3 The statement contains relevant terminology, review of basic and clinical science, ethics, regulations and best practices for considering regenerative medicine in clinical practice (figure 1). The statement seeks to educate physicians regarding a broad and emerging discipline and is not an endorsement by AMSSM of any specific product or procedure.

Figure 1

Responsible use of orthobiologics and other novel regenerative therapies requires multiple considerations before translation into routine clinical practice.

Regenerative medicine terminology

Regenerative medicine is rapidly growing with terms and definitions yet to be standardised. While originating with stem cell discovery and translation, regenerative therapies, of which orthobiologics is but one category, are no longer a single platform technology. Rather, they now encompass a heterogeneous collection of biological sources with varying activity that hold the potential to transform human health. Common orthobiologics employed in research and clinical practice are being conflated under the umbrella of ‘stem cell’ therapy in a manner detrimental to progress and confusing to patients and the public.4 To establish common understanding, the position statement defines frequently used regenerative sports medicine terms and therapies such as mesenchymal stem (stromal) cells (MSC), platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), adipose tissues and allogeneic products harvested from perinatal sources while advocating future scientific communications adhere to standards laid out by expert consensus.3 5

Supporting literature

Regardless of their label, several studies demonstrate potential for orthobiological treatments to relieve pain and/or promote healing without necessarily functioning as building blocks for tissue regeneration.6 Instead, other mechanisms (eg, anti-inflammatory, immunomodulatory and paracrine) have been proposed whereby heterogenous collections of cells, only some of which are MSCs, function as messengers that secrete a range of restorative mediators, cytokines and other biologically active factors that promote native host cell responses.7 8 Despite progress in elucidating molecular mechanisms of repair, it has been challenging to translate in vitro findings into clinical outcomes. The statement reviews the most widely used first generation therapies like PRP, BMAC and adipose while emphasising that with the exception of PRP to treat arthritic knee pain and certain tendinopathies, consistent evidence to support widescale use remains lacking for many conditions. However, reviews of even pure MSC therapies, culture expanded to larger cell doses have not demonstrated superior efficacy for any one treatment over another9 and thus, providers should thoughtfully consider the circumstances wherein it may be appropriate to make use of other currently available orthobiologic therapies for which only level 2 and 3 evidence exists.

Regulatory considerations

Regenerative medicine exists in a controversial regulatory environment. Therapeutic use of human cells, tissues and tissue products (HCT/Ps) are regulated by the US Food and Drug Administration (FDA), and similar regulators around the world. First generation orthobiological procedures in the US will often fall under the FDA Same Surgical Procedure Exception in which the HCT/P must be minimally manipulated, not combined with another substance, and treating the same patient within the same procedure.10 The concept of homologous use, whereby transplanted cells do not function differently from where they originate, may also be required.

A range of ‘off-the-shelf’ allogeneic products harvested from perinatal sources has also emerged in clinical practice. Utilisation proliferated due to their extensive availability, ease of use and widespread misinformation. The FDA recently clarified the need for premarket approval in order to use injectable perinatal cells and tissues in clinical practice and to date, none have received the requisite biologic licenses.11 Meanwhile, clinical trials using perinatal products are ongoing and some manufacturers have begun the Investigational New Drug process to obtain approval for orthopaedic indications. AMSSM advocates that clinicians introducing regenerative medicine into their practice should review and understand current medical and manufacturing regulations and appropriate quality controls.

Informed consent

Clinicians must provide understandable information to patients in an honest and balanced manner focusing on clinically indicated and scientifically justified options so patients can make informed decisions about their care. The ethical premise of informed consent is acknowledgement of patients’ right to autonomy. In regenerative medicine where evidence of safety and efficacy is rapidly evolving, physicians should scrutinise their sources of information to ensure sound scientific rationale prior to presenting patients suitable options. Clinicians should communicate clearly and accurately about the science and potential benefits and harms of individual regenerative medicine options, especially given that misinformation surrounding ‘stem cell therapies’ can heighten expectations and lead to inadequate consideration of other treatment options. Additionally, the patient should be informed that regenerative interventions are not currently considered standard of care and avoid motivations not supported by evidence such as media reports of elite athlete stem cell use.

Practice considerations

Clinicians and their staff who provide regenerative medicine options to patients may require additional training for proficiency in relevant procedures to ensure the procedure can be delivered safely. This may include training related to HCT/P harvest, material and equipment processing, biological assays, image guidance and product delivery. Sports medicine physicians should consider how novel procedures fit into their specific treatment algorithms. We advocate for the least invasive, safest, cost-effective treatment with the strongest evidence implemented first. Only after these treatment options are exhausted should more invasive and novel treatments, such as regenerative medicine options, be considered.

Conclusion

The need for scientifically validated treatments for recalcitrant musculoskeletal conditions has increased interest in orthobiologics and other regenerative therapies to address existing treatment gaps. The AMSSM position statement on regenerative medicine outlines relevant conceptswhile advocating for the advancement of orthobiological science, patient safety and education towards the responsible translation of regenerative therapies.

Ethics statements

Patient consent for publication

References

Footnotes

  • Twitter @ShaneShapiroMD, @DrKimHarmon

  • Contributors We certify that the enclosed manuscript, entitled Highlights from the American Medical Society for Sports Medicine Position Statement on Responsible Use of Regenerative Medicine and Orthobiologics in Sports Medicine, represents original work and that we have reviewed the final version and approve it for publication. Neither this manuscript nor a manuscript with substantially similar content under our authorship has been published or is currently being considered for publication by any other publication. This manuscript will not be submitted to any other publication while it is under consideration by BJSM. We certify that all individuals listed as authors of this manuscript have participated in conceptualising the research or content of the manuscript, in writing or critically editing the manuscript, and/or in analysis of data presented in the manuscript. Each author will complete the ICMJE form to document competing interests related to the subject matter, materials, and products mentioned in this manuscript. A summary of potential competing interest are listed below.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests KM is a Consultant for Lipogems. GM receives Research support and an educational stipend from Lipogems. GM is a Board member of the Interventional Orthobiologic Foundation. JTF is a member of AMSSM Board of Directors, AAPM&R Board of Governors, and the Medical Advisory Board of Sanofi. JTF receives royalties from Demos Publishing and Up to Date. TMA is a consultant Consultant for Arthrex and Fujifilm Sonosite. TMA receives research funding from InGeneron, GID-BioMiMedx, Flexion Therepeutics, and Endo Pharmaceuticals. SAS is a consultant for Bioventus and on the BOD of the Biologic Association.

  • Provenance and peer review Not commissioned; externally peer reviewed.