Ethical and Regulatory Considerations Related to Regenerative Medicine

Abstract

The possibility of modifying disease through regenerative medicine applications, particularly stem cell therapies, raises ethical and regulatory challenges in orthopedics. This review article provides historical context of stem cell research, ethical issues such as informed consent, therapeutic misconception, and equitable access, emphasizing the responsibilities of providers offering investigational treatments. It also examines the evolving role of the U.S. Food and Drug Administration (FDA) in regulating regenerative therapies through frameworks like the Regenerative Medicine Advanced Therapy (RMAT) designation, and more point-of-care enforcement discretion policies for therapies such as autologous micro-fragmented adipose tissue and bone marrow aspirate concentrate. The authors underscore the importance of innovative therapies to address unmet needs in musculoskeletal healthcare while acknowledging the need for more rigorous basic and clinical research. They call for a continuous refinement of regulatory and ethical standards as regenerative medicine advances.

Keywords

stem cells orthobiologics ethics regenerative medicine clinical trials

Get full access to this article

View all access options for this article.

References

Jayaram

Ikpeama

Rothenberg

, et al. Bone marrow–derived and adipose-derived mesenchymal stem cell therapy in primary knee osteoarthritis: a narrative review. PM&R. 2019;11:177–191.

Whittle

Johnston

McDonald

, et al. Stem cell injections for osteoarthritis of the knee. Cochrane Database Syst Rev. 2025;4:CD013342.

Zhidu

Ying

Rui

Chao

. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther. 2024;15:266.

Sharkis

. Canadian stem cell scientists take the prize. Cell. 2005;122:817–819.

Caplan

. Mesenchymal stem cells. J Orthop Res. 1991;9:641–650.

Vodyanik

Smuga-Otto

, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920.

Takahashi

Yamanaka

. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676.

Davison

. Influencing NIH policy over embryonic stem-cell research: an administrative tug-of-war between Congress and the President. J Nat’l Ass’n Admin L Judges. 2002;22:405.

Varkey

. Principles of clinical ethics and their application to practice. Med Princ Pract. 2021;30:17–28.

10.

Bydon

Moinuddin

, et al. Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial. Nat Commun. 2024;15:2201.

11.

Malecki

. “Above all, do no harm”: safeguarding pluripotent stem cell therapy against iatrogenic tumorigenesis. Stem Cell Res Ther. 2014;5:73.

12.

King

Perrin

. Ethical issues in stem cell research and therapy. Stem Cell Res Ther. 2014;5:85.

13.

Ashok Kumar

Ghimire

Haroun

, et al. Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States. Eur J Haematol. 2024;112:328–338.

14.

Robertson

. Human embryonic stem cell research: ethical and legal issues. Nat Rev Genet. 2001;2:74–78.

15.

Thurairajah

Briggs

Balogh

. Stem cell therapy for fracture non-union: the current evidence from human studies. J Orthop Surg (Hong Kong). 2021;29:23094990211036545.

16.

Henon

. Human embryonic or adult stem cells: an overview on ethics and perspectives for tissue engineering. In: Elçin

, ed. Tissue Engineering, Stem Cells, and Gene Therapies. Boston, MA: Springer US; 2005:27–45.

17.

Moradi

Mahdizadeh

Šarić

, et al. Research and therapy with induced pluripotent stem cells (iPSCs): social, legal, and ethical considerations. Stem Cell Res Ther. 2019;10:341.

18.

Lomax

Torres

Millan

. Regulated, reliable, and reputable: protect patients with uniform standards for stem cell treatments. Stem Cells Transl Med. 2020;9:547–553.

19.

Bretzner

Gilbert

Baylis

Brownstone

. Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell. 2011;8:468–475.

20.

Sutton

Erlen

Glad

Siminoff

. Recruiting vulnerable populations for research: revisiting the ethical issues. J Prof Nurs. 2003;19:106–112.

21.

Turner

Snyder

. Ethical issues concerning a pay-to-participate stem cell study. Stem Cells Transl Med. 2021;10:815–819.

22.

U.S. Food and Drug Administration. What we do. 2023. Accessed May 10, 2025. https://www.fda.gov/about-fda/what-we-do#mission

23.

U.S. Food and Drug Administration. FDA advances new efforts to promote development of safe and effective regenerative medicine products. 2019. Accessed May 11, 2025. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-advances-new-efforts-promote-development-safe-and-effective-regenerative-medicine

24.

Code of Federal Regulations. Title 21 CFR Part 1271—human cells, tissues, and cellular and tissue-based products. National Archives and Records Administration. 2025. Accessed May 13, 2025. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271

25.

Code of Federal Regulations. Title 21 CFR Part 1271 Subpart A §1271.15—National Archives and Records Administration. 2025. Accessed May 13, 2025. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.15

26.

U.S. Food and Drug Administration. Types of applications. 2014. Accessed May 13, 2025. https://www.fda.gov/drugs/how-drugs-are-developed-and-approved/types-applications

27.

U.S. Food and Drug Administration. Clinical trials guidance documents. 2024. Accessed May 13, 2025. https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/clinical-trials-guidance-documents

28.

U.S. Food and Drug Administration. Standards development for regenerative medicine therapies. 2024. Accessed May 13, 2025. https://www.fda.gov/vaccines-blood-biologics/standards-development-regenerative-medicine-therapies

29.

U.S. Food and Drug Administration. Regenerative medicine advanced therapy designation. 2023. Accessed May 13, 2025. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation

30.

U.S. Food and Drug Administration. Biologics guidances. 2025. Accessed May 13, 2025. https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances

31.

Charnoff

Rothman

Andres Bergos

Rodeo

Casey

Cheng

. Variability in patient-incurred costs and protocols of regenerative medicine procedures for musculoskeletal conditions in the United States. HSS J. 2023;19:77–84.

32.

Turner

. The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Cell Stem Cell. 2021;28:1891–1895.

33.

Berkowitz

Miller

Mir

, et al. Glioproliferative lesion of the spinal cord as a complication of “stem-cell tourism.” N Engl J Med. 2016;375:196–198.

34.

Murray

Chahla

Frank

, et al. Rogue stem cell clinics. Bone Joint J. 2020;102-B:148–154.

35.

Pean

Kingery

Strauss

Bosco

Halbrecht

. Direct-to-consumer advertising of stem cell clinics: ethical considerations and recommendations for the health-care community. J Bone Joint Surg Am. 2019;101:e103.

36.

Turner

. The US direct-to-consumer marketplace for autologous stem cell interventions. Perspect Biol Med. 2018;61:7–24.

37.

Caulfield

McGuire

. Athletes’ use of unproven stem cell therapies: adding to inappropriate media hype? Mol Ther. 2012;20:1656–1658.

38.

Matthews

KRW

Cuchiara

. U.S. National Football League athletes seeking unproven stem cell treatments. Stem Cells Dev. 2014;23(Suppl 1):60–64.

39.

Watson-Levings

Palmer

Levings

Dacanay

Evans

Ghivizzani

. Gene therapy in orthopaedics: progress and challenges in pre-clinical development and translation. Front Bioeng Biotechnol. 2022;10:901317.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB

0.19 MB