Regenerative Medicine: Tremendous Potential but Not Quite Ready for Prime-Time

Introduction

Regenerative medicine approaches for the treatment of various musculoskeletal pathologies are an area of very rapid growth in recent years. Regenerative medicine encompasses various techniques to augment the biology of orthopedic tissues, including cartilage, meniscus, tendon, ligament, bone, spinal disc, and muscle. Currently available “orthobiologics” include autologous blood formulations such as platelet-rich plasma (PRP) or autologous conditioned serum (ACS), as well as cell therapy approaches using cells derived from bone marrow, adipose tissue, or various perinatal sources, including amnion, placenta, and umbilical cord blood. Other emerging therapies in this area include gene therapy approaches, cytokines/small peptides, repurposing of drugs approved by the U.S. Food and Drug Administration (FDA), and synthetic and biologic materials used for the regeneration of bone, tendon, ligament, meniscus, and cartilage.

The inherently poor intrinsic healing potential of many musculoskeletal tissues has led to an explosion of interest in these emerging approaches to augment tissue healing, repair, and regeneration. However, despite their tremendous potential, the clinical use of these therapies has outpaced the clinical and laboratory data to support their use. Furthermore, aggressive marketing has led to the often indiscriminate use of unproven and unapproved therapies. The regulatory environment in the U.S. has also led to patients seeking treatment overseas, where these therapies are available. Such “medical tourism” is increasingly common, especially among high-level athletes looking for an edge. The more permissive regulatory framework in other countries and the lack of transparency make it difficult to provide accurate information to patients seeking these overseas treatments. This all makes clear the need for rigorous clinical and laboratory research in the emerging area of regenerative medicine.

The past year has been an exciting time in the field of cell and gene therapy. Advancements in regulatory approvals and commercialization milestones have led to innovations in chimeric antigen receptor-T cell therapies, gene editing and gene therapy, induced pluripotent stem cells, and mesenchymal stromal cells (MSCs). For example, the FDA-approved MSC therapy to treat steroid-refractory acute graft vs host disease for the first time in 2024. There has also been success in treating conditions such as Parkinson’s disease using induced pluripotent stem cells ¹ and sickle cell disease using gene-editing technology. ²

These advancements, coupled with the perception that regulation is stifling innovation in regenerative medicine, have spurred interest in providing patients with earlier access to promising new therapies. A case in point is a recent law enacted in Florida (Bill 1768) that allows physicians to provide cell therapies that are not yet FDA-approved “for orthopedic conditions, wound care, or pain management.” ³ Furthermore, in mid-2025 the new leadership at the U.S. Health and Human Services and the FDA stated their goal to lower regulatory hurdles for some regenerative medicine treatments.^4,5 At the same time, there is increasing interest in pathways to allow patient access to emerging therapies that are still in clinical trials and not yet FDA-approved. For example, the “expanded access” pathway allows a clinician to offer such a treatment to a patient with a serious or life-threatening condition who has no other good treatment options. It is important to emphasize that this pathway is not meant to be an alternate pathway to access unproven investigational products. Using the expanded access pathway for access to investigational products outside of a clinical trial requires FDA approval. This process should be distinguished from the “right to try” pathway, which is not regulated by the FDA and involves the treating physician submitting a request directly to the manufacturer of the investigational product. Approval by the FDA or an institutional review board is not required.

The concerns with these non-trial access pathways are that they may expose patients to unproven interventions or jeopardize patient enrollment in ongoing clinical trials, which could delay or even prevent market approval. Consequently, clinicians must approach regenerative medicine in a rigorous fashion, carefully informing patients of current knowledge on these treatments and avoiding indiscriminate use.

This issue of HSS Journal brings together perspectives from experts in regenerative medicine, including articles on basic concepts in the field, ethical issues related to stem cell therapy, and the current status of exosomes. Several articles address the role of cells derived from bone marrow and adipose tissue in the treatment of osteoarthritis, as well as the complications of cell therapy injections used to treat osteoarthritis. Various formulations derived from autologous blood, such as PRP, continue to be developed and studied, and are discussed in an article on the next generation of these therapies and providing some clarity to the “alphabet soup” of currently available blood formulations (PRP, ACP, APS, ACS, A2M). The concept of repurposing FDA-approved pharmaceuticals is illustrated by a study on the effect of metformin on MSCs. This issue also explores the use of novel scaffold materials for tissue regeneration, including bioactive glass grafting for bone formation, a 3D-printed peripheral nerve conduit for nerve regeneration, and the use of a collagen membrane to aid healing of the anterior cruciate ligament. Finally, an overview of the HSS Center for Regenerative Medicine describes the clinical and laboratory research program, biospecimen repository, clinical registry, and educational programs. This information may help other centers establish similar research programs, which may help to move this field forward.

As one of the guest editors, I hope that the information in this issue will stimulate ideas, questions, and discussion that will lead to further research.

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