ICL Delves into Current Research and Unanswered Questions in Orthobiologics for Shoulder and Sports Medicine

Biologics have long offered tremendous potential to heal musculoskeletal injuries. In theory, platelet-rich plasma (PRP), stem cells, and other approaches could help patients recover from a variety of musculoskeletal issues. Unfortunately, in many cases, these interventions have shown inconsistent results.

“While there’s innovation on the mechanical side—new anchors, plates, screws—fundamentally what would be transformative would be a change in healing biologically,” said Asheesh Bedi, MD, FAAOS, executive director and chief of sports medicine and shoulder surgery at the University of Michigan Medical School. “If we had an augmentation with cytokines or growth factors that give the right signals to the inherent cellular population at a healing site, that would be advantageous.”

On the first day of the AAOS 2025 Annual Meeting, an all-star panel dove into these issues during Instructional Course Lecture 150: “Orthobiologics for Shoulder and Sports Injuries: What Is the Evidence?” The group discussed different orthobiologics, how they are currently being used, and their long-term potential.

An introduction to PRP
PRP spins a patient’s blood down to concentrate the platelets and sometimes leukocytes, which are reinjected to promote healing. This approach can produce positive outcomes, but much depends on the condition treated, when it is treated, and the concentrations of platelets and leukocytes administered.

PRP releases a number of factors that can favorably influence inflammation, angiogenesis, and tissue regeneration, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF). There are more than 25 different PRP protocols, and efficacy often varies based on the formula being used and the tissue being treated. Other important factors include the richness of leukocytes and the concentration of the platelets themselves. This heterogeneity adds considerable confounders to determining the efficacy of PRP use. Specifically, designating PRP as a “proven” biological intervention has long been hindered by the dissimilar treatment protocols implemented in investigations. Such variable preparation and treatment protocols produce a vast spectrum of therapeutic arms—all of which can be referred to as “PRP,” which can be inaccurate, misrepresenting, and possibly misleading.

“There’s certainly a dose-dependent effect,” said moderator Lewis Shi, MD, associate professor of orthopaedic surgery and rehabilitation medicine at the University of Chicago. “We need to have high enough concentrations to have a therapeutic effect. The numbers we should be thinking about are one billion [platelets] per cc. If you are injecting 5 to 7 cc of PRP, you want to get to the five to 10 billion range to have an effect.”

One meta-analysis indicated that higher platelet counts provided more favorable results for treatment of knee osteoarthritis. However, the review also struck a cautious note: “Aspects like the definition of PRP, whether activation is necessary, the frequency of injections, the optimal dosage, and the preparation method remain unclear.” This uncertainty was magnified by a randomized, controlled trial that found that leukocyte-poor PRP is ineffective in knee osteoarthritis.

Overall, there is significant inconsistency across studies that may stem from methodology issues. “If you’re going to publish,” Dr. Bedi said, “you need to disclose your methodology, what it is you delivered, when you delivered it, how the whole blood was processed, and what outcome metrics you measured.”

The reality of PRP
Stem cells have two defining characteristics: They can self-renew, and they can differentiate into other cells. There are many types of stem cells, including embryonic, induced pluripotent, and mesenchymal. These cells have captured the public’s imagination, but again, the evidence of efficacy is often lacking.

“How might a stem cell work?” asked Dr. Bedi. “In an ideal world, we would simply deliver it into a tissue of choice, it would stay alive and just engraft into the healing tissue. But that’s probably a little bit of wishful thinking.”

Scott Rodeo, MD, professor of orthopaedic surgery at Weill Cornell Medical College of Cornell University, discussed cell therapy’s role in rotator cuff repair. The first question is which biologic targets need to be modulated: cell proliferation, angiogenesis, matrix remodeling, or inflammatory mediators? Surgeons need to match the biologic agent with the desired target, and one size does not fit all. There is some evidence that immunocompetent cells and activated stromal fibroblasts may be driving the inflammation in rotator cuff tendinopathy and that cell therapy could help mediate that inflammation.

One of the issues facing orthobiologics is the lack of FDA-sanctioned sources of stem cells. Surgeons can use bone marrow aspirate, adipose tissue, and a few other sources, but there are questions as to whether any approved sources contain enough stem cells to be therapeutically effective. The U.S. regulatory environment prohibits cell sorting and culture expansion to formulate cell therapies.

Still, some research has shown positive results for mesenchymal stem cells and bone marrow aspirates. These studies separately showed improvements in long-term cuff integrity and reduced re-tear rates. Dr. Rodeo pointed to some emerging approaches, including factors that can stimulate intrinsic stem cells and extracellular vesicles, that offer potential benefits.

Jason L. Koh, MD, MBA, FAAOS, the Mark R. Neaman Family Chair of Orthopaedic Surgery at Endeavor Health, discussed other options for rotator cuff repair, such as marrow channeling, collagen scaffold augmentation, and dermal allografts, which all show promise in early phases of research. Ultimately, more research is needed to identify which orthobiologics are most appropriate for specific conditions and how best to deliver them. “I think one of the challenges for all of us is that there is so much promise in orthobiologics,” Dr. Koh said, “but the challenge is seeing how we can use this in an applicable fashion.”

Josh Baxt is a freelance writer for AAOS Now.

References

1. Hohmann E: Editorial commentary: High-platelet-dose platelet-rich plasma may be the nonoperative treatment of choice for knee osteoarthritis. Arthroscopy 2025;41(3):818-20.
2. Lewis E, Merghani K, Robertson I, et al: The effectiveness of leucocyte-poor platelet-rich plasma injections on symptomatic early osteoarthritis of the knee: the PEAK randomized controlled trial. Bone Joint J 2022;104-B(6):663-71.
3. Hernigou P, Flouzat Lachaniette CH, Delambre J, et al: Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop 2014;38(9):1811-8.
4. Kim YS, Sung CH, Chung SH, et al: Does an injection of adipose-derived mesenchymal stem cells loaded in fibrin glue influence rotator cuff repair outcomes? A clinical and magnetic resonance imaging study. Am J Sports Med 2017;45(9):2010-8.
5. Cole BJ, Kaiser JT, Wagner KR, et al: Prospective randomized trial of biologic augmentation with bone marrow aspirate concentrate in patients undergoing arthroscopic rotator cuff repair. Am J Sports Med 2023;51(5):1234-42.