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Medscape Asks Dr. Bert Mandelbaum About Orthobiologics for Knee Osteoarthritis: Fact, Fiction, or Fantasy?

Orthobiologics for Knee Osteoarthritis: Fact, Fiction, or Fantasy?

Bert R. Mandelbaum, MD, DHL (Hon)

December 17, 2018

Faced with both exciting new research and dangerous hype about such treatments as platelet-rich plasma and stem cells for osteoarthritis of the knee, I've begun to adopt what I call the Orthobiological Surgeon's Prayer: I ask for the ability to help when I can, the judgment to know when I can and cannot help, and the wisdom to know the difference.

Among the many biological substances that might help chondroprotection and chondrofacilitation, platelet-rich plasma and hyaluronic acid injections are supported by early and significant evidence. It's too early yet to make confident use of stem cells or amniotic fluid, and we must warn patients to be particularly careful about claims for these substances.

Such claims are coming fast and furious as unscrupulous businesses keep popping up to exploit patients' desperation and confusion and the gap between hope and knowledge, even as the US Food and Drug Administration (FDA) attempts to clamp down on them. That makes it particularly important for clinicians to understand the fast-moving science behind them.

But eventually, I believe, the science will triumph over quackery, and orthobiologics will become an essential part of every knee surgeon's armamentarium.

It's important to remember that the FDA grants exemptions under section 361 of the Public Health Service Act for human cell, tissues, and cellular and tissue-based products only for homologous use and only if they are minimally manipulated.[1]

Even within those parameters, what most specialty stem cell clinics are offering is a lot of snake oil. But eventually, I believe, the science will triumph over quackery and orthobiologics will become an essential part of every knee surgeon's armamentarium.

The development of these treatments corresponds to other trends in medicine, including personalization, artificial intelligence, 3D printing, and robotics. It's possible to imagine the day when we can tailor a treatment to the precise genetic and anatomical needs of a particular patient.

Orthobiologics may already be approaching a tipping point when they become part of the mainstream. This trend follows the trajectory that orthopedics has already begun. We are moving away from the day when we just cut bones and moved them into place. We are now considering the knee as an organ and taking into account alignment; meniscal and ligament deficiency; and molecular, tissue, and matrix issues.

Cartilage tissue engineering in particular requires an understanding of these various components at several length scales. Performance is generally measured in meters. The organ is measured in centimeters. Tissue is measured in millimeters.

As surgeons, we must work on all these scales. Our treatments are only as strong as their weakest links. Likewise, whether an acute knee injury results in osteoarthritis depends on a "perfect storm" of factors, including the athlete's age and gender; the level of play; the age of the injury; the timing of the treatment; and modulators, such as matrix metalloproteinases and glycosaminoglycan (GAG).[2]

We must take all these factors into consideration not only in our treatment plans but in working to prevent injuries. To paraphrase a comment from the hero of the book and movie The Martian, "In the face of overwhelming odds, I'm left with only one option: I'm gonna have to science the heck out of it."[3]

That science begins with the understanding that successful tissue engineering must include cells, growth factors and cytokines, scaffolds, and biomaterials. It's like a construction site: In addition to the workers, if you don't have both rebar and concrete, your walls won't stand.

Personalizing Orthobiologics

But it's not yet clear exactly which orthobiologics are needed for which project of regeneration. The list available to us now includes glucosamine-chondroitin sulfate, hyaluronic acid, platelet-rich plasma, cytokine modulation (such as interleukin-1 receptor agonist [IL-1ra] inhibition of inflammation), stem cells (of multiple origins), and amniotic fluid.

A monosaccharide precursor to GAG, glucosamine-chondroitin appears to increase polyglycan production, decrease degradative enzymes, and inhibit interleukin-1 beta and tumor necrosis factor alpha as well as other inflammatory agents, while increasing GAG content and cartilage thickness after injury.[4,5] Multiple randomized controlled trials have shown that it can improve measures of joint pain and function, such as Knee injury and Osteoarthritis Outcome Score[6] and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores.[7]

Hyaluronic acid appears to help polyglycans and GAG bind to collagen mesh and aid in hydration, decreasing the inflammatory response, improving the cartilage viscoelastic properties, and slowing degeneration.[8] Dozens of trials have shown that it can beat placebo[9] and match nonsteroidal anti-inflammatory drugs or corticosteroids[10] in relieving symptoms of osteoarthritis of the knee. They also suggest that it is well-tolerated and safe.[11]

Platelet-rich plasma owes its benefits to the 1507 proteins in platelets. These include growth factors that stimulate cell growth, recruitment, differentiation, and gene expression; skin closure; cytokine secretion; blood vessel and collagen synthesis; growth inhibition; apoptosis, angiogenesis; mitogenesis; and chemotaxis.[12]

In clinical trials, platelet-rich plasma has enhanced superficial zone protein secretion from the synovium and cartilage.[13] It, too, has improved WOMAC scores over 6 months in randomized, controlled clinical trials of osteoarthritis of the knee.[14,15] That said, platelet-rich plasma is very complex, and its biological effects can vary with age, body mass index, nonsteroidal anti-inflammatory drugs, even diet.[12]

Autologous IL-1ra in theory stimulates the synthesis of anti-inflammatory cytokines. In early trials, it looks as if it may not have as robust an effect as platelet-rich plasma, particularly because it does not act on stem cells.[16]

These treatments may have a synergistic approach. For example, hyaluronic acid induces the release of growth factors from platelet-rich plasma.[15]

Stem cells come in many varieties: adipose derived, bone marrow aspirate concentrate, allogeneic, and induced pluripotential. There are only a handful of small studies looking at any of these in osteoarthritis of the knee. What's been done so far looks promising,[17] but some of these sources, such as bone marrow aspirate, can be very invasive.

Amniotic fluid provides another potential source of stem cells. These cells can be expanded in vitro into osteogenic, myogenic, adipogenic, endothelial, hepatic, and neurogenic cells. This literature is even more preliminary, though a registry study suggests improvements in patients with osteoarthritis.[18]

If we categorize these approaches by traffic light, we'd give amniotic fluid and glucosamine/chondroitin a yellow light because of the limited, but positive, evidence. Bone marrow aspirate and cytokine modulation would get a red light, because the evidence is even more limited. The green lights would go to platelet-rich plasma and hyaluronic acid, because of the relatively large database.

When it comes to biologic adjuvants for anterior cruciate ligament repair, the story is different. We'll explore those issues in the next column.


  1. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. US Food and Drug Administration. December 2017. Source Accessed November 7, 2018.
  2. Rai MF, Brophy RH, Sandell LJ. Osteoarthritis following meniscus and ligament injury. Curr Opin Rheumatol. 2019;31:70-79. doi:10.1097/bor.0000000000000566
  3. The Martian. 2015. IMDb. Source Accessed November 7, 2018.
  4. Shikhman AR, Kuhn K, Alaaeddine N, Lotz M. N-acetylglucosamine prevents IL-1-mediated activation of human chondrocytes. J Immunol. 2001;166:5155-5160. doi:10.4049/jimmunol.166.8.5155
  5. Lippiello L, Woodward J, Karpman R, Hammad TA. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop Relat Res. 2000;229-240. doi:10.1097/00003086-200012000-00027
  6. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med. 2003;37:45-49. doi:10.1136/bjsm.37.1.45
  7. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251-256. doi:10.1016/s0140-6736(00)03610-2
  8. Hardingham T, Muir H. The specific interaction of hyaluronic acid with cartilage proteoglycans. Biochim Biophys Acta Gen Subj. 1972;279:401-405. doi:10.1016/0304-4165(72)90160-2
  9. Wobig M, Dickhut A, Maier R, Vetter G. Viscosupplementation with Hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther. 1998;20:410-423. doi:10.1016/s0149-2918(98)80052-0
  10. Bannuru RR, Vaysbrot EE, Sullivan MC, McAlindon TE. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthritis Rheum. 2014;43:593-599. doi:10.1016/j.semarthrit.2013.10.002
  11. Bannuru RR, Osani M, Vaysbrot EE, McAlindon TE. Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthr Cartil. 2016;24:2022-2041. doi:10.1016/j.joca.2016.07.010
  12. Akeda K, An HS, Okuma M, et al. Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis. Osteoarthr Cartil. 2006;14:1272-1280. doi:10.1016/j.joca.2006.05.008
  13. Sakata R, McNary SM, Miyatake K, et al. Stimulation of the superficial zone protein and lubrication in the articular cartilage by human platelet-rich plasma. Am J Sports Med. 2015;43:1467-1473. doi:10.1177/0363546515575023
  14. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis. Am J Sports Med. 2013;41:356-364. doi:10.1177/0363546512471299
  15. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop. 2014;5:351-361. doi:10.5312/wjo.v5.i3.351
  16. Auw Yang KG, Raijmakers NJ, van Arkel ER, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthr Cartil. 2008;16:498-505. doi:10.1016/j.joca.2007.07.008
  17. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99:1681-1690. doi:10.1097/tp.0000000000000678
  18. Demesmin D, Beall D, Nalamachu S. Amniotic fluid as a homologue to synovial fluid: interim analysis of prospective, multi-center outcome observational cohort registry of amniotic fluid treatment for osteoarthritis of the knee. Program and abstracts of the American Academy of Pain Medicine 57th Annual Meeting and Exhibition; July 12-16, 2015; Anaheim, California. Source Accessed November 7, 2018.

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Cite this article: Orthobiologics for Knee Osteoarthritis: Fact, Fiction, or Fantasy? - Medscape - Dec 17, 2018.