Regenerative medicine experts and TOBI faculty Dr. Gerry Malanga and Dr. Ken Mautner recently sat down with Dr. Jonathan Halperin to discuss the basics of regenerative medicine as well as the current state of literature possible future directions. We’ve provided a brief synopsis below, but encourage you to dive into this fascinating conversation from two of the thought-leaders in this area.
The conversation starts by summarizing the past and current state of regenerative therapies. While these therapies are still early in development, they represent an opportunity to fill gaps in treatment for diseases where traditional therapies have failed. Definitions for biologics and cells are both discussed, including details regarding platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). The speakers discuss how these treatments are harvested and some of the details behind their mechanisms of action.
MSCs are discussed in detail, in particular, their likely origin as pericytes and their likely function as signaling cells. These cells were previously thought to differentiate to directly repair damaged tissue, but it was found that these cells didn’t live long enough for this to be the case.Instead, they may hone to areas of tissue damage and secrete a variety of compounds to signal to the surrounding tissues that repair is needed.
PRP is also discussed in detail, including the role of alpha granules and other paracrine compounds release by platelets that likely modulate the environment to initiate and assist with tissue healing. Both speakers comment on the irony in how many of the medications most often given for musculoskeletal diseases, like NSAIDs or steroids for example, can have a negative impact on platelet activity and may counteract healing as a result.
The preparation and components of PRP are then discussed. Both speakers comment on the wide variety of preparations that exist that may affect the properties of PRP. These parameters include the presence and concentration of white blood cells and red blood cells as well as the overall concentration of platelets. Platelet activation involves triggering the release of granule contents before application for a more rapid anti-inflammatory response, although effectiveness is under investigation. Both speakers comment on the fact that few studies report these parameters, making the literature difficult to interpret. It is partly for this reason that Drs. Mautner and Malanga developed the PLRA (Platelets/Leukocytes/Red blood cells/Activation) classification system to encourage better reporting of these parameters.
The conversation then moves to the current state of literature for MSCs. The speakers reiterate the likely role of pericytes as a class of cells that hone to damage, assess what needs to get done, and release signals to repair the damaged areas. They then likely return to their original locations. What exact preparations are needed to facilitate this process is much less clear, according to the speakers. It’s unknown how important concentration of cells or number of cells are, for example. Different harvesting methods along with the pros and cons of each are discussed, with both speakers commenting on the ability to perform these procedures in about an hour in an office setting once practitioners are familiar.
The speakers then move on to allogenic stem cell products including amniotic fluid, amniotic tissue and umbilical cord products. They comment that most are not truly stem cell products and likely work through the large amount of growth factors they contain. They also commented that, in spite of the significant advertising, they have almost no literature backing them and much more research is required.
From here, the discussion turns to how PRP modulates the healing process. In particular, they discuss how the maturation of healing tissues and collagen deposition can take weeks to months to occur. This is why tendon healing can take 6 months or longer after an injection. This differs for intraarticular injections, where decreasing inflammation is likely more important.
The speakers then run through the research and their experience treating a variety of different disorders including large and small joint osteoarthritis and tendon pathology. They also comment on the ways in which the tissue needling may affect and improve outcomes, serving as a useful adjunct to PRP or as a replacement in offices where PRP may not be available.
In comparison, the speakers both note that research on MSC is still very immature with most research uncontrolled. More research is needed to determine preparation, who should get what types of products, and whether some techniques for harvesting are better than others. They also note that the current measures for MSCs are likely imperfect. The MIBOI guidelines exist to help guide what should be reported when using these treatments. However, measures of total nucleated cells are likely imprecise despite being widely used. Other measures that are more accurate also tend to be more expensive.
Both speakers comment on the situations in which they use different treatments. For example, bot feel that PRP is generally worthwhile for tendons with some exceptions. Both rarely use MSCs for these indications. They also note that regenerative procedures do not correct biomechanical problems, which generally requires orthopedic intervention.
They emphasize the multidisciplinary approach to foster what Dr. Malanga calls “medically assisted self-healing” or “MASH.” Optimizing this healing requires a good understanding of the literature on these treatments and ongoing education to base therapy choice on evidence. Both feel that medicine is driving towards less and less invasive treatments that are more and more tailored, including the use of regenerative therapies. The delivery methods of these compounds are likely to change in ways that improve their efficacy.
Further information and resources can be found at:
– prpseminar.com (website for the TOBI meeting)
-aapmr.org including preconference offerings before the yearly meeting
-amssm.org (website of the American Medical Society for Sports Medicine)
-interventionalorthopedics.org (website for the Interventional Orthopedics Foundation)
-Clinicaltrials.gov (website that hosts ongoing trials that may be of interest)
–Regenerative Treatments in Sports Medicine by Drs. Malanga and Ibrahim