Regenerative medicine was always a strange curiosity to me. I never took it too seriously, because it seemed to operate in a gray area of medicine. Coming from the world of pharma and biotech, I pretty much wrote off much of the field because there is a lot of unregulated activity, “off label” use of treatments, and dubious claims about its efficacy.
But I heard a story about a friend’s rapid recovery from a tendon tear - he got an injection of some sort of regenerative medicine treatment, though he didn’t know what.
It turns out he got an amniotic tissue graft - this is one of the most promising and widely used forms of regenerative medicine. I wanted to dig deeper.
Amniotic Tissue
The amniotic membrane surrounds and protects the fetus in utero. It is made up of an extracellular matrix (structural element), biologically active cells including stem cells, as well as regenerative molecules. These include various types of growth factors and immunosuppressive cytokines. It’s a complex mixture which is not super well characterized.
Amniotic membrane is taken from donors who have scheduled c-sections, as this is a sterile procedure. The tissue is then washed in antibiotics and preserved, either by freezing or lyophilization (freeze drying). The latest products are shelf stable.
It’s then used in amniotic membrane grafts - effectively injecting patients with this material. It has impressive “regenerative” capabilities - it is of particular utility in wound healing and surgical recovery. Orthopedic surgeons use it to accelerate healing of diabetic foot ulcers among other slow healing wounds. I wasn’t able to find the number of procedures done per year, but it’s in the 100,000 - 1m range in the US alone.
While anecdotal data is extensive, well controlled clinical trial data is lacking. This is partially due to the economic incentives around regenerative therapies - they don’t follow the typical pharma therapeutic path, where a company owns the IP around a drug, runs trials, and ultimately commercializes it. In this case, donor tissue falls in a different regulatory framework (more on that later). Without these typical economic and regulatory incentives, funding for full scale clinical trials is limited.
Some examples of clinical trial data include improved patient outcomes after hand tendon surgery, quicker recovery and healing of diabetic foot ulcers, and as a treatment for osteoarthritis with patients experiencing less pain after 3 and 6 months. Long story short, in the limited trials that have been done, the data look good.
Stem Cells?
There are stem cells in amniotic tissue BUT they are not embryonic stem cells, and have limited ability to differentiate. There is little evidence that they play a role in the therapeutic activity of amniotic grafts. The presence of stem cells is more often than not used as a marketing ploy by makers of amniotic products and unscrupulous doctors.
Regulatory landscape
Donor tissues fall under the FDA’s 361 guidelines which state that if the tissue is “minimally manipulated” it does not need approval as a drug. Bone, ligaments, tendon, and cartilage all fall under this category. The spirit of the regulation here is to allow for donor tissues to be easily provided to patients who need them, assuming those tissues are not manipulated and serve the same purpose that they originally did (known as homologous use).
There are still requirements for these tissues including registration with the FDA, determining donor eligibility, and “Good Tissue Practices” e.g. guidance for handling, sterility, etc.
But, these amniotic tissue grafts are not considered homologous use - amniotic tissue used for wound healing is not homologous use because wound healing is not a basic function of amniotic membrane. So we’re already running afoul of 361.
In November 2017 the FDA stated that they would effectively hold off on enforcement action for 3 years, if the use of these products didn’t raise significant safety concerns “to give manufacturers time to determine if they need to submit an IND or marketing application.”
I haven’t found any information about what people expect to happen now that this grace period is almost up.
Future Directions
There is a lot more to explore in regenerative medicine - I’ve only scratched the surface. There are dozens of other 361 products out there worth exploring, with a similar mix of potential medical benefit, lack of clinical trial data, sketchy sales tactics and spurious claims.
As these products come out of the shadows, there is a ton of opportunity to make better ones. What about doing characterization of the mix of factors in amniotic tissue - treating each one as a possible drug candidate? What about really going deep on formulation and stability to increase the utility of these products?
What about recapitulating this mix with the factors made recombinantly (by engineered cell lines), increasing safety, potency and scalability?
There are few areas of medicine with so much knowledge about patient benefit, but that lack biological characterization and refinement, AND operate in an actively evolving regulatory framework.
This is a serious opportunity to build something big.