Rhonda Wallen
Oct 4, 2016 · 4 min read

Regenerative Medicine — What Happened & What’s Next (Part 1)

Or: No, you didn’t miss it, it’s (still) coming!

The following is the first in a short series designed as an introduction for science-minded non-scientists and interested business people. There are many wonderful review articles in the literature that provide fantastic levels of detail in each one of these areas if you would like further reading.

Part 1 — A quick overview: background, successes and challenges

Regenerative medicine today has come to encompass the science of tissue engineering, local delivery and/or modification of growth factors, and stem cell therapy. Though each comes with unique technical challenges, the convergence of these disciplines may be what we need to deliver the therapies that can truly repair or replace damaged or diseased tissues. In the past 5 years alone dozens of journals dedicated to this field[1] have published literally hundreds of scientific articles advancing our knowledge but also underscoring that we have a ways to go before we find the best modalities and formulations that result in clinically successful therapies.

Tissue engineering (TE) is perhaps the most well established of the regenerative modalities, having origins nearly 40 years ago when researchers first began blending materials science and tissue culture. The original goal of creating replacement organs remains closer to science fiction than fact for a variety of reasons, mainly concerning the inability to ensure an adequate blood supply for the new tissues. Thus current TE development efforts are slightly less ambitious and tend to focus on repairing or restoring function of damaged tissues. Much of the foundational research came out of the labs of Joseph Vicanti, Robert Langer and Jeffrey Hubbell working to create biocompatible materials and elucidate how cells use extracellular matrices in normal tissue remodeling and growth (more on this in later posts). Natural and synthetic materials were used to encapsulate and later, act as scaffolds to guide and promote the growth of cells from a single layer to communities of cells forming nascent tissue in 3 dimensions.

Building on this research, we are now at the point where we can design biomaterials to deliver cells or growth factors which can bolster the body’s innate healing processes, as demonstrated in preclinical models. Current research is now refining these methods and formulations in search of the approaches that are both clinically valuable and commercially viable. That there are very few marketed products in this category (early examples below and new entrants discussed in Parts 2 & 3), speaks to the many challenges of developing regenerative medicine products.

The latest hot areas under investigation for regenerative medicine, much further out on the horizon (outside the scope of this article) but worth watching are: novel biomaterials (e.g. graphene, nanomaterials) which by themselves may be able to mobilize innate stem cells and/or stimulate appropriate cell signaling; micro electromechanical systems (MEMS) which can use these mechanisms to stimulate cellular growth or repair; and small molecules (i.e. traditional pharmaceuticals) which can reprogram endogenous stem cells to differentiate into the appropriate cell types.

Early Successes

Skin grafts were the earliest demonstration of the potential of regenerative medicine with cultured human fibroblast skin products Dermagraft and Apligraf. These products were not immediate home runs however, with medical economic benefit not proven until recently, after nearly 15 years on the market. It was nearly 10 years until the next product in this class, Gintuit (cultured keratinocytes and fibroblasts in a collagen matrix), was approved for periodontal disease. Each of these products spent many years in development as the trailblazing companies wrangled with a succession of non-trivial commercialization hurdles: scaling-up manufacturing, product packaging and distribution issues, and most expensively, having to enter into complex clinical development programs with (at the time) unclear regulatory requirements. Being the first market entrants also brought the additional hurdles of changing long established physician treatment approaches as well as having to create new categories to obtain insurance coverage and reimbursement.

The long road for the skin products may be a reflection of the rather difficult clinical setting of diabetic ulcers, but these timelines are illustrative of the challenges of introduction and adoption of engineered tissue therapies.

Cell-based therapies came into clinical practice roughly 40 years ago with the use of bone marrow derived hematopoietic stem cells for blood cancers and immune system disorders. We’ve learned more recently that several other (non-stem) cell-based therapies can also deliver regenerative benefits. These are autologous indications (where patients are treated with their own cells) and are generally procedure, rather than product based. Nevertheless, several companies have built businesses around processes and tools for isolating, expanding and delivering the cells back to the patient. Examples in this category include:

  • chondrocytes for knee cartilage defects (Carticel)
  • adoptive immunotherapy with T-cells (including the promising but not yet FDA approved CAR T- approach where T-cells are engineered to recognize and attack specific cancer cells before being injected back into the patient; regenerative only in the sense that it reprograms/reboots T-cells to better enable them to do what they do best)
  • fat cells to treat sclerotic conditions
  • bone marrow mononuclear cells (used experimentally for muscular dystrophy, neurodegenerative disease and post myocardial infarct)
  • platelet-rich plasma (PRP)

Use of PRP, an intermediate (and yet to be standardized) strategy falling somewhere between delivery of growth factors and stem cells, may provide an ideal growth factor cocktail, but has yet to demonstrate improved clinical outcomes in accelerating or improving healing following orthopedic surgeries, chronic wounds, or discogenic low back pain; one potential exception being actively studied (and marketed by a growing number of enterprising surgeons) is with osteoarthritis of the knee.

Coming up next, Part 2: Current Research and New Developments: Growth Factors, Stem Cells and Tissue Engineering

For current news and views on all things regenerative, check out RegMedNet

[1] Just a few examples (year of 1st publication): J Tissue Eng & Regen Med (2007) Am J Stem Cells (2012); Cell Regeneration (2012); NPJ Regen Med (2016); Cell-Stem Cell (2010); J Regen Med (2012); J Stem Cell & Regen Bio (2006); J Biomaterials & Tissue Eng (2011); Open J Regen Med (2012)

Rhonda Wallen

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