Regenerative Medicine — What Happened & What’s Next, Part 2: Growth Factors — Current Research & New Developments
The second in a short series designed as an introduction for science-minded non-scientists and interested business people. For a quick overview of the series, check out Part 1.
Growth factors (GF) are proteins that play a key role in tissue regeneration. Produced by several different cell types, GF (such as the insulin-like GFs, platelet derived GF, transforming GF beta, etc.) deliver biological signals to cells, in particular signals governing the repair and renewal of all tissues in the body. As pleiotropic agents, GF do their best work on a highly localized scale, regulating or influencing multiple processes, binding to cells and telling them to become a new cell type (differentiate), relocate to another neighborhood where needed (migrate), or be fruitful and multiply (proliferate). Injecting GF (systemic administration — the way many drugs are given) has not been a successful strategy for most of the proteins in this class. Notable exceptions are the blood cell stimulators erythropoietin and G-CSF, widely used to replenish red and white blood cells for patients in chemotherapy. It is safe to say that these billion dollar drugs (Epogen, Neupogen, Neulasta) were the low-hanging fruit of the growth factor class. The other two systemically delivered GF on the market have very limited uses (IGF-1 in pediatric patients lacking this GF, and keratinocyte GF to treat oral complications of chemotherapy).
Generally speaking, systemic administration of GF has not been particularly effective because these proteins are not very stable, often elicit inflammatory responses, and have significant potential for off-target effects and undesirable cell growth. Thus, current R&D looking to reap the therapeutic benefits of GFs look at targeting them to specific tissues. Strategies include injection directly into the site of injury; incorporating GFs into polymer matrices which are then locally delivered; and engineering GF to increase half-life and / or help them selectively bind to the damaged tissue. Though engineering GF to home in to the correct tissue holds great promise, this approach is still at the preclinical stage. In an attempt to bypass the need for a delivery matrix, several investigators have evaluated direct injection of GF into the damaged tissue. A few dozen trials (primarily sponsored by non-corporate academic centers) are testing this approach. Judging by the large number of trials completed 3 or more years ago with no results reported or subsequent news, we might surmise that this approach has largely been unsuccessful; one possible exception in late stage trials is intra-occular injection of nerve GF for keratitis.
On the other hand, incorporation of growth factors into delivery matrices is gaining traction as a targeting strategy with significant potential for bone and tissue repair. Because first generation delivery matrices required much R&D to match matrix properties and delivery rates to the specific tissue biology and the required local GF concentration, there are just a few products that have made it through R&D and FDA approval: recombinant human (rh) BMP in a collagen matrix (approved for spinal fusions and certain dental applications) and rh PDGF in a gel matrix (approved for diabetic ulcers and periodontal applications). Interestingly (and perhaps disturbingly, given the powerful nature of these proteins) there are several topical, “cosmeceutical” GF products on the market claiming everything from firmer skin to eradication of blemishes and wrinkles. Although there are clinical studies of different GF preparations supporting some dermatologic use, none have been FDA approved to date, leaving many of their efficacy claims open to debate.
Ideal characteristics of biomaterials for local delivery of growth factors and other protein therapeutics include low immunogenic potential, ease of use for physicians, and incorporation of biomechanical and other elements similar to extracellular matrix (ECM, of which collagen is a major component), the natural environment of GFs. In addition, matrices must be able to: incorporate proteins without damaging structure or altering activity; have controlled degredation rates and predictable degredation products; and control the amount of GF released. The vast majority of development efforts here focus on next generation polymers and hydrogel matrices that have all of these characteristics, and as you might guess, it has taken a while for this science to develop.
First generation delivery matrices often used bovine collagen which can be difficult to source, complex to produce, and can cause allergic responses. Other approaches used naturally derived macromolecules that form matrices in response to changes in temperature or pH (picture fancy versions of Jell-O!). While fine for laboratory studies, their poor mechanical properties and slow / unpredictable polymerization rates made them largely unsuitable for advanced applications or clinical use. Crosslinking chemistries that work in an aqueous (tissue-friendly) environment addressed many of these limitations but either take several minutes to over an hour to solidify into a matrix, or else involve reactions that produce disorganized matrices (typically acrylate-based) whose breakdown products have unpredictable pharmacokinetics (in English — it is hard to trace what happens to these matrices once they start to dissolve, including how effectively they will be cleared from the body).
The current state of the art in matrix chemistry for local delivery of growth factors uses so called “click chemistries” which overcome these limitations and can create matrices with properties best suited for the tissue of interest as well as the ability to release the GF at the desired rates. These newer chemistries have produced matrices that are currently in clinical testing — not yet with GF but for delivery of cells (more about this in Part 3) and as dermal fillers. This approach only recently began preclinical testing with growth factors so has at least a year before we see them being used to target these therapies in clinical testing, but it is coming!
Up Next — Part 3: Hooray…? for Stem Cells!
For current news and views on all things regenerative, check out RegMedNet