A field of experimental, regenerative medicine that has not received much press to date is the field of “biomaterials.” Simply put, bio-materials are organic compounds that can self-assemble and form polymers that reinforce damaged tissues. Such biomaterials are also used to form molds of organs that are seeded with stem cells that form an artificially assembled organ. These stem cells then degrade the biomaterial to leave a newly formed organ. This use of biomaterials is termed “tissue engineering,” and it is one of the most innovative and fascinating new fields of medical research.
Recently, biomaterials have been used to treat the hearts of laboratory animals that have suffered a heart attack, and the results are more than hopeful, even if the biomaterials themselves are not yet ready for human trials. Furthermore, biomaterials can enhance the healing activities of stem cells.
If biomaterials are used on their own, they can shore up a failing heart. Alginate hydrogels, are based on compounds extracted from brown seaweeds called “alginic acids.” When crosslinked by positively charged ions like calcium, alginic acids form solid or semi-solid materials. called a hydrogel. Injection of alginate hydrogels into the heart muscle after a heart attack increases the thickness of the heart wall and decreases the amount of blood left in the large chambers of the heart after they have been filled with blood (also known as “end diastolic volume” or EDV; see Landa, et al. Circulation 2008; 117: 1388-96, and Leor, et al., J Am Coll Cardiol 2009; 54: 1014-23). In unhealthy hearts, the EDV is high because the heart beats sluggishly and waits longer before each beat. If the EDV goes down after a heart attack, it is usually evidence that the heart has recovered somewhat. Because hydrogels are biodegradable, these positive effects are temporary. For example, polyethylene glycol hydrogels also lower EDV 4 weeks after a heart attack, but this effect goes away after 3 months (Dobner, et al., J Card Fail 2009; 15: 629-36). Therefore, by themselves, biomaterials buy the heart time, but do not promote long-term healing.
In order for biomaterials to work within the heart, they must not activate the immune system to attack them, they must have similar properties to heart muscle, and be liquid at the time of injection into the heart but solid once they achieve their proper location in the heart. Matrigel, for example, was originally extracted from soft tumors, and is composed of several proteins already found in the body (laminin, collagen IV, heparan sulfate proteoglycan, and entactin for those who want to know). Matrigel is liquid at low temperatures but forms a hydrogel at 37 degrees Celsius (our body temperature). Also, because matrigel is made by living cells, is usually imbued with growth factors that can aid the ailing heart and assist the work of implanted stem cells. In fact, experiments with matrigel and embryonic stem cells in mice have shown that matrigel increases the retention of embryonic stem cells that have been injected into the heart after a heart attack and the functional efficiency of the heart compared to injections of just cells (Kofidis, et al., Circulation 2005; 112: I173-7). Matrigel, however, is extracted from mouse tumor cell lines and is not appropriate for use in human patients.
Another potential biomaterial is collagen, which is use to make the scars in the heart after a heart attack. This protein is inexpensive, nontoxic, biodegradable, and friendly to the immune system. Collagen gels have been used to prevent mesenchymal stem cells from redistributing to other organs after they have been injected into the wall of the heart after a heart attack (Dai, et al., Regen Med 2009; 4: 387-95, and Danovic, et al., PloS One 2010; 5: e12077). In large animals, collagen gels have been used to deliver mesenchymal stem cells to precise locations around the heart (Ladage, et al., Gene Therapy 2011; 18(10): 979-85). Tissue engineers have also made vascular beds from collagen gels and “endothelial progenitor cells” or EPCs (stem cells that form blood vessels). Implantation of these engineered tissues into sick rodent hearts improved heart function by increasing blood delivery to heart tissue (Frederick et al., Circulation 2010; 122: S107-17).
Another protein that can potentially serve as a biomaterial for heart attacks is fibrin, which is the material found in blood clots. Fibrin has a major advantage in that it is already recognized by the Food and Drug Administration (FDA) as a product approved for use in human patients. Fibrin can serve as a patch (like a bandage) for hearts, or it can be injected into the heart itself with stem cells. Fibrin acts as a kind of glue that helps retain stem cells in the heart after their delivery (See Breen, O’Brien and Pandit, Tissue Engineer Part B Rev. 2009; 15: 201-14; Terrovitis et al., J Am Coll Cardiol 2009; 54: 1619-26; and Lui, et al., Am J Physiol Heart Circ Physiol 2004; 287: H501-11).
Finally, there are a few artificial biomaterials that are presently being tested. These include self-assembling peptides, PLGA (polylactic-coglycol acid, which is FDA approved), and other similar compounds. These other compounds typically show dosage-dependent toxicities, and some even tend to activate the immune system. Nevertheless, some of these compounds have been used to culture heart muscle cells in the laboratory and others can be injected directly into the heart. Some self-assembling peptides that form protein nanofibers can stimulate the differentiation of bone marrow stem cells into blood vessels (Lin et al., Circulation 2010; 122: S132-41).
Biomaterials have other advantages in that they can bind protein growth factors that promote the survival or even differentiation of implanted stem cells. For this reason, some labs are investigating biomaterials for use in gene therapy.
Biomaterials may provide an adjuvant to stem cell treatments in the heart, and for that reason, biomaterials research deserves more attention than it has been receiving.