Tissue Modulation – a new Facet of Tissue Engineering and RepairWe coined the term “Tissue Modulation” at NUS to characterise research that aims to positively influence the development and composition of tissue in a wound healing and repair situation. How ? By manipulating its collagen composition using well defined synthetic pharmacological substances. The Laboratory is developing key methodologies to enable Tissue Engineers to have more collagen in their tissue constructs (Matrix Enhancement). Collagens and related ligands are major components of the connective tissue of tissues like skin, cartilage, tendon and bone. Obviously, the in vitro production of these tissues requires substantial amounts of deposited and biologically crosslinked collagens. It is not widely known that collagen production in cell culture is incomplete. Procollagen is synthesised but not trimmed intto its smaller form - collagen. As a result not enough collagen self-assembles to form fibers and a stable matrix. Since this process is rate-limiting in generation of tissue and coating of scaffolds, a solution of this problem will open up new avenues for in vitro generation of tissue constructs. Based on encouraging preliminary data, The Laboratory is currently characterising polymeric culture medium additives that accelerate the enzymatic conversion of procollagen to collagen and its crosslinking and lead to a matrix formation. However, too much of collagen in the wrong place can pose major problems. Surgeons and biomedical engineers are keen to prevent scar formation and fibrotic enshrouding of medical devices and implanted tissue constructs. For this purpose, the Laboratory characterises low molecular weight compounds that downregulate collagen production and deposition (Scar Wars). We are leading the NMRC-funded National Group on Fibrovascular Disorders Programme characterise a number of different lead compounds that exert antifibrotic properties that we envision as stand-alone antifibrotic drugs or additives to biomaterials and coating of medical devices to prevent local fibrosis. To this end we are constructing a discovery tool platform to ascertain the antifibrotic properites of the lead compounds in miniaturised cell cultures systems using collagen produding cells. The construction of this tool box alread is in full swing and we expect to be able to offer antifibrotic screening assays also to the biomedical industry. With regard to implantation of medical devices which cause local fibrotic reactions the Laboratory will strive to select suitable substances that can be delivered using such an implant as drug delivery device. In particular, the Labortaory is exploring a combination of antifibrotic and antiangiogenic effects for the treatment of fibroproliferative disorders which are most often coupled with hypervascularization. Since keloid formation and an fibroproliferative eye disorder, pterygium, are frequent in SE Asia this project has a major regional impact. Some of the antifibrotic compounds we are testing have the potential to stimulate angiogenesis. These compounds shall facilitate the design of antifibrotic biomaterials for tissue engineering that become rapidly vascularized and thus enhance the outcome of tissue repair procedures. Collagen is the optimal biomaterial and cellular environment but it is difficult to handle after extraction from tissue and cannot be synthesised industrially yet. As most of the current artificial polymers are failing to meet cellular or tissue requirements the attention is turning back to collagen as the sole component of scaffolds or as an important admixture to hybrid materials. However, most collagen materials are mechanically too instable unless chemically crosslinked. However, chemical crosslinking impairs tissue compatibility, a problem also well known with artificial materials. To solve this problem we will employ the crosslinking properties of tissue type transglutaminse, natural crosslinkers of diverse extracellular matrix structures of the body. In the framework of a group project “Collagen inspired Biomaterials” supported by the Faculty of Engineering we will focus on the design of tagged peptide sequences serving as crucial reaction partners to be incorporated into human tissue and collagen-blended nanospun fibers. The information and knowledge obtained from this project will allow to develop new collagen-based scaffolds for tissue engineering and other biomedical applications. Obviously, collagen is an evergreen and one of nature’s brilliant solutions to biomaterial applications in the animal kingdom. Our task is to understand the associated biological and biophysical principals that have evolved in the last 650 million years and to emulate them for the benefit of human health. |
