Blood Vessel Formation and Wound Healing
(Brey, Cinar, Karuri, Opara, Papavasiliou)
Models and quantitative tools for studying the influence of microenvironmental factors (e.g. soluble signals, extracellular matrix) on angiogenesis and microvascular structure are being explored. It is expected that this research will lead to novel strategies for promoting blood vessel formation as therapies for treating ischemic tissues, which are major complications of diabetes. Molecular and recombinant technologies are used to engineer proteins with unique biological functions and microcapsules are considered as drug delivery mechanisms for bioactive proteins to induce angiogenesis. These proteins are evaluated in pre-clinical models to determine their potential therapeutic efficacy.
Use of biopolymers (hydrogels) for wound healing has tremendous potential for the treatment of diabetic ulcers. Disruption of cell membranes is a major cause of tissue necrosis, which is associated with ischemia-reperfusion injuries. The capacity to prevent necrosis in injured tissue and permanent damage remains unsolved. However, it was recently demonstrated that it was possible to restore membrane integrity and intact cell function using biocompatible surfactants like poloxamer 188 (P188), an amphiphilic tri-block copolymer. It has been established that poloxamers target areas of membrane disruption, inducing sealing and prolonged viability of cells. Restoring membrane integrity with poloxamers is a potentially important mode of treatment for diabetic ulcers, but the mechanism by which P188 protects cells from a variety of necrosis-inducing stimuli remains to be understood.
One of the major limitations of successful islet cell transplantation is a lack of a microvascular supply to and within encapsulated islets. Engineering synthetic biomaterials that provide rapid and guided blood vessel formation (angiogenesis) would significantly contribute to successful islet transplantation. Studies have shown that gradients of proteins play a critical role in directing cell migration and angiogenesis in vivo. Using free-radical photopolymerization techniques, hydrogels of poly(ethylene) glycol diacrylate are being engineered in Professor Papavasiliou’s lab with gradients of crosslink density suggesting that three-dimensional gradients of angiogenic growth factors be introduced with the scaffold. Hydrogels with varying magnitudes of gradients of immobilized biomolecules previously shown to induce angiogenesis are being engineered by combining novel computational free-radical polymerization models of biofunctional hydrogel formation with experimental design. The goal of this research is that the interaction of endothelial cells with biofunctional gradient hydrogels will result in maximal endothelial cell migration and angiogenesis. Hydrogels could either be vascularized prior to implantation so that the pre-established microvasculature insoculates with host vessels upon implantation, or designed with gradients of biofunctional molecules that rapidly stimulate angiogenesis following implantation.
A major characteristic of diabetic wounds is that they have a reduced ability to assemble an extracellular matrix (ECM) known as a provisional matrix. The provisional matrix acts as a scaffold for cell adhesion, migration and contractility and is thus essential in the wound healing response. Professor Karuri’s research is focused on how interfacial chemistry can be used to tether bioactive groups onto synthetic scaffolds and how these biologically functionalized scaffolds can be used to stimulate ECM assembly. The results from these studies will be used to create dressings for diabetic wounds that promote the attachment and ECM assembly, two hallmarks of the wound healing response. Two critical research directions in Professor Karuri’s lab are:
Extracellular matrix interactions during wound healing: The goal is to understand some of the early events that take place in the extracellular matrix during wound healing and to use chemical engineering tools to characterize these events. These studies involve the use of simple model systems to elucidate extracellular matrix protein interactions that are necessary during the process of matrix remodeling after wounding.
Interfacial chemistry to mimic and direct cell function: This involves the functionalizing artificial scaffolds with domains of extracellular matrix proteins with the aim of mimicking the extracellular niche. By varying types, quantities and localization of these domains and investigating their effect on cell behavior, Professor Karuri’s research group plan to determine optimum conditions for cell functions that are linked to enhanced tissue regeneration.