Cell transplantation has great potential for treating a wide variety of human diseases and injuries; however, due to a local inflammatory microenvironment and mechanical damage during the injection procedure, cell viability following simple injection protocols remains low. We are developing functional cell delivery materials to protect cells from mechanical stress during injection, localize them to the transplantation site, and direct their organization and differentiation in vivo. Our engineered materials are built from two classes of engineered proteins that create physically crosslinked hydrogels when mixed under constant physiological conditions. These mixing-induced three-component hydrogels (MITCH) allow cytocompatible 3D cell encapsulation and are shear-thinning and self-healing, making them ideal injectable vehicles for delivering encapsulated cells to a therapy site.
We are designing a new family of biomaterials that are made entirely of engineered proteins. By carefully selecting the primary amino acid sequence of our engineered proteins, we can create biomaterials with independently tunable biochemical and biomechanical properties that mimic many of the essential properties of natural tissues including elasticity, proteolytic remodeling, and cell binding and signaling. An essential component of these engineered protein-based materials are elastin-like peptide sequences that provide excellent mechanical resilience. These elastin-like biomaterials are being investigated for use both as ex vivo tissue mimics to study the fundamentals of cell-matrix interactions and as in vivo tissue mimics for regenerative medicine applications. Current systems under study include neuronal, cardiac, vascular, and bone tissues amongst others.
In spite of recent significant achievements identifying and controlling stem cell differentiation, maintenance, and proliferation, fundamental interactions between the microenvironment and stem cells in vitro represent an urgent area for investigation due to several limitations: 1) lack of preservation of appropriate 3D tissue architecture, 2) ill-defined physiological parameters for in vitro culture, and 3) unclear knowledge of cell-cell interactions during co-culture of stem cells with neighboring cell types. We hypothesize that these limitations may be addressed through use of customizable biomimetic protein scaffolds that mimic the native stem cell niche to provide direct control over in vitro stem cell cultures. To test our hypothesis, we are focusing on the recapitulation of the intestinal stem cell niche in collaboration with Prof. Calvin Kuo at the Stanford School of Medicine.
Microfluidic devices are tools capable of recreating natural microenvironments of cells and tissues in a controllable and reductionist manner. Here, we implement these helpful devices to study the mechanism of 2D and 3D cellular responses to stable gradients of soluble biochemicals. Because these devices are fabricated from optically clear materials, we can visualize cellular dynamics, including cell motion, cell morphology, and receptor localization, within a variety of biomaterial scaffolds and biochemical gradients. Current projects cover a wide range of medically relevant cellular activities including endothelial cell migration and sprout formation, neuronal axon navigation, immune cell chemotaxis during infection, and stem cell chemotaxis and differentiation.
