Biomaterials and Scaffolds

At the molecular level, our lab focuses on developing polymeric materials that control receptor-mediated cell behaviors. One emphasis area is on developing a mechanistic understanding of how the physical context of ligand presentation controls processes such as cell adhesion, migration, and growth. A guiding example from the natural environment of the cell is the extracellular matrix molecule tenascin-C, a molecule upregulated in development and wound healing which is in structure a large hexabrachion comprising multiple adhesion and growth factor domains. We speculate that the nanoscale clustering of adhesion domains within the molecule may serve to cluster integrin receptors and influence their biological function. Using small peptide adhesion ligands, we have shown that clustering integrin ligands indeed exerts a profound influence on integrin-mediated cell adhesion and migration. Following up on the initial studies, we are currently examining the interplay of integrin ligand clustering with integrin type, ligand affinity, and mechanical context in dictating adhesion and motility behaviors. Tenascin-C contains multiple EGF-like repeats and some of these repeats can activate the epidermal growth factor receptor (EGFR). We thus speculate that another role of the tenascin-C structure is to control EGFR activation -- perhaps limiting activation to the cell surface and juxtaposing integrin and EGFR in ways that will influence the ultimate signaling properties of both. We are thus using polymeric biomaterials to control the activation of EGFR by restricting the internalization, and examining the influence on downstream cell behaviors (such as adhesion, migration and growth) as well as intracellular signaling pathways. Some of these materials and model systems are available through the NIH Cell Migration Consortium (see below). A second emphasis area is using materials that present defined adhesion and growth factor ligands to control cell behaviors for applications ranging from connective tissue progenitor cell selection and growth on bone regeneration scaffolds to control of liver cell adhesion for in vitro organogenesis of liver.

At the level of tissue-scale devices, we seek to fabricate scaffolds with defined architectures over length scales ranging from a few tens of microns to centimeters, and to do so with a range of materials important for tissue engineering. We are thus implementing a solid free-form fabrication technique, the 3DP TM printing process, in which devices are built as a series of thin two-dimensional layers beginning with a computer design of the desired architecture. This process was invented at MIT and has been commercialized for tissue engineering applications by Therics, Inc. The main application we are currently pursuing is generation of scaffolds for use in large segmental defects in bone.