The paradigm of modern biomaterials research is the design of materials that can respond to specific stimuli and elicit a desired biological response. The revolution in structural biology toward quantitative understanding of biomacromolecular and cellular behavior offers important information for the rational design of materials with desirable bioactivity. One of the primary goals of this proposal is the assembly of novel, noncovalently crosslinked hydrogel matrices via the interaction between biologically important proteins (such as growth factors) and polysaccharides; the thermodynamics and kinetics of the association will be manipulated to control materials properties and release profiles. The interactions used to control assembly will also permit delivery of the proteins by ligand exchange with cell surface receptors. Exploiting ligand exchange mechanisms as a strategy for delivery and erosion will be relevant to many in vivo processes in which cells overexpress certain receptors, and by this unique coordination of activities, the matrices will find application in the targeted delivery of growth factors for chemotherapeutic, tissue engineering, and wound healing applications. In addition to producing novel materials for macromolecular delivery, this work will also utilize new quantitative approaches for characterizing the mechanical response of these biomaterials on length and timescales that are relevant to cells. New quantitative approaches such as tracer particle microrheology and micromanipulation with laser tweezers will be applied to directly measure microscopic mechanics and relaxation timescales of these hydrogels. When coupled with the synthetic strategies above, these investigations will allow us to understand the specific impact of noncovalent molecular interactions on the structure and rheological properties of hydrogel matrices. This will permit the rational design of microscopic mechanical responses, molecular delivery kinetics, and functionality on length and timescales of cellular processes. The proposed strategies will therefore result in materials in which cellular and polymer responses are coupled, and will broadly impact the development of new biomaterials targeted to specific cellular events.
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