Cell-Adaptable Protein Scaffolds for Spinal Cord Nerve Regeneration
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1062-NN03-05
Cell-Adaptable Protein Scaffolds for Spinal Cord Nerve Regeneration Karin Straley1, Cheryl Wong Po Foo2, and Sarah Heilshorn2 1 Chemical Engineering, Stanford University, Stanford, CA, 94305 2 Materials Science and Engineering, Stanford University, Stanford, CA, 94305 ABSTRACT A key attribute missing from current state-of-the-art biomaterials is the ability to be remodeled by the host after implantation. In contrast, the natural extracellular matrix (ECM) is constantly being remodeled by proteases secreted from cells in response to local environmental changes. Mimicking this strategy, we have designed a new protein-based scaffold that can be degraded and remodeled on demand by the growth cones of regenerating neurites. Using recombinant protein techniques, we synthesized a family of biodegradable and biologically active scaffold materials. The scaffolds include peptide sequences derived from natural ECM proteins. Interspersed with these ECM domains are proteolytic sequences readily degraded by tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), two proteases secreted by the growth cones of extending neurites. By altering the primary amino acid sequences of the protease cleavage domains, we can tune the degradation rates of otherwise identical engineered proteins in a controlled and predictable manner over approximately two orders of magnitude. These recombinant proteins are crosslinked to form bulk, protein-based scaffolds with mechanical properties that can be tuned to match that of the spinal cord. Initial cell experiments have shown that the proteins support growth and differentiation of the model PC-12 neuronal-like cell line. By tailoring the scaffold degradation rate to the tPA and uPA secretion levels of specific neuronal populations, we aim to fabricate a scaffold that will promote neurite extension through the matrix by allowing local degradation to occur specifically around the neuronal growth cone while maintaining the bulk integrity of the overall scaffold. INTRODUCTION The treatment of spinal cord injuries presents a difficult challenge in medicine due to the inability of the central nervous system to spontaneously regenerate after injury. It is widely believed that a combinatorial therapy involving implantation of a material scaffold supplemented with cells and growth factors is the most promising approach [1]. We propose constructing the scaffold from crosslinked, engineered protein polymers. Due to the absolute molecular-level control over protein polymer synthesis, the mechanical and biological properties of this scaffold can be highly controlled [2, 3]. The fundamental structure of our engineered proteins involves repeated units of structural sequences derived from the natural protein elastin [4] and bioactive sequences known to mimic actions of extracellular matrix proteins. To date, we have synthesized protein polymers containing cell-binding domains to promote adhesion of neurons to the scaffold surface and protease cleavage domains to allow neurons to gro
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