A long-term goal of this program is to exploit knowledge from the fields of cell and molecular biology to develop biological modifications to materials that improve function and performance of disabled individuals. The term biological modification (or biomimetics) implies altering a material's performance by covalently coupling to the material's surface a biologically relevant molecule that the tissue surrounding the material recognizes through a cellular or bimolecular pathway. Prior to the currently funded grant, this approach had never been applied to materials used in orthopaedic surgery. This application will address biological modifications to modulate the bonding of bone tissue to prosthetic materials. A major drawback to implant operations is the recuperation period needed before the patient is able to load the implant. A significant reduction in the time needed for adequate interfacial bonding between the implant and bone could reduce prolonged hospitalization associated with the procedure, decrease disability before function is restored, decrease morbidity, increase function, and ultimately lead to making therapies more widely available. In an effort to reduce this period, this research program proposes to alter the kinetics of bone tissue response to the material by modifying the material's surface with peptides containing domains found in the non- collagenous extracellular matrix protein, bone sialoprotein (BSP), which is localized near osteoblasts in vivo. BSP contains domains for osteoblasts thought to be important for attachment to the extracellular matrix. By utilizing peptides incorporating the osteoblast attachment domain(s) on BSP, one could conceivably promote adhesion of osteoblasts to the implant during the healing stage, which may improve the stability and kinetics of formation mineralized tissue at the bone-material interface. The major goal of this application is to test the hypotheses that monolayer (i.e., one molecular layer) coatings of biologically active peptides affect osteoblast attachment to implant materials through the integrin receptors alpha1beta1, alpha3beta1, and alpha4beta1, and that surfaces modified with these will also preferentially induce cell organization and mineralization in complex biological environments. To test these hypotheses, the following Specific Aims must be met: use computer-aided chemistry to optimize the structure-activity relationships between the peptides and osteoblasts; create a surface containing covalently immobilized biospecific peptides that prevents non-specific protein binding and cell adhesion, but is highly selective for human osteoblast attachment; measure the probability distribution of the interfacial shear stresses required to remove primary human bone cells from various biomimetic materials; assess peptide activity (i.e., attachment rate constant) by comparison of the distribution of adhesion strengths on the materials; and verify the response is mediated by the immobilized peptides, and to determine the integrin receptors involved in the adhesion process.
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