Combinatorial Polymer Synthesis and High-Throughput Screening Technology to Identify Optimal Approaches for Mineralized Tissue Engineering

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Doctor of Philosophy (PhD)
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combinatorial library
high-throughput screening
mesenchymal stem cells
bone tissue engineering
Molecular, Cellular, and Tissue Engineering
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The general tissue engineering approach is to combine cells, scaffolding, and signaling molecules in a manner that treats damaged or diseased tissues. Progress in the field has been made incrementally since changes to these inputs require meticulous iterative steps. However, recent advances in combinatorial chemistry and high through-put screening (HTS) technology have made available a wider range of potential scaffold materials with diverse properties, as well as new methods to accelerate the process of testing soluble factors or combinations of factors. To this end, a library of poly(β-amino ester)s has been developed as the first combinatorial library of photopolymerizable and biodegradable materials. Polymers formed from this library were characterized with respect to changes in chemistry, macromer molecular weight, and macromer branching, which all affected the degradation, mechanics, and cellular interactions of the materials. Using set design criteria with respect to degradation and cellular interactions, the library was screened to identify an osteoconductive material for use in bone tissue engineering. The identified macromer, A6, was processed into porous scaffolds using a particulate leaching technique. When implanted, A6 scaffolds had minimal inflammation and tissue readily invaded the porous structure, but no bone formation was observed with A6 scaffolds alone. However, in intramuscular and critical-sized cranial defect studies, the addition of BMP-2 led to the induction of bone formation throughout the scaffold, which surpassed control groups. Yet, in a femur window defect model, the empty defect healed equally to the A6 scaffold with BMP-2, illustrating the importance of a critical-sized defect in assessing tissue engineering approaches. Using HTS techniques, a library of 1040 soluble factors was screened for promoters and inhibitors of osteogenesis in mesenchymal stem cells. 36 potential promoters and 20 potential inhibitors were identified, using statistical outcomes to identify hits that met criteria related to alkaline phosphatase activity and viability. Three of the promoters were investigated further using traditional culture to confirm their osteogenic behavior. This work illustrates the importance of combinatorial libraries and HTS techniques in identifying new materials and soluble factors towards tissue regeneration applications and can be expanded to target a number of different tissues and diseases.

Jason A Burdick
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