17 Additionally, mechanical mismatching can lead to issues such as stress shielding, which weakens the surrounding bone in orthopaedic applications. Mechanical properties are important for the stability of a scaffold, but have also been implicated in the differentiation of cells (e.g., mesenchymal stem cells, MSCs). 16 Degradation allows a material to be replaced with cells and tissue over time, but is also important for the temporal mechanical properties and the release of degradation products. For tissue engineering, these criteria may include properties such as: degradation rate, mechanics, cell attachment, cytotoxicity, and biocompatibility. 7Īn important step in this approach is the identification of effective criteria that permit material selection for specific applications. For example, 3456 different individual combinations and ratios of 24 polymers were mixed in nanoliter spots on an array in order to determine cell-material interactions. Additionally, combinatorial synthesis on the nanoliter scale can greatly accelerate material discovery.
were able to optimize the combination of poly(D,L-lactide) and poly(ε-caprolactone) 10 and tyrosine-derived polycarbonates, 11 respectively, for desirable osteoblast interactions. Using these approaches, both Meredith et al. 13 Experimentally measured values showed agreement in many of the predicted properties, which opens the door for future, faster and cheaper biomaterial development procedures.īeyond distinct chemical libraries, gradients of materials may also be used to identify optimal formulations to meet a given set of criteria. 15 These models were then utilized to virtually design a polymethacrylate combinatorial library that predicted cell attachment, cell growth, and fibrinogen adsorption. 9 This library has been used to develop predictive computational models of chemical structures and physical properties, 13 cell growth, 14 and protein adsorption.
developed a library of 112 polyarylates that exhibited a range of physical and cellular characteristics. 8– 12 For scaffold development, combinatorial syntheses are able to produce libraries of materials that can be screened and developed for a specific application based on desired properties. More recently, combinatorial libraries are being utilized to develop materials for biomedical applications including gene delivery vehicles, 4, 5 substrates for the culture of stem cells, 6, 7 and potential biodegradable materials for tissue engineered scaffolds. 2 This approach has been used widely in the pharmaceutical industry to greatly expand the pool of drugs for investigation, and to help identify structure-property relationships of bioactive molecules. 1 In general, combinatorial synthesis is a method to produce large libraries of compounds and materials through simplified single-step reactions. Fortunately, technology is continuously being developed to accelerate various steps in the tissue engineering process, including the high-throughput screening of materials and small molecule mediators of cellular behavior, the use of microdevices to screen cellular microenvironments, technology to rapidly assess material properties, and the use of combinatorial polymer syntheses. Traditional polymer development for tissue engineering applications has been a time consuming and tedious process, as polymer synthesis often requires multiple reactions and purification steps. These results illustrate a process to identify a candidate scaffolding material from a combinatorial polymer library, and specifically for the identification of an osteoconductive scaffold with osteoinductive properties via the inclusion of a growth factor. The samples in both locations displayed mineralized tissue formation in the presence of BMP-2, as evident through radiographs, micro-computed tomography, and histology, while samples without BMP-2 showed minimal or no mineralized tissue. The scaffolds were then implanted intramuscularly and into a critically-sized cranial defect either alone or loaded with bone morphogenetic protein-2 (BMP-2). The most promising candidate, A6, was then processed into 3-dimensional porous scaffolds and implanted subcutaneously and only presented a mild inflammatory response. In this work, the PBAE library was assessed for candidate materials that met design criteria (e.g., physical properties such as degradation and mechanical strength and in vitro cell viability and osteoconductive behavior) for scaffolding in mineralized tissue repair.
We recently developed a library of photopolymerizable and biodegradable poly(β-amino ester)s (PBAEs) that possessed a range of tunable properties. Combinatorial polymer syntheses are now being utilized to create libraries of materials with potential utility for a wide variety of biomedical applications.