NSF/FDA SIR: Assurance of Cellular Function in High-Shear Three-Dimensional Bioprinting

Overview. The prediction of human physiological interaction with pharmaceutical compounds, biologics, and medical devices continues to challenge the human health community. Each year, drugs and biologics continue to fail in late stage human trials, resulting in detrimental health outcomes to trial subjects and billions in lost capital. The gap between animal models and human tissues remains too great to consistently predict safety and efficacy. Bioprinting is expected to modernize biocompatibility and biomaterial performance testing strategies to assess medical devices for a reasonable assurance of safety and effectiveness. For these printed tissue models to recapitulate the physiological function, the tissue- and cell- level transport must be consistent with the mimicked tissue. Prior efforts focus on establishing process parameters to rapidly print cells onto in vitro constructs with high fidelity and resolution to capture tissue level tissue transport. Critically, transport at the cellular level is fundamentally altered by damage to the bioprinted cells during the printing process. Even without direct necrosis of the cells, damage to the cell membrane and surface receptors will directly alter the intracellular transport mechanisms. We seek to collaborate with FDA to determine the timescale of recovery to normal cellular transport in bioprinted cells, and the corresponding impact of irregular transport on drug efficacy. Additionally, we will evaluate cellular encapsulation as a method to preserve normal cellular transport during high-shear bioprinting. Our team incorporates expertise in cellular biomechanics (Shin, FDA, CDRH), bioprinting (Vorvolakos, FDA, CDRH), and materials science (Berron, UK Engineering). Intellectual Merit. The proposed work directly addresses a critical knowledge gap relating bioprinting conditions and cellular damage with quantitative relationships between bioprinting-induced shear stress, chemical transport, and cell function outcome measures (viability, phenotypic expression). Additionally, we hypothesize cell-encapsulation strategies will mitigating shear stress effects. The PI will employ his novel technology to encapsulate individual cells or cell populations in a biocompatible polymer to protect them against the high-shear environments expected to be generated during bioprinting. Broader Impacts. Bioprinting lies at the intersection of robotics, engineering, and biology. There is a great potential to motivate undergraduate learning in core STEM disciplines. We propose to generate tutorial videos centered on bioprinting and the potential involvement of mechanobiology in cell damage mechanisms. The PI previously designed, illustrated, and narrated tutorial videos for undergraduate engineering education. His videos have been viewed >36,000 times in the last 3 years. The PI will also work with the FDA Office of Communication and Education to develop educational videos would also serve as an information source for FDA scientists. The 2017 CDRH Regulatory Science Priority areas emphasize a need leverage new technologies to enhance current regulatory tools to predict and monitor the clinical safety and performance of medical products. Bioprinting used to develop more physiologically representative in vitro tests that may help reduce the need for animal testing and improve our present capacity to predict human interactions with novel devices and agents. This study falls in line with CDRH priorities to “modernize biocompatibility” and “advance test methods for predicting and monitoring medical device performance”. Additionally, bioprinting offers great potential for developing autologous tissues and patient-specific tests to support the “precision medicine” priority area within CDRH.