(I-356) Additive Textile Manufacturing Helically Aligned Biohybrid Ventricle Models using Focused Rotary Jet Spinning (FRJS)

Introduction:: The human heart is made up of structural subunits whose shape gives rise to their mechanical function. One such structure-function relationship is that of the myofibers in the left ventricle, which are organized in a helical fashion. It has long been thought that this helical alignment is critical for preserving healthy ejection fractions in patients (60-80%). This is important, as certain cardiomyopathies, such as hypertensive remodeling can disrupt this organization, leading to increased mortality rates and potential heart failure. However, testing this biomechanical relationship is difficult, as cardiac remodeling is often concomitant with changes in metabolism and protein expression. Therefore, to test this theory we built a humanized tissue engineered ventricle model in vitro with helical alignments. To manufacture this model microphysiological system we employed a new form of additive textile manufacturing, Focused Rotary Jet Spinning (FRJS), which allows for the conformal deposition of micro/nanofibers with controlled alignments onto three-dimensional (3D) substrates. As micron scale fibers can provide topological cues to promote tissue morphogenesis, this allowed for the formation of 3D tissues constructs with controlled tissue alignments. Using this approach, we showed how both helically and circumferentially aligned ventricle models could be used to directly measure clinically relevant metrics of heart disease in vitro, including cardiac output and ejection fractions. Overall, this work allows for a streamlined approach to fabricating aligned tissues models in three dimensions, while demonstrating how helical architectures are critical to achieving healthy cardiac performance.


Materials and Methods:: Tissue engineered constructs were formed using a nanofiber-based ventricle model. Nanofiber scaffolds were fabricated using FRJS, which works by extruding a polymer solution through a small orifice via centrifugal spinning, which then undergoes jet elongation, forming thin polymer fibers. Prior to deposition, fibers are entrained into a focused air stream, which aligns and concentrates them, allowing for the controlled conformal deposition of nanofibers onto a collection surface. These scaffolds composed of gelatin nanofibers, were then seeded with either human stem cell derived (hiPSC-CMs) or rodent derived (neonatal rat ventricular cardiomyocytes, NRVMs) cardiomyocytes. This provided a basis for forming 3D tissue engineered ventricles models which could be used to model the effects of tissue alignment on cardiac output.


Results, Conclusions, and Discussions:: In this work we demonstrate how FRJS can be used as a rapid approach to nanofiber manufacturing, allowing for the formation of tissue engineered scaffolds with programmable tissue alignments in 3D. Basing our experimental design on analytical predictions made more than half a century ago, we formed both circumferentially, and helically ventricle scaffolds. Using this approach, we then examined how tissue alignment impacts factors in ventricle performance, demonstrating that helically aligned ventricle models displayed increased strain uniformity, axial shortening, axial-basal calcium propagation rates, cardiac outputs and ejection fractions as compared to circumferential alignments. Additionally, we demonstrate how helically ventricles were capable of preserving some features of cardiac performance not previously demonstrated in in vitro models, such as ventricle twist, which has been proposed as a potential alternative to ejection fraction as a metric of cardiac health. Overall, this work demonstrates how a FRJS based approach to biofabrication can allow for the formation of robust 3D models of organ systems, with controlled alignments and increased geometric complexity. Furthermore, it demonstrates how tissue engineered microphysiological systems can be used to examine basic structure-function relationships in human physiology.


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