Chemical Tuning of Fibers Drawn from Extensible Hyaluronic Acid Networks

© 2020 American Chemical Society. Polymer fibers with specific chemical and mechanical properties are key components of many biomaterials used for regenerative medicine and drug delivery. Here, we develop a bioinspired, low-energy process to produce mechanically tunable biopolymer fibers drawn from aqueous solutions. Hyaluronic acid (HA) forms dynamic cross-links with branched polyethylene glycol polymers end-functionalized with boronic acids of varied structure to produce extensible polymer networks. This dynamic fiber precursor (DFP) is directly drawn by pultrusion into HA fibers that display high aspect ratios, ranging from 4 to 20 μm in diameter and up to ∼10 m in length. Dynamic rheology measurements of the DFP and tensile testing of the resulting fibers reveal design considerations to tune the propensity for fiber formation and fiber mechanical properties, including the effect of polymer structure and concentration on elastic modulus, tensile strength, and ultimate strain. The materials' humidity-responsive contractile behavior, a unique property of spider silks rarely observed in synthetic materials, highlights possibilities for further biomimetic and stimulus-responsive fiber applications. This work demonstrates that chemical modification of dynamic interactions can be used to tune the mechanical properties of pultrusion-based fibers and their precursors.Leona M. and Harry B. Helmsley Charitable Trust (Grant 2017PG-T1D027)NIH (Grants F32DK118785, K99EB025254 and PDF-2015-90-A-N)National Cancer Institute (Grant P30-CA14051

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC

3D modeling of aflibercept transport in the vitreous humor

Aflibercept is an anti-vascular endothelial growth factor (anti-VEGF) drug used to treat several retinal diseases such as macular degeneration. It accomplishes this by binding and inhibiting VEGF, which is the growth factor that is responsible for abnormal blood vessel growth. Overexpression of VEGF can lead to interference with the macula, and subsequent vision loss. Aflibercept is prescribed to treat macular degeneration due to VEGF overexpression. It is administered via intravitreal injection. Analysis of the transport of aflibercept through the vitreous humor is critical to understanding whether or not patients are receiving appropriate amounts of drug at the macula boundary, where the abnormal growth of blood vessels is contributing to macular degeneration. This study will assess if the current market dose of aflibercept is successfully inhibiting VEGF for an appropriate time period. The scope of analysis involved construction of a three-dimensional geometry of the vitreous humor in COMSOL, an implementation of physical properties and parameters of the vitreous humor and aflibercept, an illustration of key results, a sensitivity analysis on certain parameters, and a validation of the COMSOL implementation. The analysis was conducted for a 3D diffusion problem, coupled with convection. Convection is due to pressure-driven flow, a result of the inherent pressure difference in the vitreous humor. Degradation or inactivation of aflibercept was also considered by modeling the second-order binding of aflibercept to VEGF. The distribution of aflibercept throughout the vitreous humor was successfully determined. Due to asymmetry in the injection site, or the placement of drug, it was found that the distribution of drug is asymmetric at early times, and becomes more uniform at later times. A similar result was found at the macula boundary, which is the target area of interest for this study. It was also shown that VEGF concentration is successfully inhibited upon the introduction of aflibercept. Based on the model, VEGF began to accumulate after initial suppression within 20 to 40 days of aflibercept injection. This coincides with the recommended interval between aflibercept injections, which is 28 days. Improvements in future model implementation could provide a result that more accurately represents the transport of aflibercept in the eye. These improvements include implementing an initial injection velocity when aflibercept is introduced, and the use of a more realistic geometry, such as an MRI scan, to build the geometry in the COMSOL model