The ability to direct cell behavior has been central to the success of numerous therapeutics to regenerate tissue or facilitate device integration. Biomaterial scientists are challenged to understand and modulate the interactions of biomaterials with biological systems in order to achieve effective tissue repair. One key area of research investigates the use of extracellular matrix-derived ligands to target specific integrin interactions and induce cellular responses, such as increased cell migration, proliferation, and differentiation of mesenchymal stem cells. These integrin-targeting proteins and peptides have been implemented in a variety of different polymeric scaffolds and devices to enhance tissue regeneration and integration. This review first presents an overview of integrin-mediated cellular processes that have been identified in angiogenesis, wound healing, and bone regeneration. Then, research utilizing biomaterials are highlighted with integrin-targeting motifs as a means to direct these cellular processes to enhance tissue regeneration. In addition to providing improved materials for tissue repair and device integration, these innovative biomaterials provide new tools to probe the complex processes of tissue remodeling in order to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.
The design of tissue engineered scaffolds based on polymerized high internal phase emulsions (polyHIPEs) has emerged as a promising bone grafting strategy. We previously reported the ability to 3D print emulsion inks to better mimic the structure and mechanical properties of native bone while precisely matching defect geometry. In the current study, redox-initiated hydrogel carriers were investigated for in situ delivery of human mesenchymal stem cells (hMSCs) utilizing the biodegradable macromer, poly(ethylene glycol)-dithiothreitol. Hydrogel carrier properties including network formation time, sol-gel fraction, and swelling ratio were modulated to achieve rapid cure without external stimuli and a target cell-release period of 5-7 days. These in situ carriers enabled improved distribution of hMSCs in 3D printed polyHIPE grafts over standard suspension seeding. Additionally, carrier-loaded polyHIPEs supported sustained cell viability and osteogenic differentiation of hMSCs post-release. In summary, these findings demonstrate the potential of this in situ curing hydrogel carrier to enhance the cell distribution and retention of hMSCs in bone grafts. Although initially focused on improving bone regeneration, the ability to encapsulate cells in a hydrogel carrier without relying on external stimuli that can be attenuated in large grafts or tissues is expected to have a wide range of applications in tissue engineering.
Water excretion by the kidney is regulated by the neurohypophyseal peptide hormone vasopressin through actions in renal collecting duct cells to regulate the water channel protein, aquaporin-2. Vasopressin signalling is initiated by binding to a G-protein coupled receptor V2R, which signals through Gsα, adenylyl cyclase 6, and activation of the cAMP-regulated protein kinase (PKA). Signaling events coupling PKA activation and aquaporin-2 regulation were largely unknown until the advent of modern protein mass spectrometry techniques that allow proteomewide quantification of protein phosphorylation changes (phosphoproteomics). This short review documents phosphoproteomic findings in collecting duct cells describing the response to V2selective vasopressin agonists and antagonists, the response to CRISPR-mediated deletion of PKA, results from in vitro phosphorylation studies using recombinant PKA, the response to the broad spectrum kinase inhibitor H89, and the responses underlying lithium-induced nephrogenic diabetes insipidus. These phosphoproteomic datasets have been made available online for modelling vasopressin signalling and signalling downstream from other Gsα-coupled receptors.
Polymerization of high internal phase emulsions (polyHIPEs) is a well-established method for the production of high porosity foams. Researchers are often regulated to using a time-intensive trial and error approach to achieve target pore architectures. In this work, we performed a systematic study to identify the relative effects of common emulsion parameters on pore architecture (mixing speed, surfactant concentration, organic phase viscosity, molecular hydrophobicity). Across different macromer chemistries, the largest magnitude of change in pore size was observed across surfactant concentration (~6 fold, 5–20 wt%), whereas changing mixing speeds (~4 fold, 500–2000 RPM) displayed a reduced effect. Furthermore, it was observed that organic phase viscosity had a marked effect on pore size (~4 fold, 6–170 cP) with no clear trend observed with molecular hydrophobicity in this range (logP = 1.9–4.4). The efficacy of 1,4-butanedithiol as a reactive diluent was demonstrated and provides a means to reduce organic phase viscosity and increase pore size without affecting polymer fraction of the resulting foam. Overall, this systematic study of the microarchitectural effects of these macromers and processing variables provides a framework for the rational design of polyHIPE architectures that can be used to accelerate design and meet application needs across many sectors.
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