Browsing by Author "Kiick, Kristi L."
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Item Genetic Fusion of Thermoresponsive Polypeptides with UCST-type Behavior Mediates 1D Assembly of Coiled-Coil Bundlemers(Angewandte Chemie International Edition, 2023-05-09) Patkar, Sai S.; Tang, Yao; Bisram, Arriana M.; Zhang, Tianren; Saven, Jeffery G.; Pochan, Darrin J.; Kiick, Kristi L.Graphical Abstract: Available at: https://doi.org/10.1002/anie.202301331 Computationally designed coiled coil-forming peptides were functionalized with thermoresponsive resilin-like polypeptides (RLPs) of various lengths and produced via biosynthetic methods in bacterial expression hosts. Interactions between RLPs upon cooling below their upper critical solution temperature (UCST) resulted in nanofibrillar assembly. Abstract Thermoresponsive resilin-like polypeptides (RLPs) of various lengths were genetically fused to two different computationally designed coiled coil-forming peptides with distinct thermal stability, to develop new strategies to assemble coiled coil peptides via temperature-triggered phase separation of the RLP units. Their successful production in bacterial expression hosts was verified via gel electrophoresis, mass spectrometry, and amino acid analysis. Circular dichroism (CD) spectroscopy, ultraviolet-visible (UV/Vis) turbidimetry, and dynamic light scattering (DLS) measurements confirmed the stability of the coiled coils and showed that the thermosensitive phase behavior of the RLPs was preserved in the genetically fused hybrid polypeptides. Cryogenic-transmission electron microscopy and coarse-grained modeling revealed that functionalizing the coiled coils with thermoresponsive RLPs leads to their thermally triggered noncovalent assembly into nanofibrillar assemblies.Item Growth factors and growth factor gene therapies for treating chronic wounds(Bioengineering and Translational Medicine, 2023-12-28) Mullin, James A.; Rahmani, Erfan; Kiick, Kristi L.; Sullivan, Millicent O.Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics. Translational Impact Statement Chronic wounds persist as a healthcare challenge despite extensive research on various treatments, including growth factors and gene therapies. Progress in translating these therapeutics to clinical use has been slow, with many growth factor approaches demonstrating promise in preclinical studies but providing limited benefits in clinical trials or clinical application. This review presents recent advances in growth factor therapies and growth factor gene therapies, discusses obstacles to regulatory approval, and offers perspectives on potential innovations for successful clinical translation.Item Sequence-Encoded Differences in Phase Separation Enable Formation of Resilin-like Polypeptide-Based Microstructured Hydrogels(Biomacromolecules, 2023-08-14) Patkar, Sai S.; Garcia, Cristobal Garcia; Palmese, Luisa L.; Kiick, Kristi L.Microstructured hydrogels are promising platforms to mimic structural and compositional heterogeneities of the native extracellular matrix (ECM). The current state-of-the-art soft matter patterning techniques for generating ECM mimics can be limited owing to their reliance on specialized equipment and multiple time- and energy-intensive steps. Here, a photocross-linking methodology that traps various morphologies of phase-separated multicomponent formulations of compositionally distinct resilin-like polypeptides (RLPs) is reported. Turbidimetry and quantitative 1H NMR spectroscopy were utilized to investigate the sequence-dependent liquid–liquid phase separation of multicomponent solutions of RLPs. Differences between the intermolecular interactions of two different photocross-linkable RLPs and a phase-separating templating RLP were exploited for producing microstructured hydrogels with tunable control over pore diameters (ranging from 1.5 to 150 μm) and shear storage moduli (ranging from 0.2 to 5 kPa). The culture of human mesenchymal stem cells demonstrated high viability and attachment on microstructured hydrogels, suggesting their potential for developing customizable platforms for regenerative medicine applications.