Porous Scaffold-Hydrogel Composites Spatially Regulate 3D Cellular Mechanosensing.

Cells encapsulated in 3D hydrogels exhibit differences in cellular mechanosensing based on their ability to remodel their surrounding hydrogel environment. Although cells in tissue interfaces feature a range of mechanosensitive states, it is challenging to recreate this in 3D biomaterials. Human mesenchymal stem cells (MSCs) encapsulated in methacrylated gelatin (GelMe) hydrogels remodel their local hydrogel environment in a time-dependent manner, with a significant increase in cell volume and nuclear Yes-associated protein (YAP) localization between 3 and 5 days in culture. A finite element analysis model of compression showed spatial differences in hydrogel stress of compressed GelMe hydrogels, and MSC-laden GelMe hydrogels were compressed (0-50%) for 3 days to evaluate the role of spatial differences in hydrogel stress on 3D cellular mechanosensing. MSCs in the edge (high stress) were significantly larger, less round, and had increased nuclear YAP in comparison to MSCs in the center (low stress) of 25% compressed GelMe hydrogels. At 50% compression, GelMe hydrogels were under high stress throughout, and this resulted in a consistent increase in MSC volume and nuclear YAP across the entire hydrogel. To recreate heterogeneous mechanical signals present in tissue interfaces, porous polycaprolactone (PCL) scaffolds were perfused with an MSC-laden GelMe hydrogel solution. MSCs in different pore diameter (~280-430 µm) constructs showed an increased range in morphology and nuclear YAP with increasing pore size. Hydrogel stress influences MSC mechanosensing, and porous scaffold-hydrogel composites that expose MSCs to diverse mechanical signals are a unique biomaterial for studying and designing tissue interfaces.

Controlled Release of Multiple Therapeutics From Silicone Hydrogel Contact Lenses for Post-Cataract/Post-Refractive Surgery and Uveitis Treatment.

Purpose: This work demonstrates seven-day controlled and extended in vitro physiological flow dual release of multiple post-ocular surgery therapeutics from extended-wear contact lenses as a dropless alternative for treatment of uveitis and corneal inflammation, pain, and infection. Lens replacement each week optimizes treatment matching patient recall time with the ability to increase or decrease dosage. Methods: Lenses were synthesized using molecular imprinting to create lenses with macromolecular memory for diclofenac sodium (DS) and dexamethasone sodium phosphate (DMSP), as well as bromfenac sodium (BS) and moxifloxacin (MOX). Drug uptake and release were analyzed, and physical properties were measured and compared to commercial standards. Results: DS + DMSP-loaded lenses demonstrated seven-days-plus release of each, whereas controls released more than 85% of their payload within the first day. Lenses loaded with BS + MOX demonstrated release of BS and MOX for 11 and eight days, respectively. Structural analysis demonstrated statistically similar mesh size and average molecular weight between crosslinks between imprinted lenses and controls, suggesting that release extension was due to formation of macromolecular memory sites rather than a tighter polymer architecture. Conclusions: Lenses demonstrated in this work have significant clinical applications as an eye drop alternative, possessing the ability to be worn continuously for one week while delivering a consistent amount of therapeutic for the duration of wear. Translational Relevance: In vitro physiological flow release results demonstrate the clinical potential of therapeutic contact lenses as a dropless vehicle for ocular drug delivery.

Hydrogel screening approaches for bone and cartilage tissue regeneration.

The extracellular matrix (ECM) of bone and cartilage presents stem cells with a dynamic and complex array of biochemical and biomechanical signals that regulate proliferation and differentiation into bone and cartilage tissue-producing cells. Due to the multitude of signals present in this ECM, it is challenging to develop biomaterials that accurately recapitulate bone and cartilage tissues, thereby limiting the ability to present cells with multiple factors for enhanced biomaterial-induced osteogenic and chondrogenic differentiation. Conventional techniques to evaluate stem cell responses to engineered materials are laborious and time-consuming, and high-throughput screening techniques can address these limitations. Our review overviews developmental environments and signals present in bone and cartilage ECM, with a focus on applying hydrogel-based screening approaches to identify biomaterial environments that promote stem cell-mediated bone and cartilage tissue regeneration.