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  1. Abstract Due to limited intrinsic healing capacity of the meniscus, meniscal injuries pose a significant clinical challenge. The most common method for treatment of damaged meniscal tissues, meniscectomy, leads to improper loading within the knee joint, which can increase the risk of osteoarthritis. Thus, there is a clinical need for the development of constructs for meniscal repair that better replicate meniscal tissue organization to improve load distributions and function over time. Advanced three-dimensional bioprinting technologies such as suspension bath bioprinting provide some key advantages, such as the ability to support the fabrication of complex structures using non-viscous bioinks. In this work, the suspension bath printing process is utilized to print anisotropic constructs with a unique bioink that contains embedded hydrogel fibers that align via shear stresses during printing. Constructs with and without fibers are printed and then cultured for up to 56 d in vitro in a custom clamping system. Printed constructs with fibers demonstrate increased cell and collagen alignment, as well as enhanced tensile moduli when compared to constructs printed without fibers. This work advances the use of biofabrication to develop anisotropic constructs that can be utilized for the repair of meniscal tissue. 
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    Free, publicly-accessible full text available April 12, 2024
  2. Abstract

    Many cell types require direct cell–cell interactions for differentiation and function; yet, this can be challenging to incorporate into 3‐dimensional (3D) structures for the engineering of tissues. Here, a new approach is introduced that combines aggregates of cells (spheroids) with similarly‐sized hydrogel particles (microgels) to form granular composites that are injectable, undergo interparticle crosslinking via light for initial stabilization, permit cell–cell contacts for cell signaling, and allow spheroid fusion and growth. One area where this is important is in cartilage tissue engineering, as cell–cell contacts are crucial to chondrogenesis and are missing in many tissue engineering approaches. To address this, granular composites are developed from adult porcine mesenchymal stromal cell (MSC) spheroids and hyaluronic acid microgels and simulations and experimental analyses are used to establish the importance of initial MSC spheroid to microgel volume ratios to balance mechanical support with tissue growth. Long‐term chondrogenic cultures of granular composites produce engineered cartilage tissue with extensive matrix deposition and mechanical properties within the range of cartilage, as well as integration with native tissue. Altogether, a new strategy of injectable granular composites is developed that leverages the benefits of cell–cell interactions through spheroids with the mechanical stabilization afforded with engineered hydrogels.

     
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  4. Abstract

    Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile‐containing baricitinib for drug tethering, which is confirmed with1H and13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod‐induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.

     
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  5. Abstract

    Cellular models are needed to study human development and disease in vitro, and to screen drugs for toxicity and efficacy. Current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprinted in vitro model is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and the screening of drugs, particularly where high cell densities and heterogeneity are important.

     
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  6. Abstract

    The fabrication of perfusable hydrogels is crucial for recreating in vitro microphysiological environments. Existing strategies to fabricate complex microchannels in hydrogels involve sophisticated equipment/techniques. A cost‐effective, facile, versatile, and ultra‐fast methodology is reported to fabricate perfusable microchannels of complex shapes in photopolymerizable hydrogels without the need of specialized equipment or sophisticated protocols. The methodology utilizes one‐step ultraviolet (UV) light‐triggered cross‐linking and a photomask printed on inexpensive transparent films to photopattern PEG‐norbornene hydrogels. Complex and intricate patterns with high resolution, including perfusable microchannels, can be fabricated in <1 s. The perfusable hydrogel is integrated into a custom‐made microfluidic device that permits connection to external pump systems, allowing continuous fluid perfusion into the microchannels. Under dynamic culture, human endothelial cells form a functional and confluent endothelial monolayer that remains viable for at least 7 days and respond to inflammatory stimuli. Finally, approach to photopattern norbornene hyaluronic acid hydrogels is adapted, highlighting the versatility of the technique. This study presents an innovative strategy to simplify and reduce the cost of biofabrication techniques for developing functional in vitro models using perfusable three‐dimensional (3D) hydrogels. The approach offers a novel solution to overcome the complexities associated with existing methods, allowing engineering advanced in vitro microphysiological environments.

     
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