Optimization of Oxygen Delivery Within Hydrogels.

The field of tissue engineering has been continuously evolving since its inception over three decades ago with numerous new advancements in biomaterials and cell sources and widening applications to most tissues in the body. Despite the substantial promise and great opportunities for the advancement of current medical therapies and procedures, the field has yet to capture wide clinical translation due to some remaining challenges, including oxygen availability within constructs, both in vitro and in vivo. While this insufficiency of nutrients, specifically oxygen, is a limitation within the current frameworks of this field, the literature shows promise in new technological advances to efficiently provide adequate delivery of nutrients to cells. This review attempts to capture the most recent advances in the field of oxygen transport in hydrogel-based tissue engineering, including a comparison of current research as it pertains to the modeling, sensing, and optimization of oxygen within hydrogel constructs as well as new technological innovations to overcome traditional diffusion-based limitations. The application of these findings can further the advancement and development of better hydrogel-based tissue engineered constructs for future clinical translation and adoption.

A Hydrogel Strategy to Augment Tissue Adenosine to Improve Hindlimb Perfusion.

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Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit, Myonuclear-, and Mitochondrial-Domains.

Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations to skeletal muscle homeostasis. Although recent research has investigated the tissue-specific responses to ischemia, the role of the muscle stem cell in the regeneration of its niche components within skeletal muscle has been limited. To elucidate the regenerative mechanism of the muscle stem cell in response to ischemic insults, we explored cellular interactions between the vasculature, neural network, and muscle fiber within the muscle stem cell niche. Using a surgical murine hindlimb ischemia model, we first discovered a significant increase in subsynaptic nuclei and remodeling of the neuromuscular junction following ischemia-induced denervation. In addition, ischemic injury causes significant alterations to the myofiber through a muscle stem cell-mediated accumulation of total myonuclei and a concomitant decrease in myonuclear domain size, possibly to enhance the transcriptional and translation output and restore muscle mass. Results also revealed an accumulation of total mitochondrial content per myonucleus in ischemic myofibers to compensate for impaired mitochondrial function and high turnover rate. Taken together, the findings from this study suggest that the muscle stem cell plays a role in motor neuron reinnervation, myonuclear accretion, and mitochondrial biogenesis for skeletal muscle regeneration following ischemic injury.

The small heat shock protein HSPB1 protects mice from sepsis.

In vitro studies have implicated the small heat shock protein HSPB1 in a range of physiological functions. However, its in vivo relevance is unclear as the phenotype of unstressed HSPB1-/- mice is unremarkable. To determine the impact of HSPB1 in injury, HSPB1-/- and wild type (WT) mice were subjected to cecal ligation and puncture, a model of polymicrobial sepsis. Ten-day mortality was significantly higher in HSPB1-/- mice following the onset of sepsis (65% vs. 35%). Ex vivo mechanical testing revealed that common carotid arteries from HSPB1-/- mice were more compliant than those in WT mice over pressures of 50-120 mm Hg. Septic HSPB1-/- mice also had increased peritoneal levels of IFN-γ and decreased systemic levels of IL-6 and KC. There were no differences in frequency of either splenic CD4+ or CD8+ T cells, nor were there differences in apoptosis in either cell type. However, splenic CD4+ T cells and CD8+ T cells from HSPB1-/- mice produced significantly less TNF and IL-2 following ex vivo stimulation. Systemic and local bacterial burden was similar in HSPB1-/- and WT mice. Thus while HSPB1-/- mice are uncompromised under basal conditions, HSPB1 has a critical function in vivo in sepsis, potentially mediated through alterations in arterial compliance and the immune response.

The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice.

Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, Nɛ-(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth.