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When adipose tissue (AT) is impaired by trauma or disease, AT engineering could provide a shelf-ready structural and functional restoration as alternative to current clinical ...treatments, which mainly aim at aesthetic replacement. Yet, the lack of an efficient vascular network within the scaffolds represents a major limitation to their translation application in patients. Here, we propose the use of microstructured crosslinked gelatin hydrogels with an embedded prevascular channel as scaffolding materials for AT engineering. The scaffolds are fabricated using – simultaneously – alginate-based microbeads and 3D printed filaments as sacrificial material encapsulated in gelatin at the point of material fabrication and removed post-crosslinking. This method yields the formation of microstructures that resemble the micro-architecture of physiological human fat tissue and of microvessels that can facilitate vascularization through anastomosis with patients’ own blood vessels. The cytocompatible method used to prepare the gelatin scaffolds showed structural stability over time while allowing for cell infiltration and protease-based remodeling/degradation. Scaffolds’ mechanical properties were also designed to mimic the one of natural breast adipose tissue, a key parameter for AT regeneration. Scaffold’s embedded channel (∅ = 300–400 µm) allowed for cell infiltration and enabled blood flow in vitro when an anastomosis with a rat blood artery was performed using surgical glue. In vitro tests with human mesenchymal stem cells (hMSC) showed colonization of the porous structure of the gelatin hydrogels, differentiation into adipocytes and accumulation of lipid droplets, as shown by Oil Red O staining.
The potential clinical use of scaffolds for adipose tissue (AT) regeneration is currently limited by an unmet simultaneous achievement of adequate structural/morphological properties together with a promoted scaffold vascularization. Sacrificial materials, currently used either to obtain a tissue-mimicking structure or hollow channels to promote scaffold’ vascularization, are powerful versatile tools for the fabrication of scaffolds with desired features. However, an integrated approach by means of sacrificial templates aiming at simultaneously achieving an adequate AT-mimicking structure and hollow channels for vascularization is missing. Here, we prove the suitability of crosslinked gelatin scaffolds obtained by using sacrificial alginate microbeads and 3D printed strands to achieve proper features and hollow channels useful for scaffolds vascularization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent advances in rehabilitation robotics suggest that it may be possible for hand-amputated subjects to recover at least a significant part of the lost hand functionality. The control of robotic ...prosthetic hands using non-invasive techniques is still a challenge in real life: myoelectric prostheses give limited control capabilities, the control is often unnatural and must be learned through long training times. Meanwhile, scientific literature results are promising but they are still far from fulfilling real-life needs. This work aims to close this gap by allowing worldwide research groups to develop and test movement recognition and force control algorithms on a benchmark scientific database. The database is targeted at studying the relationship between surface electromyography, hand kinematics and hand forces, with the final goal of developing non-invasive, naturally controlled, robotic hand prostheses. The validation section verifies that the data are similar to data acquired in real-life conditions, and that recognition of different hand tasks by applying state-of-the-art signal features and machine-learning algorithms is possible.
OBJECTIVE—In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and ...characterize microRNAs that regulate angiogenesis in response to tissue injury.
APPROACH AND RESULTS—We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3′ untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury.
CONCLUSIONS—These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS–mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury.
Abstract Wound healing is a physiological reparative response to injury and a well-orchestrated process that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix ...deposition, and wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. Herein, we investigate the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to high glucose in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~ 3.5-fold) four days post-wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to ~ 80%), increased granulation tissue thickness (by 2.5-fold) and accelerated wound closure (53% after nine days) compared to scrambled anti-miR controls in db/db mice. These effects were independent of altered M1/M2 macrophage ratios. Mechanistically, inhibition of miR-26a increased its target gene SMAD1 in ECs nine days post-wounding of diabetic mice. In addition, high glucose reduced activity of the SMAD1-3′-UTR. Diabetic dermal wounds treated with LNA-anti-miR-26a had increased expression of ID1, a downstream modulator or SMAD1, and decreased expression of the cell cycle inhibitor p27. These findings establish miR-26a as an important regulator on the progression of skin wounds of diabetic mice by specifically regulating the angiogenic response after injury, and demonstrate that neutralization of miR-26a may serve as a novel approach for therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BACKGROUND:Advances in reconstructive surgery are leading to an increased number of flaps at risk for ischemic necrosis, because of either intrinsic (e.g., larger flap size) or extrinsic (e.g., ...diabetes) factors. Methods to preoperatively improve flap vascularity and limit postoperative ischemia are lacking. Noninvasive suction, using either a macrodeformational silicone cup interface (external volume expansion) or a microdeformational polyurethane foam interface (foam-mediated external volume expansion), has been shown to induce angiogenesis in tissues. The authors investigated whether the preoperative use of external volume expansion/foam-mediated external volume expansion improves flap survival in an obesity-induced diabetic animal model.
METHODS:Db/Db mice underwent either mechanical stimulation with suction for 5 days using either external volume expansion or foam-mediated external volume expansion, or received no stimulation (n = 8 per group). Five days after the last stimulation, a critical-size, axial-pattern, fasciocutaneous flap was raised in all animals. Postoperatively, flap survival was monitored with digital imaging for 10 days. After this period, flaps were harvested to assess tissue survival, angiogenesis, and inflammation, using histology and polymerase chain reaction.
RESULTS:Foam-mediated external volume expansion preconditioning significantly increased the viable flap area (28 percent), viable flap volume (27 percent), and flap capillary density (36 percent) in comparison to controls; vascular endothelial growth factor was also up-regulated (>300 percent). In contrast, external volume expansion resulted in a severe inflammatory response and increased flap necrosis.
CONCLUSIONS:Foam-mediated external volume expansion improves flap survival in obese diabetic mice. This procedure may allow for improved clinical rates of flap survival in high-risk patients.
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