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  • Reed Blackwell posted an update 2 months, 2 weeks ago

    This NIR-based imaging system for non-invasive cell monitoring in vivo could play an active role in validating the cell fate in cell-based tissue engineering applications.Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three-dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus-like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys.Carbon tetrachloride (CCl4)-induced liver injury is predominantly caused by free radicals, in which mitochondrial function of hepatocytes is impaired, accompanying with the production of ROS and decreased ATP energy supply in animals intoxicated with CCl4. Here we explored a novel therapeutic approach, mitochondrial transplantation therapy, for treating the liver injury. The results showed that mitochondria entered hepatocytes through macropinocytosis pathway, and thereby cell viability was recovered in a concentration-dependent manner. Mitochondrial therapy could increase ATP supply and reduce free radical damage. In liver injury model of mice, mitochondrial therapy significantly improved liver function and prevented tissue fibrogenesis. Transcriptomic data revealed that mitochondrial unfold protein response (UPRmt), a protective transcriptional response of mitochondria-to-nuclear retrograde signaling, would be triggered after mitochondrial administration. Then the anti-oxidant genes were up-regulated to scavenge free radicals. YM155 The mitochondrial function was rehabilitated through the transcriptional activation of respiratory chain enzyme and mitophage-associated genes. The protective response re-balanced the cellular homeostasis, and eventually enhanced stress resistance that is linked to cell survival. The efficacy of mitochondrial transplantation therapy in the animals would suggest a novel approach for treating liver injury caused by toxins.Biodistribution studies are essential in drug carrier design and translation, and radiotracing provides a sensitive quantitation for this purpose. Yet, for biodegradable formulations, small amounts of free-label signal may arise prior to or immediately after injection in animal models, causing potentially confounding biodistribution results. In this study, we refined a method to overcome this obstacle. First, we verified free signal generation in animal samples and then, mimicking it in a controllable setting, we injected mice intravenously with a radiolabeled drug carrier formulation (125I-antibody/3DNA) containing a known amount of free radiolabel (125I), or free 125I alone as a control. Corrected biodistribution data were obtained by separating the free radiolabel from blood and organs postmortem, using trichloroacetic acid precipitation, and subtracting the confounding signal from each tissue measurement. Control free 125I-radiolabel was detected at ≥85% accuracy in blood and tissues, validating the method. It biodistributed very heterogeneously among organs (0.6-39 %ID/g), indicating that any free 125I generated in the body or present in an injected formulation cannot be simply corrected to the free-label fraction in the original preparation, but the free label must be empirically measured in each organ. Application of this method to the biodistribution of 125I-antibody/3DNA, including formulations directed to endothelial target ICAM-1, showed accurate classification of free 125I species in blood and tissues. In addition, this technique rendered data on the in vivo degradation of the traced agents over time. Thus, this is a valuable technique to obtain accurate measurements of biodistribution using 125I and possibly other radiotracers.In clinical terms, bone grafting currently involves the application of autogenous, allogeneic, or xenogeneic bone grafts, as well as natural or artificially synthesized materials, such as polymers, bioceramics, and other composites. Many of these are associated with limitations. The ideal scaffold for bone tissue engineering should provide mechanical support while promoting osteogenesis, osteoconduction, and even osteoinduction. There are various structural complications and engineering difficulties to be considered. Here, we describe the biomimetic possibilities of the modification of natural or synthetic materials through physical and chemical design to facilitate bone tissue repair. This review summarizes recent progresses in the strategies for constructing biomimetic scaffolds, including ion-functionalized scaffolds, decellularized extracellular matrix scaffolds, and micro- and nano-scale biomimetic scaffold structures, as well as reactive scaffolds induced by physical factors, and other acellular scaffolds. The fabrication techniques for these scaffolds, along with current strategies in clinical bone repair, are described. The developments in each category are discussed in terms of the connection between the scaffold materials and tissue repair, as well as the interactions with endogenous cells. As the advances in bone tissue engineering move toward application in the clinical setting, the demonstration of the therapeutic efficacy of these novel scaffold designs is critical.Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16-20 months and a 5-year survival rates of less then 5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony-stimulating factor 1 (CSF-1) signaling pathway of tumor-associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer-mediated immunotherapy to deliver CSF-1R inhibitor BLZ945 (D-BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D-BLZ targeted to TAMs decreases pro-tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer-drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off-target effects.Sutures are applied almost universally at the site of trauma or surgery, making them an ideal platform to modulate the local, postoperative biological response, and improve surgical outcomes. To date, the only globally marketed drug-eluting sutures are coated with triclosan for antibacterial application in general surgery. Loading drug directly into the suture rather than coating the surface offers the potential to provide drug delivery functionality to microsurgical sutures and achieve sustained drug delivery without increasing suture thickness. However, conventional methods for drug incorporation directly into the suture adversely affect breaking strength. Thus, there are no market offerings for drug-eluting sutures, drug-coated, or otherwise, in ophthalmology, where very thin sutures are required. Sutures themselves help facilitate bacterial infection, and antibiotic eye drops are commonly prescribed to prevent infection after ocular surgeries. An antibiotic-eluting suture may prevent bacterial colonization of sutures and preclude patient compliance issues with eye drops. We report twisting of hundreds of individual drug-loaded, electrospun nanofibers into a single, ultra-thin, multifilament suture capable of meeting both size and strength requirements for microsurgical ocular procedures. Nanofiber-based polycaprolactone sutures demonstrated no loss in strength with loading of 8% levofloxacin, unlike monofilament sutures which lost more than 50% strength. Moreover, nanofiber-based sutures retained strength with loading of a broad range of drugs, provided antibiotic delivery for 30 days in rat eyes, and prevented ocular infection in a rat model of bacterial keratitis.As wearable healthcare monitoring systems advance, there is immense potential for biological sensing to enhance the management of type 1 diabetes (T1D). The aim of this work is to describe the ongoing development of biomarker analytes in the context of T1D. Technological advances in transdermal biosensing offer remarkable opportunities to move from research laboratories to clinical point-of-care applications. In this review, a range of analytes, including glucose, insulin, glucagon, cortisol, lactate, epinephrine, and alcohol, as well as ketones such as beta-hydroxybutyrate, will be evaluated to determine the current status and research direction of those analytes specifically relevant to T1D management, using both in-vitro and on-body detection. Understanding state-of-the-art developments in biosensing technologies will aid in bridging the gap from bench-to-clinic T1D analyte measurement advancement.

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