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Clinical translation requires many areas of expertise, including preclinical research, technology transfer, process development, regulatory adherence, manufacturing, quality assurance, quality control, clinical trial design, and human trials. The resulting work proposed that adipose‐derived human perivascular stem cells were a new cell source for efforts in skeletal regenerative medicine and are a stem cell‐based therapeutic that may be readily approvable by the U.S. Food and Drug Administration, with potentially increased safety, purity, identity, potency, and efficacy.The article “Bioprinted Amniotic Fluid‐Derived Stem Cells Accelerate Healing of Large Skin Wounds,” by Soker and colleagues 4, investigated whether amniotic fluid‐derived stem cells could augment wound healing in a mouse model of skin regeneration. In the article “Mesenchymal Stem Cell‐Derived Extracellular Vesicles as Mediators of Anti‐Inflammatory Effects: Endorsement of Macrophage Polarization,” Tasso and colleagues 7 looked at how mesenchymal stem cell paracrine activity favors tissue repair modulating inflammation‐associated immune cells and offer an alternative approach to regulate the inflammatory response. [...]osteoarthritis is the most widespread musculoskeletal disorder in adults, leading to cartilage damage, inflammation, pain, and disability.

In the second most‐read paper, Campbell et al reported on the first randomized controlled trial of allogeneic corneal epithelial stem cells cultured on amniotic membrane in the treatment of severe bilateral limbal stem cell deficiency, demonstrating the feasibility and safety of this approach. The most‐read papers also included important laboratory research findings, such as the third most‐read paper from Mellough et al, which compared retinal organoid differentiation from human pluripotent stem cells and revealed stage specific, cell line, and methodological differences. In another example, Zhu et al found, for the first time, that diabetes mellitus impairs the bone regenerative effect of exosomes derived from bone marrow MSCs, suggesting that the autologous transplantation of these cells to promote bone regeneration may be inadequate in these patients.

Existing methods for evaluating the potential gonadotoxicity of environmental agents and pharmaceutical compounds rely heavily on animal studies. The current gold standard in vivo functional assays in animals are limited in their human predictive capacity. In addition, existing human twodimensional in vitro models of testicular toxicity do not accurately reflect the in vivo situation. A more reliable testicular in vitro model system is needed to better assess the gonadotoxic potential of drugs prior to progression into clinical trials. The overall goal of this study was to develop a three-dimensional (3D) in vitro human testis organoid culture system for use as both a predictive first tier drug-screening tool and as a model of human testicular function. Multicellular human testicular organoids composed of Spermatogonial Stem Cells, Sertoli, Leydig and peritubular cells were created and evaluated over time for morphology, viability, androgen production and ability to support germ cell differentiation. Enzyme-linked immunosorbent assay measurements confirmed that the organoids produced testosterone continuously with and without hCG stimulation. Upregulation of postmeiotic genes including PRM1 and Acrosin, detected by quantitative-PCR, digital PCR and Immunofluorescence, indicated the transition of a small percentage of diploid to haploid germ cells. As a novel screening tool for reproductive toxicity, 3D organoids were exposed to four chemotherapeutic drugs, and they responded in a dose-dependent manner and maintained IC50 values significantly higher than 2D cultures. This 3D human testis organoid system has the potential to be used as a novel testicular toxicity-screening tool and in vitro model for human spermatogenesis. Summary Sentence Human testicular organoid produces testosterone and provides a niche for germ cell differentiation.

Complex urethral problems can occur as a result of injury, disease, or congenital defects and treatment options are often limited. Urethras, similar to other long tubularised tissues, can stricture after reconstruction. We aimed to assess the effectiveness of tissue-engineered urethras using patients' own cells in patients who needed urethral reconstruction. Five boys who had urethral defects were included in the study. A tissue biopsy was taken from each patient, and the muscle and epithelial cells were expanded and seeded onto tubularised polyglycolic acid:poly(lactide-co-glycolide acid) scaffolds. Patients then underwent urethral reconstruction with the tissue-engineered tubularised urethras. We took patient history, asked patients to complete questionnaires from the International Continence Society (ICS), and did urine analyses, cystourethroscopy, cystourethrography, and flow measurements at 3, 6, 12, 24, 36, 48, 60, and 72 months after surgery. We did serial endoscopic cup biopsies at 3, 12, and 36 months, each time in a different area of the engineered urethras. Patients had surgery between March 19, 2004, and July 20, 2007. Follow-up was completed by July 31, 2010. Median age was 11 years (range 10–14) at time of surgery and median follow-up was 71 months (range 36–76 months). AE1/AE3, α actin, desmin, and myosin antibodies confirmed the presence of cells of epithelial and muscle lineages on all cultures. The median end maximum urinary flow rate was 27·1 mL/s (range 16–28), and serial radiographic and endoscopic studies showed the maintenance of wide urethral calibres without strictures. Urethral biopsies showed that the engineered grafts had developed a normal appearing architecture by 3 months after implantation. Tubularised urethras can be engineered and remain functional in a clinical setting for up to 6 years. These engineered urethras can be used in patients who need complex urethral reconstruction. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

A bioengineered skeletal muscle construct that mimics structural and functional characteristics of native skeletal muscle is a promising therapeutic option to treat extensive muscle defect injuries. We previously showed that bioprinted human skeletal muscle constructs were able to form multi-layered bundles with aligned myofibers. In this study, we investigate the effects of neural cell integration into the bioprinted skeletal muscle construct to accelerate functional muscle regeneration in vivo. Neural input into this bioprinted skeletal muscle construct shows the improvement of myofiber formation, long-term survival, and neuromuscular junction formation in vitro. More importantly, the bioprinted constructs with neural cell integration facilitate rapid innervation and mature into organized muscle tissue that restores normal muscle weight and function in a rodent model of muscle defect injury. These results suggest that the 3D bioprinted human neural-skeletal muscle constructs can be rapidly integrated with the host neural network, resulting in accelerated muscle function restoration. 3D bioprinting of skeletal muscle using primary human muscle progenitor cells results in correct muscle architecture, but functional restoration in rodent models is limited. Here the authors include human neural stem cells into bioprinted skeletal muscle and observe improved architecture and function in vivo.

A bioengineered skeletal muscle tissue as an alternative for autologous tissue flaps, which mimics the structural and functional characteristics of the native tissue, is needed for reconstructive surgery. Rapid progress in the cell-based tissue engineering principle has enabled in vitro creation of cellularized muscle-like constructs; however, the current fabrication methods are still limited to build a three-dimensional (3D) muscle construct with a highly viable, organized cellular structure with the potential for a future human trial. Here, we applied 3D bioprinting strategy to fabricate an implantable, bioengineered skeletal muscle tissue composed of human primary muscle progenitor cells (hMPCs). The bioprinted skeletal muscle tissue showed a highly organized multi-layered muscle bundle made by viable, densely packed, and aligned myofiber-like structures. Our in vivo study presented that the bioprinted muscle constructs reached 82% of functional recovery in a rodent model of tibialis anterior (TA) muscle defect at 8 weeks of post-implantation. In addition, histological and immunohistological examinations indicated that the bioprinted muscle constructs were well integrated with host vascular and neural networks. We demonstrated the potential of the use of the 3D bioprinted skeletal muscle with a spatially organized structure that can reconstruct the extensive muscle defects.

The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.

The skin is the largest organ of the body, which meets the environment most directly. Thus, the skin is vulnerable to various damages, particularly burn injury. Skin wound healing is a serious interaction between cell types, cytokines, mediators, the neurovascular system, and matrix remodeling. Tissue regeneration technology remarkably enhances skin repair via re-epidermalization, epidermal-stromal cell interactions, angiogenesis, and inhabitation of hypertrophic scars and keloids. The success rates of skin healing for burn injuries have significantly increased with the use of various skin substitutes. In this review, we discuss skin replacement with cells, growth factors, scaffolds, or cell-seeded scaffolds for skin tissue reconstruction and also compare the high efficacy and cost-effectiveness of each therapy. We describe the essentials, achievements, and challenges of cell-based therapy in reducing scar formation and improving burn injury treatment.

The blood–brain barrier (BBB) is an efficient barrier for molecules and drugs. Multicellular 3D spheroids display reproducible BBB features and functions. The spheroids used here were composed of six brain cell types: Astrocytes, pericytes, endothelial cells, microglia cells, oligodendrocytes, and neurons. They form an in vitro BBB that regulates the transport of compounds into the spheroid. The penetration of fluorescent ultrasmall gold nanoparticles (core diameter 2 nm; hydrodynamic diameter 3–4 nm) across the BBB was studied as a function of time by confocal laser scanning microscopy, with the dissolved fluorescent dye (FAM-alkyne) as a control. The nanoparticles readily entered the interior of the spheroid, whereas the dissolved dye alone did not penetrate the BBB. We present a model that is based on a time-dependent opening of the BBB for nanoparticles, followed by a rapid diffusion into the center of the spheroid. After the spheroids underwent hypoxia (0.1% O 2 ; 24 h), the BBB was more permeable, permitting the uptake of more nanoparticles and also of dissolved dye molecules. Together with our previous observations that such nanoparticles can easily enter cells and even the cell nucleus, these data provide evidence that ultrasmall nanoparticle can cross the blood brain barrier.

Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood–brain barrier (BBB). Nanoparticles can be an attractive solution for the treatment of GBM as they can transport drugs across the BBB into the tumor. In this study, normal and GBM organoids comprising six brain cell types were developed and applied to study the uptake, BBB penetration, distribution, and efficacy of fluorescent, ultrasmall gold nanoparticles (AuTio-Dox-AF647s) conjugated with doxorubicin (Dox) and AlexaFluor-647-cadaverine (AF647) by confocal laser scanning microscopy (CLSM), using a mixture of dissolved doxorubicin and fluorescent AF647 molecules as a control. It was shown that the nanoparticles could easily penetrate the BBB and were found in normal and GBM organoids, while the dissolved Dox and AF647 molecules alone were unable to penetrate the BBB. Flow cytometry showed a reduction in glioblastoma cells after treatment with AuTio-Dox nanoparticles, as well as a higher uptake of these nanoparticles by GBM cells in the GBM model compared to astrocytes in the normal cell organoids. In summary, our results show that ultrasmall gold nanoparticles can serve as suitable carriers for the delivery of drugs into organoids to study BBB function.