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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.

Many drugs have progressed through preclinical and clinical trials and have been available – for years in some cases – before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

3D bioprinting of tissues and organs will find application in tissue engineering, research, drug discovery and toxicology. Additive manufacturing, otherwise known as three-dimensional (3D) printing, is driving major innovations in many areas, such as engineering, manufacturing, art, education and medicine. Recent advances have enabled 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities requires the integration of technologies from the fields of engineering, biomaterials science, cell biology, physics and medicine. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery and toxicology.

The human airways are complex structures with important interactions between cells, extracellular matrix (ECM) proteins and the biomechanical microenvironment. A robust, well-differentiated in vitro culture system that accurately models these interactions would provide a useful tool for studying normal and pathological airway biology. Here, we report the development and characterization of a physiologically relevant air–liquid interface (ALI) 3D airway ‘organ tissue equivalent’ (OTE) model with three novel features: native pulmonary fibroblasts, solubilized lung ECM, and hydrogel substrate with tunable stiffness and porosity. We demonstrate the versatility of the OTE model by evaluating the impact of these features on human bronchial epithelial (HBE) cell phenotype. Variations of this model were analyzed during 28 days of ALI culture by evaluating epithelial confluence, trans-epithelial electrical resistance, and epithelial phenotype via multispectral immuno-histochemistry and next-generation sequencing. Cultures that included both solubilized lung ECM and native pulmonary fibroblasts within the hydrogel substrate formed well-differentiated ALI cultures that maintained a barrier function and expressed mature epithelial markers relating to goblet, club, and ciliated cells. Modulation of hydrogel stiffness did not negatively impact HBE differentiation and could be a valuable variable to alter epithelial phenotype. This study highlights the feasibility and versatility of a 3D airway OTE model to model the multiple components of the human airway 3D microenvironment.

The COVID-19 pandemic, driven by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has underscored the need to understand the virus’s evolution due to its global health impact. This study employed RNA sequencing (RNA-Seq) to analyze gene expression differences across multiple SARS-CoV-2 variants. We used publicly available datasets from the Gene Expression Omnibus (GEO) with IDs GSE157103, GSE171110, GSE189039, and GSE201530, which contain RNA-Seq data extracted from white blood cells, whole blood, or PBMCs of individuals infected with the Original Wuhan variant (both hospitalized and non-hospitalized), the French variant (hospitalized), the Beta variant (hospitalized), and the Omicron variant (moderate and mild cases), along with COVID-negative controls. Our first objective was to examine differences in gene expression dynamics using Generalized Linear Models with Quasi-Likelihood F-tests and the Magnitude-Altitude Scoring (GLMQL-MAS) technique, followed by Gene Ontology (GO) and pathway analyses. Our second objective was to employ Cross-MAS to identify a robust set of genes indicative of SARS-CoV-2 infection regardless of the variant and to assess their classification performance. GO and pathway analyses revealed a significant evolutionary shift in how SARS-CoV-2 interacts with the host. Early variants such as the Original Wuhan and French cases primarily affected pathways related to viral replication, including Eukaryotic Translation Elongation and Viral mRNA Translation. In contrast, later variants like Beta and Omicron showed a strategic shift toward modulating and evading the host immune response, engaging immune-related pathways such as Interferon Alpha/Beta signaling and Cytokine signaling in the immune system. To evaluate the classification potential of the identified genes, we tested them on held-out datasets GSE152418, PMC8202013, GSE161731, and GSE166190, which contain RNA-Seq data from whole blood or PBMCs of COVID-positive and healthy individuals. Using top-ranked genes such as IFI27, CDC20, RRM2, HJURP, and CDC45 in linear models including logistic regression and linear SVM, we achieved 97.31% accuracy, with precision and recall rates of 0.97 and 0.99, respectively. These signatures also achieved perfect classification (100% accuracy, precision, and recall) in two additional datasets: GSE294888, which includes blood-derived plasmacytoid dendritic cells (pDCs) and type 2 conventional dendritic cells (DC2s) stimulated with Delta or Omicron variants, and GSE239595, which features Omicron-infected nasopharyngeal tissue. These findings demonstrate the potential of transcriptomic signatures for variant-agnostic COVID-19 detection and provide a foundation for flexible diagnostic and therapeutic approaches in response to SARS-CoV-2 evolution.

Mpox re-emerged globally in 2022 with atypical clinical features and efficient human-to-human transmission, which underscores the need to better understand host immune responses. We conducted an integrative transcriptomic analysis of mpox virus (MPXV) infection in nonhuman primates by leveraging RNA-Seq datasets from whole-blood and skin. We applied the Generalized Linear Model with Quasi-Likelihood F-test and Magnitude-Altitude Score (GLMQL-MAS), a method that combines rigorous statistical testing with a ranking metric to identify and prioritize differentially expressed genes (DEGs), and the Cross-Magnitude-Altitude Score (Cross-MAS) gene selection strategy, which integrates results across multiple time points to identify reproducible signatures, to define compact and robust markers of infection. Longitudinal analysis of whole-blood revealed a staged immune trajectory: early induction of interferon-stimulated genes ( IFI27 , ISG15 ) was followed by proliferative and hematopoietic programs and later enrichment of adaptive immune signatures, including B cell activation and TNF signaling. A minimal six-gene panel ( IFI27 , ISG15 , MYO7B , HEY1 , VASH1 , CNTD2 ) distinguished infected from control animals with 100% accuracy in both training and independent held-out test sets. In contrast, skin transcriptomes showed upregulation of keratinocyte-related genes ( KRT10 , KRT1 , SOSTDC1 ) and downregulation of immune mediators ( IL1B , CXCL8 , S100A8 , ISG15 ), which suggests epithelial remodeling with limited local immune activation. Cross-tissue comparisons revealed that under stringent criteria (BH-adjusted p -value < 0.05 and |log₂FC|> 1), only 10 genes were commonly significant between whole-blood and skin, and all (100%) exhibited opposite regulation. When thresholds were relaxed for exploratory purposes (unadjusted p -value < 0.05 and |log₂FC|> 1), 58 common significant immune-related genes were identified from the curated nCounter® Host Response Panel, of which 74.1% were oppositely regulated. Shared immune genes such as ISG15 , MX1 , IFIT2 , and OAS2 were upregulated in blood but suppressed in skin, and Reactome enrichment of discordant genes highlighted interferon and cytokine signaling pathways. These contrasts suggest that MPXV may trigger systemic interferon activation while suppressing local antiviral responses in lesions; however, because they are derived from independent secondary datasets in different species, they should be regarded as hypothesis-generating signals that require confirmation in matched, longitudinal studies.

There is a need for effective wound treatments that retain the bioactivity of a cellular treatment, but without the high costs and complexities associated with manufacturing, storing, and applying living biological products. Previously, we developed an amnion membrane‐derived hydrogel and evaluated its wound healing properties using a mouse wound model. In this study, we used a full thickness porcine skin wound model to evaluate the wound‐healing efficacy of the amnion hydrogel and a less‐processed amnion product comprising a lyophilized amnion membrane powder. These products were compared with commercially available amnion and nonamnion wound healing products. We found that the amnion hydrogel and amnion powder treatments demonstrated significant and rapid wound healing, driven primarily by new epithelialization versus closure by contraction. Histological analysis demonstrated that these treatments promote the formation of a mature epidermis and dermis with similar composition to healthy skin. The positive skin regenerative outcomes using amnion hydrogel and amnion powder treatments in a large animal model further demonstrate their potential translational value for human wound treatments.

Many immune‐mediated conditions are associated with a dysregulated imbalance toward a Th1 response leading to disease onset, severity, and damage. Many of the therapies such as immunomodulators or anti‐TNF‐α antibodies often fall short in preventing disease progression and ameliorating disease conditions. Thus, new therapies that can target inflammatory environments would have a major impact in preventing the progression of inflammatory diseases. We investigated the role of human stromal cells derived from the amniotic fluid (AFSCs), the placenta (PLSCs), and bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) in modulating the inflammatory response of in vitro‐stimulated circulating blood‐derived immune cells. Immune cells were isolated from the blood of healthy individuals and stimulated in vitro with antigens to activate inflammatory responses to stimuli. AFSC, BM‐MSCs, and PLSCs were cocultured with stimulated leukocytes, neutrophils, or lymphocytes. Inflammatory cytokine production, neutrophil migration, enzymatic degranulation, T cell proliferation, and subsets were evaluated. Coculture of all three stromal cell types decreased the gene expression of inflammatory cytokines and enzymes such as IL‐1β, IFN‐γ, TNF‐α, neutrophil elastase, and the transcription factor NF‐κB in lipopolysaccharide‐stimulated leukocytes. With isolated phytohemagglutinin‐stimulated peripheral blood mononuclear cells, cells coculture leads to a decrease in lymphocyte proliferation. This effect correlated with decreased numbers of Th1 lymphocytes and decreased secreted levels of IFN‐γ. Perinatal cells suppress the proliferation of Th1 cells and their associated cytokines.

The early and effective treatment of wounds is vital to ensure proper wound closure and healing with appropriate functional and cosmetic outcomes. The use of human amnion membranes for wound care has been shown to be safe and effective. However, the difficulty in handling and placing thin sheets of membrane, and the high costs associated with the use of living cellularized tissue has limited the clinical application of amniotic membrane wound healing products. Here, we describe a novel amnion membrane‐derived product, processed to result in a cell‐free solution, while maintaining high concentrations of cell‐derived cytokines and growth factors. The solubilized amnion membrane (SAM) combined with the carrier hyaluronic acid (HA) hydrogel (HA‐SAM) is easy to produce, store, and apply to wounds. We demonstrated the efficacy of HA‐SAM as a wound treatment using a full‐thickness murine wound model. HA‐SAM significantly accelerated wound closure through re‐epithelialization and prevented wound contraction. HA‐SAM‐treated wounds had thicker regenerated skin, increased total number of blood vessels, and greater numbers of proliferating keratinocytes within the epidermis. Overall, this study confirms the efficacy of the amnion membrane as a wound treatment/dressing, and overcomes many of the limitations associated with using fresh, cryopreserved, or dehydrated tissue by providing a hydrogel delivery system for SAM. Stem Cells Translational Medicine 2017;6:2020–2032 Time‐course images from in vivo wound healing study. A 2 × 2 cm full‐thickness wound was created on the back of nude mice and received one of three treatment options; (A): Untreated other than standard bandaging; (B): HA‐gel only or; (C): HA‐SAM gel.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.