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Fabrication of engineered thin membranous tissues (TMTs) presents a significant challenge to researchers, as these structures are small in scale, but present complex anatomies containing multiple stratified cell layers. While numerous methodologies exist to fabricate such tissues, many are limited by poor mechanical properties, need for post-fabrication, or lack of cytocompatibility. Extrusion bioprinting can address these issues, but lacks the resolution necessary to generate biomimetic, microscale TMT structures. Therefore, our goal was to develop a strategy that enhances bioprinting resolution below its traditional limit of 150 µm and delivers a viable cell population. We have generated a system to effectively shrink printed gels via electrostatic interactions between anionic and cationic polymers. Base hydrogels are composed of gelatin methacrylate type A (cationic), or B (anionic) treated with anionic alginate, and cationic poly-L-lysine, respectively. Through a complex coacervation-like mechanism, the charges attract, causing compaction of the base GelMA network, leading to reduced sample dimensions. In this work, we evaluate the role of both base hydrogel and shrinking polymer charge on effective print resolution and cell viability. The alginate anion-mediated system demonstrated the ability to reach bioprinting resolutions of 70 µm, while maintaining a viable cell population. To our knowledge, this is the first study that has produced such significant enhancement in extrusion bioprinting capabilities, while also remaining cytocompatible.
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Bone defects due to age, trauma, and surgery, which are exacerbated by medication side effects and common diseases like osteoporosis, diabetes, and rheumatoid arthritis, are a problem of epidemic scale. The present clinical standard for treating these defects includes autografts and allografts. While both treatments can promote robust regenerative outcomes, they fail to strike a desirable balance of availability, side effect profile, consistent regenerative efficacy, and affordability. This difficulty has contributed to the rise of bone tissue engineering (BTE) as a potential avenue through which enhanced bone regeneration could be delivered. BTE is founded upon a paradigm of using biomaterials, bioactive factors, osteoblast lineage cells (ObLCs), and vascularization to cue deficient bone tissue into a state of regeneration. Despite promising preclinical results, BTE has had modest success in being translated into the clinical setting. One barrier has been the simplicity of its paradigm relative to the complexity of biological bone. Therefore, this paradigm must be critically examined and expanded to better account for this complexity. One potential avenue for this is a more detailed consideration of osteoclast lineage cells (OcLCs). While these cells ostensibly oppose ObLCs and bone regeneration through their resorptive functions, myriad investigations have shed light on their potential to influence bone equilibrium in more complex ways through their interactions with both ObLCs and bone matrix. Most BTE research has not systematically evaluated their influence. Yet contrary to expectations associated with the paradigm, a selection of BTE investigations have demonstrated that this influence can enhance bone regeneration in certain contexts. Additionally, much work has elucidated the role of many controllable scaffold parameters in both inhibiting and stimulating the activity of OcLCs in parallel to bone regeneration. Therefore, this review aims to detail and explore the implications of OcLCs in BTE, and how they can be leveraged to improve upon the existing BTE paradigm.
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Osteochondral defects, characterized by structural compromises to articular cartilage and subchondral bone, can cause pain and lead to progressive cartilage damage and eventual osteoarthritis. Unfortunately, repairing these defects remains difficult due to the poor regenerative properties of cartilage and complex mechanical demands of the joint. As such, the field of tissue engineering aims to develop multiphasic implants that replace pathological cartilage and bone tissue and restore mechanical functionality to the joint. Recent bone physiology investigations have demonstrated that osteoclast lineage cells are inextricably involved in osteoblastic bone formation through an extensive network of anabolic signaling pathways, and so the co-delivery osteoclast and osteoblast lineage cells within scaffolds is being actively explored for bone tissue engineering purposes. However, it remains unclear how these cells can be incorporated into the design of multiphasic osteochondral scaffolds to potentially enhance subchondral bone formation and subsequent implant osseointegration. To explore this question, we examined direct surface seeding and hydrogel encapsulation as potential scaffold cellularization strategies. First, we examined how osteoclast precursor cells (OCps) and peripheral blood monocytes (PBMCs) influence early-stage bone matrix development and osteogenesis in 2D co-culture. Then, we evaluated the osteogenic potential of mesenchymal stem cells (MSCs) and PBMCs co-cultures encapsulated within a gelatin methacrylate (GelMA) hydrogel system. Our findings demonstrate that co-culturing PBMCs with MSCs in 2D cultures significantly enhanced cell proliferation, early bone matrix deposition, and the formation of cell clusters by Day 28. However, we observed no significant difference in Type I collagen (COLI) deposition between GelMA hydrogel scaffolds cultured in basal and OC conditions during the same period. Additionally, we found that the GelMA hydrogel system with MSC/PBMC co-cultures in OC conditions exhibited decreased osteogenic activity by Day 28. Collectively, our findings support the osteogenic potential of osteoclast-lineage cells in 2D culture conditions, and the potential benefits of surface-seeding for the co-delivery of osteoclast-lineage cells and MSCs in osteo-scaffolds for enhanced osteochondral regeneration and broader bone tissue engineering purposes.
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This perspective, marking the 30th anniversary of the Tissue Engineering journal, discusses the exciting trends in the global commercialization of tissue engineering technology. Within a historical context, we present an evolution of challenges and a discussion of the last 5 years of global commercial successes and emerging market trends, highlighting the continued expansion of the field in the northeastern United States. This leads to an overview of the last 5 years' progress in clinical trials for tissue-engineered therapeutics, including an analysis of trends in success and failure. Finally, we provide a broad overview of preclinical research and a perspective on where the state-of-the-art lies on the horizon.
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Osteoarthritis is a debilitating chronic joint disorder that affects millions of people worldwide. Since palliative and surgical treatments cannot completely regenerate hyaline cartilage within the articulating joint, osteochondral (OC) tissue engineering has been explored to heal OC defects. Utilizing computational simulations and three-dimensional (3D) printing, we aimed to build rationale around fabricating OC scaffolds with enhanced biomechanics. First, computational simulations revealed that interfacial fibrils within a bilayer alter OC scaffold deformation patterns by redirecting load-induced stresses toward the top of the cartilage layer. Principal component analysis revealed that scaffolds with 800 µm long fibrils (scaffolds 8A-8H) possessed optimal biomechanical properties to withstand compression and shear forces. While compression testing indicated that OC scaffolds with 800 µm fibrils did not have greater compressive moduli than other scaffolds, interfacial shear tests indicated that scaffold 8H possessed the greatest shear strength. Lastly, failure analysis demonstrated that yielding or buckling models describe interfacial fibril failure depending on fibril slenderness S. Specifically for scaffolds with packing density n = 6 and n = 8, the yielding failure model fits experimental loads with S < 10, while the buckling model fitted scaffolds with S < 10 slenderness. The research presented provides critical insights into designing 3D printed interfacial scaffolds with refined biomechanics toward improving OC tissue engineering outcomes.
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Impresión Tridimensional , Andamios del Tejido , Soporte de Peso , Andamios del Tejido/química , Animales , Ingeniería de Tejidos/métodos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Humanos , Análisis de Elementos Finitos , Estrés MecánicoRESUMEN
OBJECTIVES: The goal of this project was to develop and validate a patient-specific, anatomically correct graft for cartilage restoration using magnetic resonance imaging (MRI) data and 3-dimensional (3D) printing technology. The specific aim was to test the accuracy of a novel method for 3D printing and implanting individualized, anatomically shaped bio-scaffolds to treat cartilage defects in a human cadaveric model. We hypothesized that an individualized, anatomic 3D-printed scaffold designed from MRI data would provide a more optimal fill for a large cartilage defect compared to a generic flat scaffold. METHODS: Four focal cartilage defects (FCDs) were created in paired human cadaver knees, age <40 years, in the weight-bearing surfaces of the medial femoral condyle (MFC), lateral femoral condyle (LFC), patella, and trochlea of each knee. MRIs were obtained, anatomic grafts were designed and 3D printed for the left knee as an experimental group, and generic flat grafts for the right knee as a control group. Grafts were implanted into corresponding defects and fixed using tissue adhesive. Repeat post-implant MRIs were obtained. Graft step-off was measured as the distance in mm between the surface of the graft and the native cartilage surface in a direction perpendicular to the subchondral bone. Graft contour was measured as the gap between the undersurface of the graft and the subchondral bone in a direction perpendicular to the joint surface. RESULTS: Graft step-off was statistically significantly better for the anatomic grafts compared to the generic grafts in the MFC (0.0 â± â0.2 âmm vs. 0.7 â± â0.5 âmm, p â< â0.001), LFC (0.1 â± â0.3 âmm vs. 1.0 â± â0.2 âmm, p â< â0.001), patella (-0.2 â± â0.3 âmm vs. -1.2 â± â0.4 âmm, p â< â0.001), and trochlea (-0.4 â± â0.3 vs. 0.4 â± â0.7, p â= â0.003). Graft contour was statistically significantly better for the anatomic grafts in the LFC (0.0 â± â0.0 âmm vs. 0.2 â± â0.4 âmm, p â= â0.022) and trochlea (0.0 â± â0.0 âmm vs. 1.4 â± â0.7 âmm, p â< â0.001). The anatomic grafts had an observed maximum step-off of -0.9 âmm and a maximum contour mismatch of 0.8 âmm. CONCLUSION: This study validates a process designed to fabricate anatomically accurate cartilage grafts using MRI and 3D printing technology. Anatomic grafts demonstrated superior fit compared to generic flat grafts. LEVEL OF EVIDENCE: Level IV.
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Cadáver , Cartílago Articular , Imagen por Resonancia Magnética , Impresión Tridimensional , Humanos , Imagen por Resonancia Magnética/métodos , Adulto , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/cirugía , Articulación de la Rodilla/cirugía , Articulación de la Rodilla/diagnóstico por imagen , Andamios del Tejido , Masculino , FemeninoRESUMEN
While the field of tissue engineering has progressed rapidly with the advent of 3D bioprinting and human induced pluripotent stem cells (hiPSCs), impact is limited by a lack of functional, thick tissues. One way around this limitation is to 3D bioprint tissues laden with hiPSCs. In this way, the iPSCs can proliferate to populate the thick tissue mass prior to parenchymal cell specification. Here we design a perfusion bioreactor for an hiPSC-laden, 3D-bioprinted chamber with the goal of proliferating the hiPSCs throughout the structure prior to differentiation to generate a thick tissue model. The bioreactor, fabricated with digital light projection, was optimized to perfuse the interior of the hydrogel chamber without leaks and to provide fluid flow around the exterior as well, maximizing nutrient delivery throughout the chamber wall. After 7 days of culture, we found that intermittent perfusion (15 s every 15 min) at 3 ml min-1provides a 1.9-fold increase in the density of stem cell colonies in the engineered tissue relative to analogous chambers cultured under static conditions. We also observed a more uniform distribution of colonies within the tissue wall of perfused structures relative to static controls, reflecting a homogeneous distribution of nutrients from the culture media. hiPSCs remained pluripotent and proliferative with application of fluid flow, which generated wall shear stresses averaging â¼1.0 dyn cm-2. Overall, these promising outcomes following perfusion of a stem cell-laden hydrogel support the production of multiple tissue types with improved thickness, and therefore increased function and utility.
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Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes , Humanos , Andamios del Tejido/química , Ingeniería de Tejidos , Perfusión , Diferenciación Celular , Hidrogeles , Reactores BiológicosRESUMEN
Generation of thin membranous tissues (TMT), such as the cornea, epidermis, and periosteum, presents a difficult fabrication challenge in tissue engineering (TE). TMTs consist of several cell layers that are less than 100 µm in thickness per layer. While traditional methods provide the necessary resolution for TMT fabrication, they require significant handling and incorporation of several layers is limited. Extrusion bioprinting offers precise control over deposition of different biomaterials and cell populations within the same construct but lacks the resolution to generate biomimetic TMTs. For the first time, a 4D bioprinting strategy that allows for the generation of cell-laden TMTs is developed. Anionic gelatin methacrylate (GelMA) hydrogels are treated with cationic poly-l-lysine (PLL), which induces charge attraction, microscale network collapse, and macroscale hydrogel shrinking. The impact of shrinking on hydrogel properties, print resolution, and cell viability is presented. Additionally, this work suggests that a novel mechanism is occurring, where PLL exhibits a contractile force on GelMA and PLL molecular weight drives GelMA shrinking capabilities. Finally, it is shown that this phenomenon can occur while maintaining an encapsulated cell population. These findings address a critical barrier by generating macroscale tissue structures with their microscale TMT counterparts in the same print.
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Bioimpresión , Ingeniería de Tejidos , Materiales Biocompatibles/química , Hidrogeles/química , Gelatina/química , Metacrilatos/química , Andamios del Tejido/química , Impresión TridimensionalRESUMEN
Thin membranous tissues (TMTs) are anatomical structures consisting of multiple stratified cell layers, each less than 100 µm in thickness. While these tissues are small in scale, they play critical roles in normal tissue function and healing. Examples of TMTs include the tympanic membrane, cornea, periosteum, and epidermis. Damage to these structures can be caused by trauma or congenital disabilities, resulting in hearing loss, blindness, dysfunctional bone development, and impaired wound repair, respectively. While autologous and allogeneic tissue sources for these membranes exist, they are significantly limited by availability and patient complications. Tissue engineering has therefore become a popular strategy for TMT replacement. However, due to their complex microscale architecture, TMTs are often difficult to replicate in a biomimetic manner. The critical challenge in TMT fabrication is balancing fine resolution with the ability to mimic complex target tissue anatomy. This Review reports existing TMT fabrication strategies, their resolution and material capabilities, cell and tissue response, and the advantages and disadvantages of each technique.
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Ingeniería de Tejidos , Andamios del Tejido , Humanos , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Biomimética/métodos , Cicatrización de HeridasRESUMEN
[This retracts the article DOI: 10.1021/acscentsci.8b00050.].
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Extracellular vesicles (EVs) are implicated as promising therapeutics and drug delivery vehicles in various diseases. However, successful clinical translation will depend on the development of scalable biomanufacturing approaches, especially due to the documented low levels of intrinsic EV-associated cargo that may necessitate repeated doses to achieve clinical benefit in certain applications. Thus, here the effects of a 3D-printed scaffold-perfusion bioreactor system are assessed on the production and bioactivity of EVs secreted from bone marrow-derived mesenchymal stem cells (MSCs), a cell type widely implicated in generating EVs with therapeutic potential. The results indicate that perfusion bioreactor culture induces an ≈40-80-fold increase (depending on measurement method) in MSC EV production compared to conventional cell culture. Additionally, MSC EVs generated using the perfusion bioreactor system significantly improve wound healing in a diabetic mouse model, with increased CD31+ staining in wound bed tissue compared to animals treated with flask cell culture-generated MSC EVs. Overall, this study establishes a promising solution to a major EV translational bottleneck, with the capacity for tunability for specific applications and general improvement alongside advancements in 3D-printing technologies.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Ratones , Vesículas Extracelulares/metabolismo , Reactores Biológicos , Perfusión , Impresión TridimensionalRESUMEN
Skin cancer is one of the most ubiquitous forms of cancer that is often overdiagnosed or missed by traditional diagnostic techniques. Bioimpedance spectroscopy (BIS) is a technology that aims to take advantage of the variations in electrical properties of tissue to identify ectopic formations. It is difficult to develop BIS technologies without obtaining tumor tissue samples. One solution is to use a "tissue phantom," a synthetic structure that mimics the properties of tissue. Current solutions using natural biomaterials, such as gelatin, have not been able to create complex tissue geometries that are vital to honing BIS diagnostics. However, semi-synthetic polymers, such has gelatin methacrylate (GelMA), offer the benefits of possessing similar electrical properties to their respective source biomaterial while being 3D printable. In this work, we first measured the impedance of porcine dermal tissue. We then applied these impedance measurements to create an electrically accurate tissue phantom using a photocurable hydrogel, GelMA, and varying concentrations of NaCl, aluminum powder, and titanium dioxide powder.
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Materiales Biocompatibles , Gelatina , Porcinos , Animales , Gelatina/química , Polvos , Materiales Biocompatibles/química , Impedancia Eléctrica , Ingeniería de Tejidos/métodos , Impresión Tridimensional , Hidrogeles/química , Andamios del Tejido/química , Metacrilatos/químicaRESUMEN
Diabetes is a disease that plagues over 463 million people globally. Approximately 40 million of these patients have type 1 diabetes mellitus (T1DM), and the global incidence is increasing by up to 5% per year. T1DM is where the body's immune system attacks the pancreas, specifically the pancreatic beta cells, with antibodies to prevent insulin production. Although current treatments such as exogenous insulin injections have been successful, exorbitant insulin costs and meticulous administration present the need for alternative long-term solutions to glucose dysregulation caused by diabetes. Encapsulated islet transplantation (EIT) is a tissue-engineered solution to diabetes. Donor islets are encapsulated in a semipermeable hydrogel, allowing the diffusion of oxygen, glucose, and insulin but preventing leukocyte infiltration and antibody access to the transplanted cells. Although successful in small animal models, EIT is still far from commercial use owing to necessary long-term systemic immunosuppressants and consistent immune rejection. Most published research has focused on tailoring the characteristics of the capsule material to promote clinical viability. However, most studies have been limited in scope to biochemical changes. Current mechanobiology studies on the effect of substrate stiffness on the function of leukocytes, especially macrophages-primary foreign body response (FBR) orchestrators, show promise in tailoring a favorable response to tissue-engineered therapies such as EIT. In this review, we explore strategies to improve the clinical viability of EIT. A brief overview of the immune system, the FBR, and current biochemical approaches will be elucidated throughout this exploration. Furthermore, an argument for using substrate stiffness as a capsule design parameter to increase EIT efficacy and clinical viability will be posed.
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Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos , Animales , Diabetes Mellitus Tipo 1/terapia , Insulina , Ingeniería de Tejidos , Glucosa , Islotes Pancreáticos/fisiologíaRESUMEN
Macrophages are a primary contributor to the orchestration and severity of the foreign body response. As phagocytes and antigen-presenting cells, macrophages engage foreign objects, producing chemokines, degrading enzymes, and proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Encapsulated islet transplantation (EIT) is a return of function therapy in which donor insulin-secreting cells are encased in a biomaterial and implanted into a diabetic patient to regulate blood glucose levels. However, the foreign body response by macrophages to the encapsulated islet allograft may cause rejection. Recent studies have shown that substrate stiffness affects macrophage activity, which can inform EIT capsule design. However, due to the dysregulation of glucose maintenance in diabetic patients, varying from normoglycemic to hypoglycemic or hyperglycemic conditions, it is imperative to determine if glucose dysregulation affects macrophage mechanosensitivity to EIT biomaterials. This study explores the relationship between glucose metabolism and mechanosensitivity and the ultimate impact on proinflammatory macrophage function in static hyperglycemic and normoglycemic conditions. Using a 2-dimensional (2D) polyacrylamide model of 3-order magnitude in stiffness, 2, 15, and 274 kPa Young's moduli, the effect of glycemic condition on the mechanosensitive characteristics of unstimulated and proinflammatory RAW264.7 macrophage function in vitro using lipopolysaccharide (LPS) was examined. Hyperglycemic conditions were found to impact macrophage response to substrate stiffness significantly. Notably, TNF-α secretion was significantly reduced as substrate stiffness increased in LPS-stimulated hyperglycemic conditions, whereas normoglycemic macrophages held similar secretion across all stiffnesses. Stiffness-influenced differences in cytokine secretion were also induced in IL-6 secretion by hyperglycemic conditions. Hyperglycemic conditions promoted a biphasic trend in IL-6 cytokine secretion and gene expression by proinflammatory macrophages with significantly decreased production when cultured on 15 kPa compared to production on 2 and 274 kPa. Although hyperglycemic conditions drastically increased IL-10 secretion, stiffness-influenced differences were not shown when compared to the same glycemic condition. Furthermore, under LPS stimulation, lactate secretion had an inverse relationship to TNF-α secretion. However, no significant stiffness-influenced difference was demonstrated in glucose transporter 1 (GLUT1) expression, glucose uptake, or GAPDH. These findings suggest that hyperglycemic conditions enhance the mechanosensitivity of proinflammatory macrophages and should be explored further. Impact statement The work presented increases our understanding of the effect of glycemic condition on macrophage mechanosensitivity related to substrate stiffness. This has ramifications on the design of material-based therapies, such as encapsulated islet transplantation, for type 1 diabetic patients who experience glycemic dysregulation.
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Interleucina-6 , Factor de Necrosis Tumoral alfa , Humanos , Factor de Necrosis Tumoral alfa/farmacología , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Citocinas/metabolismo , Glucosa/farmacología , Materiales Biocompatibles/farmacologíaRESUMEN
3D printing has rapidly become a critical enabling technology in tissue engineering and regenerative medicine for the fabrication of complex engineered tissues. 3D bioprinting, in particular, has advanced greatly to facilitate the incorporation of a broad spectrum of biomaterials along with cells and biomolecules of interest forin vitrotissue generation. The increasing complexity of novel bioink formulations and application-dependent printing conditions poses a significant challenge for replicating or innovating new bioprinting strategies. As the field continues to grow, it is imperative to establish a cohesive, open-source database that enables users to search through existing 3D printing formulations rapidly and efficiently. Through the efforts of the NIH/NIBIB Center for Engineering Complex Tissues, we have developed, to our knowledge, the first bioink database for extrusion-based 3D printing. The database is publicly available and allows users to search through and easily access information on biomaterials and cells specifically used in 3D printing. In order to enable a community-driven database growth, we have established an open-source portal for researchers to enter their publication information for addition into the database. Although the database has a broad range of capabilities, we demonstrate its utility by performing a comprehensive analysis of the printability domains of two well-established biomaterials in the printing world, namely poly(ϵ-caprolactone) and gelatin methacrylate. The database allowed us to rapidly identify combinations of extrusion pressure, temperature, and speed that have been used to print these biomaterials and more importantly, identify domains within which printing was not possible. The data also enabled correlation analysis between all the printing parameters, including needle size and type, that exhibited compatibility for cell-based 3D printing. Overall, this database is an extremely useful tool for the 3D printing and bioprinting community to advance their research and is an important step towards standardization in the field.
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Bioimpresión , Andamios del Tejido , Impresión Tridimensional , Ingeniería de Tejidos , Materiales BiocompatiblesRESUMEN
Wound healing is a highly conserved process that restores the integrity and functionality of injured tissues. Transforming growth factor (TGF)-ß is a master regulator of wound healing, whose signaling is attenuated by the E3 ubiquitin ligase Smurf2. Herein, the roles of Smurf2 in cutaneous wound healing were examined using a murine incisional cutaneous model. Loss of Smurf2 increased early inflammation in the wounds and led to narrower wounds with greater breaking strength. Loss of Smurf2 also led to more linearized collagen bundles in normal and wounded skin. Gene expression analyses by real-time quantitative PCR indicated that Smurf2-deficient fibroblasts had increased levels of TGF-ß/Smad3 signaling and changes in expression profile of genes related to matrix turnover. The effect of Smurf2 loss on wound healing and collagen bundling was attenuated by the heterozygous loss of Smad3. Together, these results show that Smurf2 affects inflammation and collagen processing in cutaneous wounds by down-regulating TGF-ß/Smad3 signaling.
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Factor de Crecimiento Transformador beta1 , Factor de Crecimiento Transformador beta , Ratones , Animales , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Colágeno , Cicatrización de Heridas , Inflamación , Factores de Crecimiento TransformadoresRESUMEN
Accumulation of senescent cells (SnCs) in various tissue types has been connected to an occurrence of different age-related diseases that are indicated by its own tissue-specific hallmarks. Discovery of novel senolytic compounds that target major cellular mechanisms to inhibit the level of SnCs within the specific tissues or organs has been an emerging field in the age-related disease research. Although the positive effect of senolytics in global suppression of SnCs has been well studied in the past, effective tissue-specific delivery strategy of senotherapeutics before clinical application needs to be further investigated. In this review, we discuss the latest biological insights to currently available senotherapeutic options and explore the impactful in vitro tissue-engineered models possibly as a testbed for replicable testing of tissue-specific potency of senolytics. Impact statement Senotherapy, the inhibition of accumulated senescent cells, is recognized as a significantly impactful way to treat various human diseases. However, there is limited comprehensive reviews on this topic. This review provides in-depth discussion on diverse delivery strategies of senolytic agents and latest updates on a novel senotherapeutic research.
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Senoterapéuticos , Ingeniería de Tejidos , HumanosRESUMEN
Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell-derived microphysiological system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell-derived miniature joint system (miniJoint) is generated, in which engineered osteochondral complex, synovial-like fibrous tissue, and adipose tissue are integrated into a microfluidics-enabled bioreactor. This novel design facilitates different tissues communicating while still maintaining their respective phenotypes. The miniJoint exhibits physiologically relevant changes when exposed to interleukin-1ß mediated inflammation, which are similar to observations in joint diseases in humans. The potential of the miniJoint in predicting in vivo efficacy of drug treatment is confirmed by testing the "therapeutic effect" of the nonsteroidal anti-inflammatory drug, naproxen, as well as four other potential disease-modifying OA drugs. The data demonstrate that the miniJoint recapitulates complex tissue interactions, thus providing a robust organ chip model for the study of joint pathology and the development of novel therapeutic interventions.