Cellular senescence, a process that induces irreversible cell cycle arrest in response to diverse stressors, is a primary contributor to aging and age-related diseases. Currently, exposure to hydrogen peroxide is a widely used technique for establishing in vitro cellular senescence models; however, this traditional method is inconsistent, laborious, and ineffective in vivo. To overcome these limitations, we have developed a hydrogen peroxide-releasing hydrogel that can readily and controllably induce senescence in conventional 2-dimensional cell cultures as well as advanced 3-dimensional microphysiological systems. Notably, we have established 2 platforms using our hydrogen peroxide-releasing hydrogel for investigating senolytics, which is a promising innovation in anti-geronic therapy. Conclusively, our advanced model presents a highly promising tool that offers a simple, versatile, convenient, effective, and highly adaptable technique for inducing cellular senescence. This innovation not only lays a crucial foundation for future research on aging but also markedly accelerates the development of novel therapeutic strategies targeting age-related diseases.

Introduction: Skeletal muscle possesses a remarkable regenerative capacity due to the presence of dedicated stem cells, also known as muscle satellite cells (MuSCs), but this ability declines with age. Recent studies utilizing heterochronic parabiosis, in which two animals are surgically joined to share a common blood circulation, have demonstrated remarkable rejuvenation effects across various aged tissues. Despite these findings, the complexity of in vivo parabiosis experiments has made it challenging to identify the underlying mechanisms and key rejuvenation factors. Here, we developed a vascularized 3D muscle microphysiological system (MPS) that replicates essential features of the native MuSC niche. We hypothesized that this engineered platform would enable detailed mechanistic studies of cellular interactions and molecular dynamics relevant to aging in a parabiosis-like environment. Methods: We designed a dual layer microphysiological device separated by a porous membrane with 8 µm pore size. The MuSC vascular network was recreated by co-culturing muscle-relevant cells (myotube-like fibers, endothelial cells, and MuSCs) in an ECM-mimetic hydrogel within the device. Quiescent MuSCs (Pax7 + ) and serum were isolated from the hindlimb muscles of GFP + mice using flow cytometry. Experiments focused on investigating the effects of (1) systemic aging and oxidative stress, (2) vascular microenvironments, and (3) parabiotic circulation on myogenic differentiation of MuSCs. Cytokine profiling during young-old chip interconnection was conducted using Luminex immunoassays to identify rejuvenating factors. RESULTS AND DISCUSSION: We successfully established a vascularized 3D MuSC niche in engineered MPS, where young (3–4 months) and aged (20–24 months) MuSCs were cultured in myofibrillar-like structures embedded in hydrogels covered by an endothelial cell monolayer. This platform enabled real-time monitoring of sequential MuSC myogenic events and sensitive detection of systemic factors. Notably, blood circulation between young and aged MPS systems significantly enhanced myogenic differentiation of aged MuSCs, recapitulating the rejuvenating effects observed in heterochronic parabiosis. After cytokine screening, we identified vascular endothelial growth factor (VEGF) as a key factor contributing to aged MuSC rejuvenation. SIGNIFICANCE/CLINICAL RELEVANCE: Using the 3D muscle MPS integrating young and aged muscle models, we investigated the myogenic activities of MuSCs and systemic cytokine profiles during heterochronic parabiotic circulation. Our 3D MPS model offers significant potential as a preclinical tool to identify anti-geronic factors that promote muscle rejuvenation. References: Lee et al., Adv. Funct. Mater. (2020). National Institute of Health under award number (R01AG072309, R01AR080169, R21AR072287) and Department of Defense under award number W81XWH-20-1-0336. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Volumetric muscle loss (VML) injuries result in chronic fibrosis, inflammation, and persistent functional deficits. Fibro-adipogenic progenitor (FAP) cells are a heterogeneous, muscle-resident stromal cell population that play a crucial role in muscle regeneration, but also contribute to fibrosis in muscle disease. The role of FAPs in VML is not well established and may be critical target to ensure functional muscle regeneration after VML. We utilized a VML model in the mouse quadriceps to study the location, secretome, surface marker distribution, gene expression, and single-cell transcriptional profile of FAPs after VML. After VML, a subpopulation of FAPs highly expressed β1-integrin and were elevated in the post-VML muscle tissue; these FAPs had increased fibrotic gene expression and increased myofibroblast differentiation potential. Transforming growth factor-β1 (TGF-β1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) were identified as secreted proteins from VML derived FAPs that produced both pro-fibrotic and anti-myogenic signaling. These data establish an aberrant FAP sub-population that are elevated in VML injury and provides novel targets for future scarless muscle regeneration in VML.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration, with respiratory muscle weakness significantly impacting patient outcomes. Early detection of disease progression is critical for evaluating treatment strategies. This study investigates the feasibility of ultrasound shear wave elasticity imaging (US-SWEI) for assessing early-stage respiratory muscle changes in mdx mice, a model for DMD, aged 3 to 6 months. Longitudinal in vivo imaging evaluated the diaphragm’s viscoelastic properties, with group and phase velocities measured to capture biomechanical changes. In mdx mice, group velocity increased from 3.47±0.15to4.20±0.20m/s, whereas wild-type values changed only modestly (2.76±0.11to3.01±0.16m/s). Histological analysis confirmed a significant positive correlation between group velocity and collagen deposition (R2=0.54,P=0.025), supporting fibrosis as a primary factor driving changes in diaphragm viscoelastic properties. These findings establish US-SWEI as a noninvasive, feasible approach for monitoring respiratory muscle health and advancing preclinical DMD research. By identifying early-stage changes in diaphragm properties, this approach enables the development of therapeutic interventions targeting respiratory complications. Furthermore, US-SWEI presents a potential avenue for assessing and monitoring neuromuscular diseases.

Parkinson's disease (PD) is the second most common neurodegenerative disease that affects movement and cognitive function, resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neurons. It affects nearly one million people in the United States and 8.5 million worldwide. While there are some pharmacological and surgical options available, they only provide symptomatic relief, as there is currently no cure for PD. In contrast, exercise training, a non-pharmacological intervention, has emerged as a powerful strategy to enhance the psychological, cognitive, and physiological (motor) impairments associated with PD. Given that the beneficial effects of exercise differ based on the intensity and type of training, gaining a thorough understanding of the molecular mechanisms underlying exercise-induced protection is crucial for developing innovative therapies that improve the quality of life for PD patients around the globe. This review discusses PD pathogenesis and pathophysiology and provides recent clinical evidence of neuroprotective benefits from various exercise modalities and intensity. Furthermore, the molecular mechanisms of exercise in PD pathogenesis (e.g., modulations on neurotrophic factors, oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and autophagy) will be emphasized.

Introduction: Skeletal muscle regeneration is an energy-demanding process that relies on mitochondria to generate ATP. While healthy skeletal muscle fibers have organized interfibrillar mitochondrial networks organizing architecture segregated into columns along the Z-line of the myofiber, regenerating fibers exhibits altered mitochondrial networks that span several sarcomeres. Despite links between muscle regeneration and altered mitochondrial dynamics and biogenesis, the role of specific cells in remodeling these networks remains unclear. Because muscle stem cells (MuSCs) play a critical role in muscle regeneration, we explored the relationship between MuSCs and mitochondria in regenerating muscle fibers. Methods: To induce muscle regeneration, we used the hindlimb ischemia mouse model of peripheral artery disease (PAD) and the mdx mouse model of Duchenne’s muscular dystrophy (DMD). Furthermore, transgenic reporter mice such as Pax7-tdTomato, H2B-EGFP, and mitoDendra2 were used to mark MuSCs, track nuclei, and label mitochondria, respectively. Fluorescently labeled MuSCs were also transplanted into BaCl 2 -injured muscle to elucidate their behavior and interactions throughout muscle regeneration. Immunofluorescence, single fiber staining, and biochemical assays from harvested muscles were performed for data analysis. Results: Following injury, a significant increase in the number of endogenous MuSCs was observed 7 days post-injury compared to contralateral control, while a dramatic increase in the fusion of MuSCs into myofibers was noted at days 14 and 28. Interestingly, all fused myofibers at days 14 and 28 displayed central nucleation, a hallmark of regeneration that fusion of the MuSC is critical for myofiber regeneration. Primary MuSCs from H2B-EGFP reporter mice were isolated and transplanted into the injured muscle to determine the origin of the centrally located myonuclei. In myofibers where the transplanted MuSCs had fused, centrally located myonuclei were GFP + , indicating their origin from MuSCs. Surprisingly, regenerating muscle fibers isolated from the mitoDendra2 mouse model exhibited high densities of mitochondrial content near the centrally located myonuclei. To evaluate whether MuSCs contribute to producing these central myonuclei near mitochondria, primary MuSCs isolated from mitoDendra2 reporter mice were transplanted into mdx mice. Fused myofibers indeed exhibited high Dendra2 + mitochondrial density between central nuclei along with a restoration of the mitochondrial network. Finally, we also observed a change in myogenic potential and mitochondrial respiration after transplanting MuSCs that have been preconditioned to enhance mitochondrial biogenesis. SIGNIFICANCE RELEVANCE: Overall, these data indicate that MuSC-derived myonuclei synthesize new mitochondria to generate the bioenergetics for myofiber regeneration after muscle injury. This relationship between MuSCs and myofiber mitochondria provides a basis for MuSC-derived mitochondrial transplantation as a therapeutic approach for muscular diseases associated with mitochondrial dysfunction. Acknowledgements: This work was supported by the NIH R01AR080169, R01AG072309, VA Merit Award I02RX005009 (to YCJ) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.

Achieving large-scale, cost-effective, and reproducible manufacturing of stem cells with the existing devices is challenging. Traditional single-use cell-bag bioreactors, limited by their rigid and single-point sensors, struggle with accuracy and scalability for high-quality cell manufacturing. Here, we introduce a smart bioreactor system that enables multi-spatial sensing for real-time, wireless culture monitoring. This scalable system includes a low-profile, label-free thin-film sensor array and electronics integrated with a flexible cell bag, allowing for simultaneous assessment of culture properties such as pH, dissolved oxygen, glucose, and temperature, to receive real-time feedback for up to 30 days. The experimental results show the accurate monitoring of time-dynamic and spatial variations of stem cells and myoblast cells with adjustable carriers from a plastic dish to a 2-liter cell bag. These advances open up the broad applicability of the smart sensing system for large-scale, lower-cost, reproducible, and high-quality engineered cell manufacturing for broad clinical use.

Stem cell therapy has shown remarkable promise for treating various diseases and disorders. This strategy attenuates disease symptoms and stimulates endogenous and exogenous regeneration processes. However, several clinical trial shortcomings revealed that injecting only stem cells was insufficient to achieve satisfactory therapeutic benefits. This may be attributed to low cell survival, short-term cell retention, and limited functional improvements. To overcome this challenge, biofunctional hydrogels have been explored as a potential cell delivery platform and offer new possibilities for the next generation of stem cell-based therapies in clinics. Although the importance and impacts of hydrogels for stem cell delivery are clearly defined, this strategy should be carefully developed with all potential barriers in mind before moving to early-phase clinical trials. This review aims to provide a comprehensive overview of the design principles and applications of hydrogels for stem cell delivery in tissue engineering. We discuss the importance of creating cell-instructive hydrogels that mimic the three-dimensional (3D) stem cell niches and explore various hydrogel formulations employed in tissue engineering approaches. Finally, we review the remaining challenges of the current stem cell/hydrogel strategies in clinical trials and propose potential approaches for achieving successful clinical outcomes.

A visible light- and reactive oxygen species (ROS)-responsive pressure/strain sensor based on carbon dot (CD)-loaded conductive hydrogel was developed for detecting high-fat diet (HFD) and preventing the risk of non-alcoholic fatty liver disease. The designed nanoparticle consisted of a diselenide polymer dot (dsPD) loaded with a visible light-responsive CD to form dsPD@CD (DSCD). The influence of visible light irradiation and ROS on DSCD facilitated the electron transport, enhancing the conductivity of DSCD-embedded hydrogel (DSCD hydrogel) from 1.3 to 35.9 mS/m. Alternatively, the tensile modulus of the DSCD hydrogel enhanced to 223 % after light-induced ROS treatment, which simultaneously impacted the capacitive response (120 %). The hydrogel implantation into inguinal white adipose tissue of HFD mice showed 82 % higher conductivity and 83 % enhanced pressure sensing response to HFD-generated high ROS levels compared with the normal diet-fed mice. Additionally, the ROS scavenging activity of DSCD hydrogel was confirmed by the downregulation of ROS-responsive genes, such as Sod2, Nrf2, and catalase (Cat) in murine primary hepatocytes isolated from fatty liver-induced mice. In addition, in vivo animal studies also confirmed the suppression of hepatic lipogenesis, as shown by decreased Pparγ and Fasn expression and hypertrophy of adipocytes in HFD mice. The distinguishable real-time wireless resistance response observed with pressure sensing indicates the potential application of the device for monitoring the risk of non-alcoholic fatty liver disease. STATEMENT OF SIGNIFICANCE: A visible-light-induced ROS-responsive carbon dot-loaded conductive hydrogel was developed for the detection of HFD-induced alterations in ROS levels by evaluating the conductivity and electrochemical responses with applied pressure/strain. The implanted hydrogel facilitates the recovery of the inflated adipocytes induced by NAFLD, which reduces fat accumulation in the liver, preventing the risk of NAFLD. Real-time detection based on the resistance response during local compression of the hydrogel is possibly performed utilizing a wireless sensing device, demonstrating the ease of NAFLD monitoring.

Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical injury or critical VML in the murine quadriceps, respectively. We found that critical VML resulted in a sustained presence of M2-like and CD206 hi Ly6C hi ‘hybrid’ macrophages whereas subcritical defects resolved these populations. Notably, the retained M2-like macrophages from critical VML injuries presented with aberrant cytokine production which may contribute to fibrogenesis, as indicated by their co-localization with fibroadipogenic progenitors (FAPs) in areas of collagen deposition within the defect. Furthermore, several T cell subpopulations were significantly elevated in critical VML compared to subcritical injuries. These results demonstrate a dysregulated immune response in critical VML that is unable to fully resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment within the first week after injury. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML.

Skeletal muscle regeneration is an energy-demanding biological process that relies on mitochondria to generate ATP. While interfibrillar mitochondrial networks in healthy skeletal muscle fibers exhibit an organized architecture segregated into columns along the Z-line of the myofiber, regenerating fibers demonstrate altered mitochondrial networks that span several sarcomeres. Although it’s been established that skeletal muscle regeneration parallels altered mitochondrial dynamics and biogenesis, the cells that mediate the remodeling of mitochondrial networks have not been thoroughly investigated. Because muscle stem cells (MuSCs) play a critical role in muscle regeneration, we explored the relationship between MuSCs and mitochondria in regenerating muscle fibers. In order to induce muscle regeneration, we employed the hindlimb ischemia mouse model of peripheral artery disease (PAD) and the mdx mouse model of Duchenne’s muscular dystrophy (DMD). Furthermore, transgenic reporter mice such as Pax7-tdTomato, H2B-EGFP, and mitoDendra2 were used mark MuSCs, track nuclei, and label mitochondria, respectively. Fluorescently-labelled MuSCs were also transplanted into BaCl2-injured muscle to elucidate their behavior and interactions throughout muscle regeneration. Immunofluorescence, single fiber staining, and biochemical assays from harvested muscles were performed for data analysis. Following injury, there was a dramatic increase in the number of endogenous MuSCs 7 days post-injury compared to contralateral control while there was a significant increase in fusion of the accreted MuSCs into the myofiber at days 14 and 28. Interestingly, all fused myofibers at days 14 and 28 were regenerating, demarcated by central nucleation, suggesting that fusion of the MuSC is critical for myofiber regeneration. To determine the origin of the centrally located myonuclei, primary MuSCs from H2B-EGFP reporter mice were isolated and transplanted into injured muscle. For myofibers in which the transplanted MuSCs fused into, centrally located myonuclei were GFP+, implying that these myonuclei were derived from MuSCs. Surprisingly, regenerating muscle fibers isolated from the mitoDendra2 mouse model exhibited high densities of mitochondrial content adjacent to the centrally located myonuclei. In order to test whether MuSCs are responsible for producing these central myonuclei near mitochondria, primary MuSCs isolated from mitoDendra2 reporter mice were transplanted into mdx mice and fused myofibers indeed exhibited high Dendra2+ mitochondrial density between central nuclei as well as a restoration of the mitochondrial network. Finally, we also observed a change in myogenic potential and mitochondrial respiration after transplanting MuSCs that have been preconditioned to enhance mitochondrial biogenesis. Overall, these data indicate that following skeletal muscle injury, MuSC-derived myonuclei synthesize new mitochondria to generat This work was supported by the National Institute of Health under award number (R01AG072309, R21AR072287), Department of Defense under award number W81XWH-20-1-0336, and Regenerative Engineering and Medicine Grant. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle has an exceptional regenerative capacity that relies on the temporal activation and regulation of immune cells, fibro-adipogenic progenitors (FAPs), and muscle stem cells (MuSCs). However, following traumatic injury to skeletal muscle, such as in extensive muscle deficits caused by injury or surgery, also known as volumetric muscle loss (VML), this coordinated regenerative response is diminished, leading to fibrosis, inflammation, and chronic functional deficiencies. The goal of this study was to compare the temporal response and phenotype of key cell populations, including macrophages, FAPs, and MuSCs following critical and sub-critical VML injuries in the mouse quadriceps. We hypothesize that traumatic injury, specifically VML, drives cell phenotypic variability amongst these cell populations. Unilateral VML injuries were used to quantify cell type distribution via flow cytometry at 1, 3, and 7 days post-VML (pVML, n=4 per injury size and time point). At day 7 pVML, anti-inflammatory M2 macrophages, FAPs, and MuSCs were all present in significantly elevated numbers per tissue volume in critical (3-mm) injuries compared to sub-critical (2-mm) injuries (p<0.05). Using multi-dimensional flow cytometry analysis, a distinct sub-population of FAPs was identified in critically sized VML injuries which had larger cell content and highly expressed the β1-integrin cell-surface marker. FAPs from quadriceps at day 7 pVML (VML-FAPs) were purified using fluorescence-activated cell sorting and cultured in vitro. VML-FAPs exhibited increased proliferation, increased cell area, and showed elevated levels of β1-integrin expression. In co-culture experiments, VML-FAPs were also shown to significantly decrease the myogenic capacity of primary MuSCs by quantification of myotube formation (p<0.05). When cultured with the anti-inflammatory cytokine TGF-β1, VML-FAPs more readily differentiated down a fibroblastic lineage. Collectively, these results indicate that following traumatic injury, namely VML, there is an aberrant shift in the FAPs cell population, possibly driven by the accumulation of M2 macrophages, towards a lineage which is persistent, pro-fibrotic, and anti-myogenic. The identification of this shift in VML-FAPs will be key to the development of pro-regenerative therapeutics for VML, as success of these VML-FAP interventions will rely on the ability to downregulate the fibrotic lineage of FAPs while maintaining their traditional pro-myogenic qualities during regeneration. Furthermore, this study also provokes investigation of differing FAP phenotypes in other traumatic muscle injuries to identify possible trends or incongruencies that may exist. Funding: This work was supported by the National Institute of Health under award number R01AG072309, R01AR071708, and Department of Defense under award number W81XWH-20-1-0336. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

INTRODUCTION: Skeletal muscle homeostasis is maintained by resident stem cells, called muscle satellite cells (MuSCs). Similar to other adult stem cells, MuSC function is coordinated by the cellular and acellular components of their microenvironment, or niche. While the processes that couple neurotransmission and muscle contraction have been well characterized, little is known about the reciprocal crosstalk between neural network and MuSCs. We postulated that nerve injury coupled with stem cell transplantation would enrich MuSC function in muscle regeneration. METHODS: To induce peripheral nerve injury, we used sciatic nerve pinch, in which epineurium is intact, in C57BL6 mice. Following seven days of nerve injury, MuSCs were purified using FACS. A combination of in vitro proliferation, differentiation, in vivo muscle regeneration, MuSC transplantation, immunofluorescence, gene expression, and protein analyses were performed to assess differences in myogenesis. In addition, denervation response in aged (22 – 24 months) mice and a mouse model of Duchenne muscular dystrophy ( mdx) were compared to that of young (2 – 4 months) mice. RESULTS AND DISCUSSION: After seven days of mild peripheral nerve perturbation, we observed a significant increase in Pax7+ MuSC bioavailability as well as augmented myogenesis, as measured by proliferation, differentiation, and fusion in vitro. This enhancement in myogenesis was correlated with an increase in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial oxidative metabolism. Moreover, MuSCs from denervated muscle displayed a significant increase in the protein synthesis pathway. We further validated synergistic interactions between nerve and MuSCs using transplantation experiments. Both as donors and recipients, nerve injured MuSCs showed a significant increase in transplantation efficiency. However, chronic disruption or degeneration of the neuromuscular junction (NMJ) that occurs in muscular dystrophy and with biological aging diminishes the MuSC-motor unit interactions, causing significant deficits in muscle regeneration. Overall, these results underscore the importance of NMJs and the neural network as essential components of the MuSC niche. SIGNIFICANCE/CLINICAL RELEVANCE: Determining the significance of MuSC-nerve interactions and their functional outcomes, as well as the possibility of modulating these connections, would have important implications for understanding neuromuscular disease pathology and developing new therapeutic interventions. REFERENCES: [1] Larouche JA et al. eLife https://doi.org/10.7554/eLife.66749 This work was supported by the National Institute of Health under award number (R01AG072309, R21AR072287) and Department of Defense under award number W81XWH-20-1-0336. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Duchenne muscular dystrophy (DMD) causes patients to suffer from ambulatory disability and cardiores-piratory failure, the latter of which leads to premature death. Due to its role in respiration, the diaphragm is an important muscle for study. A common method for evaluating diaphragm function is ex vivo force testing, which only allows for an end point measurement. In contrast, ultrasound shear wave elastography imaging (US-SWEI) can assess diaphragm function over time; however, US-SWEI studies in dystrophic pa-tients to date have focused on the limbs without preclinical studies. In this work, we used US-SWEI to estimate the shear wave speed (SWS) in diaphragm muscles of healthy (WT) mice, mdx mice, and mdx mice haploinsufficient for utrophin (mdx-utr) at 6 and 12 months of age. Diaphragms were then subjected to ex vivo force testing and histological analysis at 12 months of age. Between 6 and 12 months, a 23.8% increase in SWS was observed in WT mice and a 27.8% increase in mdx mice, although no significant dif-ference was found in mdx-utr mice. Specific force generated by mdx-utr diaphragms was lower than that of WT diaphragms following twitch stimulus. A strong correlation between SWS and collagen deposition was observed, as well as between SWS and muscle fiber size. Together, these data demonstrate the abil-ity of US-SWEI to evaluate dystrophic diaphragm functionality over time and predict the biochemical and morphological make-up of the diaphragm. Additionally, our results highlight the advantage of US-SWEI over ex vivo testing by obtaining longitudinal measurements in the same subject.Statement of significanceIn DMD patients, muscles experience cycles of regeneration and degeneration that contribute to chronic inflammation and muscle weakness. This pathology only worsens with time and leads to muscle wasting, including in respiratory and cardiac muscles. Because respiratory failure is a major contributor to pre-mature death in DMD patients, the diaphragm muscle is an important muscle to evaluate and treat over time. Currently, diaphragm function is assessed using ex vivo force testing, a technique that only allows measurement at sacrifice. In contrast, ultrasonography, particularly shear wave elasticity imaging (USS-WEI), is a promising tool for longitudinal assessment; however, most US-SWEI in DMD patients aimed for limb muscles only with the absence of preclinical studies. This work broadens the applications of US-SWE imaging by demonstrating its ability to track properties and function of dystrophic diaphragm muscles longitudinally in multiple dystrophic mouse models.& COPY; 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In this study, a reactive oxygen species (ROS)‐responsive hydrogel sensor (PD/MnO 2 hydrogel) is developed that can efficiently detect senescent cells. Using immature murine articular chondrocytes with serial passages, the sensor can identify small interfering RNA (siRNA) knockdown of peroxisome proliferator‐activated receptor‐alpha (PPARα) based on the concentration of ROS in cells, simultaneously maintaining its balance via scavenging activity to prevent cartilage degradation in osteoarthritis (OA). The hydrogel sensor exhibits a change in electronic properties, with a distinct resistance from 201.9 kΩ for P0 to 362.9 kΩ for P3, and fluorescence off/on performance with an increase in passaging time. In vitro investigation using PPARα‐specific siRNA reveals a correlation between pressure sensitivity and senescent activity, wherein an elevation in observed signal occurred (41.5%). In vivo analysis reveals significant decrease in degradation of the cartilage of both young, 3 months old aged, 18 months old, and PPAR α −/− mice compared to PPAR α +/+ mice based on safranin O stains. The expression level of interleukin‐1β is reduced in the cartilage of aged PPAR α −/− mice after implantation with hydrogel, indicating the potential of PD/MnO 2 hydrogel as a therapeutic modality against OA.

Atherosclerosis is a prominent cause of coronary artery disease and broader cardiovascular diseases, the leading cause of death worldwide. Angioplasty and stenting is a common treatment, but in-stent restenosis, where the artery re-narrows, is a frequent complication. Restenosis is detected through invasive procedures and is not currently monitored frequently for patients. Here, we report an implantable vascular bioelectronic device using a newly developed miniaturized strain sensor via microneedle printing methods. A capillary-based printing system achieves high-resolution patterning of a soft, capacitive strain sensor. Ink and printing parameters are evaluated to create a fully printed sensor, while sensor design and sensing mechanism are studied to enhance sensitivity and minimize sensor size. The sensor is integrated with a wireless vascular stent, offering a biocompatible, battery-free, wireless monitoring system compatible with conventional catheterization procedures. The vascular sensing system is demonstrated in an artery model for monitoring restenosis progression. Collectively, the artery implantable bioelectronic system shows the potential for wireless, real-time monitoring of various cardiovascular diseases and stent-integrated sensing/treatments.

Skeletal muscle has an innate regenerative capacity to restore their structure and function following acute damages and injuries. However, in congenital muscular dystrophies, large volumetric muscle loss, cachexia, or aging, the declined regenerative capacity of skeletal muscle results in muscle wasting and functional impairment. Recent studies indicate that muscle mass and function are closely correlated with morbidity and mortality due to the large volume and location of skeletal muscle. However, the options for treating neuromuscular disorders are limited. Biomedical engineering strategies such as nanotechnologies have been implemented to address this issue.In this review, we focus on recent studies leveraging nano-sized materials for regeneration of skeletal muscle. We look at skeletal muscle pathologies and describe various proof-of-concept and pre-clinical studies that have used nanomaterials, with a focus on how nano-sized materials can be used for skeletal muscle regeneration depending on material dimensionality.Depending on the dimensionality of nano-sized materials, their application have been changed because of their different physical and biochemical properties.Nanomaterials have been spotlighted as a great candidate for addressing the unmet needs of regenerative medicine. Nanomaterials could be applied to several types of tissues and diseases along with the unique characteristics of nanomaterials. However, when confined to muscle tissue, the targets of nanomaterial applications are limited and can be extended in future research.

ABSTRACT Introduction Metabolic disorder promotes premature senescence and poses more severe cardiac dysfunction in females than males. Although endurance exercise (EXE) has been known to confer cardioprotection against metabolic diseases, whether EXE-induced cardioprotection is associated with mitigating senescence in females remains unknown. Thus, the aim of the present study was to examine metabolic disorder–induced cardiac anomalies (cellular senescence, metabolic signaling, and autophagy) using a mouse model of obese/type 2 diabetes induced by a high-fat/high-fructose (HFD/HF) diet. Methods Female C57BL/6 mice (10 wk old) were assigned to three groups (n = 11/group): normal diet group (CON), HFD/HF group, and HFD/HF diet + endurance exercise (HFD/HF + EXE) group. Upon confirmation of hyperglycemia and overweight after 12 wk of HFD/HF diet, mice assigned to HFD/HF + EXE group started treadmill running exercise (60 min·d−1, 5 d·wk−1 for 12 wk), with HFD/HF diet continued. Results EXE ameliorated HFD/HF-induced body weight gain and hyperglycemia, improved insulin signaling and glucose transporter 4 (GLUT4) levels, and counteracted cardiac disruption. EXE reversed HFD/HF-induced myocyte premature senescence (e.g., prevention of p53, p21, p16, and lipofuscin accumulation), resulting in suppression of a senescence-associated secretory phenotype such as inflammation (tumor necrosis factor α and interleukin-1β) and oxidative stress (protein carbonylation). Moreover, EXE restored HFD/HF-induced autophagy flux deficiency, evidenced by increased LC3-II concomitant with p62 reduction and restoration of lysosome function-related proteins (LAMP2, CATHEPSIN L, TFEB, and SIRT1). More importantly, EXE retrieved HFD/HF-induced apoptosis arrest (e.g., increased cleaved CASPASE3, PARP, and TUNEL-positive cells). Conclusions Our study demonstrated that EXE-induced antisenescence phenotypes, autophagy restoration, and promotion of propitiatory cell removal by apoptosis play a crucial role in cardiac protection against metabolic distress–induced cardiac disruption.