Magnitude and angle dynamics in training single ReLU neurons.

Understanding the training dynamics of deep ReLU networks is a significant area of interest in deep learning. However, there remains a lack of complete elucidation regarding the weight vector dynamics, even for single ReLU neurons. To bridge this gap, our study delves into the training dynamics of the gradient flow w(t) for single ReLU neurons under the square loss, dissecting it into its magnitude ‖w(t)‖ and angle φ(t) components. Through this decomposition, we establish upper and lower bounds on these components to elucidate the convergence dynamics. Furthermore, we demonstrate the empirical extension of our findings to general two-layer multi-neuron networks. All theoretical results are generalized to the gradient descent method and rigorously verified through experiments.

Recent Advances in Minimally Invasive Management of Osteolytic Periacetabular Skeletal Metastases.

Painful skeletal osteolytic metastases, impending pathological fractures, and nondisplaced fractures present as a devastating clinical problem in advanced stage cancer patients. Open surgical approaches provide excellent mechanical stabilization but are often associated with high complication rates and slow recovery times. Percutaneous minimally invasive interventions have arisen as a pragmatic and logical treatment option for patients with late-stage cancer in whom open surgery may be contraindicated. These percutaneous interventions minimize soft tissue dissection, allow for the immediate initiation or resumption of chemotherapies, and present with fewer complications. This review provides the most up-to-date technical and conceptual framework for the minimally invasive management of osseous metastases with particular focus on periacetabular lesions. Fundamental topics discussed are as follows: (1) pathogenesis of cancer-induced bone loss and the importance of local cytoreduction to restore bone quality, (2) anatomy and biomechanics of the acetabulum as a weight-bearing zone, (3) overview of ablation options and cement/screw techniques, and (4) combinatorial approaches. Future studies should include additional studies with more long-term follow-up to better assess mechanical durability of minimally invasive interventions. An acetabulum-specific functional and pain scoring framework should be adopted to allow for better cross-study comparison.

An Effective Catholyte for Sulfide-Based All-Solid-State Batteries Utilizing Gas Absorbents.

All-solid-state batteries (ASSBs) possess the advantage of ensuring safety while simultaneously maximizing energy density, making them suitable for next-generation battery models. In particular, sulfide solid electrolytes (SSEs) are viewed as promising candidates for ASSB electrolytes due to their excellent ionic conductivity. However, a limitation exists in the form of interfacial side reactions occurring between the SSEs and cathode active materials (CAMs), as well as the generation of sulfide-based gases within the SSE. These issues lead to a reduction in the capacity of CAMs and an increase in internal resistance within the cell. To address these challenges, cathode composite materials incorporating zinc oxide (ZnO) are fabricated, effectively reducing various side reactions occurring in CAMs. Acting as a semiconductor, ZnO helps mitigate the rapid oxidation of the solid electrolyte facilitated by an electronic pathway, thereby minimizing side reactions, while maintaining electron pathways to the active material. Additionally, it absorbs sulfide-based gases, thus protecting the lithium ions within CAMs. In this study, the mass spectrometer is employed to observe gas generation phenomena within the ASSB cell. Furthermore, a clear elucidation of the side reactions occurring at the cathode and the causes of capacity reduction in ASSB are provided through density functional theory calculations.

Draft genome sequence of bacterium Bacillus proteolyticus strain IMGN4 from soil.

Here, we present the draft genome of Bacillus proteolyticus IMGN4, the gram-positive, soil-dwelling bacterium discovered in mountain Maemi, Republic of Korea in May 2019. The assembly resulted in 7 contigs, comprising a total of 6,063,502 base pairs and have 6,115 coding sequences.

Evaluation of Gamma Aminobutyric Acid and Sodium Butyrate in Juvenile Red Seabream (Pagrus major) Diets Containing Graded Levels of Fish Meal and Soy Protein Concentrate.

The experiment was conducted to evaluate the supplementary effects of gamma aminobutyric acid (GABA) and sodium butyrate (SB) when a graded level of fish meal (FM) was replaced with soy protein concentrate (SPC) in diets for juvenile red seabream (Pagrus major). A control diet was designed to contain 60% FM (F60). Two other diets were formulated by reducing FM levels to 40% and 20% with SPC (F40 and F20). Six more diets were formulated by adding 0.02% GABA or 0.2% SB to each F60, F40 and F20 diets (F60G, F60S, F40G, F40S, F20G and F20S). Each diet was randomly assigned to a triplicate group of fish (5.52 g/fish) and provided for eight weeks. Final body weight, weight gain and specific growth rate of fish fed F60G, F60S, F40G and F40S diets were comparable and significantly higher (p < 0.05) than other groups. The growth of fish fed SB-containing diets was significantly increased (p < 0.05) compared to fish fed the respective control diets. The feed efficiency and protein efficiency ratios were significantly higher (p < 0.05) in the fish fed all diets containing 60% and 40% FM compared to F20 and F20G groups. The F40S diet resulted in the highest feed utilization values. The F20S group exhibited significantly higher (p < 0.05) feed utilization than the F20 and F20G groups. Serum lysozyme activity was significantly higher (p < 0.05) in fish fed the GABA- and SB-containing diets compared to the F20 group. The F60S group exhibited the highest lysozyme activity which was significantly higher (p < 0.05) than in the F20 and F40 groups. Therefore, the growth performance, feed utilization and innate immunity of red seabream can be enhanced by dietary supplementation with GABA or SB in low-FM diets containing SPC. The FM level in the juvenile red seabream diet can be reduced to 40% with SPC and GABA or SB while maintaining performance better than a diet containing 60% FM.

High gain quasi-omnidirectional dipole array fed by radial power divider for millimeter-wave IoT sensing.

This article presents the design and implementation of a dipole array antenna based on a radial waveguide power divider for millimeter-wave IoT sensing applications. The dipole array and radial waveguide power divider techniques are used in tandem to achieve high gain with omnidirectional radiation properties. The proposed antenna is comprised of eight non-uniform array dipole structures, a circular radiating loop, and shorting vias. The one-to-eight power divider is created with the shorting vias to feed the circularly arranged eight non-uniform dipole arrays simultaneously. The proposed antenna is simulated and manufactured on Rogers-RO3003C substrate with a thickness of 8 mils. Both simulated and tested results confirm that the proposed method enables the antenna to offer a quasi-omnidirectional pattern with a high peak gain of 5.42 dBi. The antenna offers an impedance bandwidth (S11 < ‒ 10 dB) of more than 1 GHz ranging from 27.93 to 29.13 GHz. Moreover, by optimizing the parameters of the power divider network the proposed antenna can be tuned between a wide bandwidth range of 14.53 GHz as the designed dipole array offering the operating bandwidth from 25.56 to 40.09 GHz. Due to its comprehensive set of performance attributes, particularly for the quasi-omnidirectional radiation characteristics, the presented antenna is a viable candidate for the 5G millimeter wave wireless IoT sensing applications. Additionally, this work will accommodate other researchers to explore the proposed method for developing high-gain omnidirectional antennas for millimeter-wave applications.

Slow dynamic elasticity at short times.

It has been reported that slow dynamic nonlinear elastic relaxations, widely thought to proceed universally in proportion to the logarithm of time after cessation of mechanical conditioning, actually recover with a smaller slope at early times, with a time of transition that varies with the grain size of the material. This would constitute a heretofore unreported failure of the claimed universality, while suggesting application to nondestructive evaluation and structural health monitoring. Here, we present further observations at short times, in the single bead system, in cement paste, mortar, concrete, sandstone, and granite. Within the limits imposed by finite-duration ring-down such that the effective instant of conditioning cessation is imprecise, and the corresponding ambiguity as to the time at which relaxation begins, we find no reliable sign of such a transition, even in samples of large grain-size mortar and concrete similar to those described elsewhere as having clear and late cutoffs.

Ferroelectric Stochasticity in 2D CuInP2S6 and Its Application for True Random Number Generator.

True random number generators (TRNGs), which create cryptographically secure random bitstreams, hold great promise in addressing security concerns regarding hardware, communication, and authentication in the Internet of Things (IoT) realm. Recently, TRNGs based on nanoscale materials have gained considerable attention for avoiding conventional and predictable hardware circuitry designs that can be vulnerable to machine learning (ML) attacks. In this article, a low-power and low-cost TRNG developed by exploiting stochastic ferroelectric polarization switching in 2D ferroelectric CuInP2S6 (CIPS)-based capacitive structures, is reported. The stochasticity arises from the probabilistic switching of independent electrical dipoles. The TRNG exhibits enhanced stochastic variability with near-ideal entropy, uniformity, uniqueness, Hamming distance, and independence from autocorrelation variations. Its unclonability is systematically examined using device-to-device variations. The generated cryptographic bitstreams pass the National Institute of Standards and Technology (NIST) randomness tests. This nanoscale CIPS-based TRNG is circuit-integrable and exhibits potential for hardware security in edge devices with advanced data encryption.

Population pharmacokinetic modeling of sufentanil in adult Korean patients undergoing cardiopulmonary bypass surgery.

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 µg loading dose and 40 µg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 µg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

Identifying factors related to delayed neck metastasis after surgical treatment in patients with oral squamous cell carcinoma.

BACKGROUND: General treatment of oral squamous cell carcinoma (OSCC) is surgical treatment with or without neck dissection. Although the incidence of delayed neck metastasis is rare, it may occur after the surgery and is known to be the most important factor in the prognosis. The purpose of is study is to evaluate the clinical and histopathological factors associated with delayed neck metastasis case among patients. METHODS: A total of 195 patients who underwent surgical treatment for OSCC from 2016 to 2022 were investigated. Among them, delayed neck metastasis (DNM) was analyzed. The criterion for delayed neck metastasis was a newly developed neck lesion after the primary operation without neck dissection in cN0 necks. To identify the correlation between prognostic factors and the incidence of delayed neck metastasis, χ2 analysis with phi correlation and Cramer's V test was performed. Cumulative survival rates (CRS) were compared between the groups with the incidence of DNM and without DNM. Also, the log rank test for CSR and Cox proportional hazard model was analyzed to estimate the significance of the CSR and confirm the correlations between prognostic factors and DNM. RESULT: Among 195 patients, 14 were discovered to have DNM. The primary tumor locations were the tongue (n = 5), floor of the mouth (n = 2), mandibular gingiva (n = 1), maxillary gingiva (n = 4), retromolartrigone (n = 1), and buccal mucosa (n = 2) each. The cases consisted of TNM stage I (n = 1), stage II (n = 3), stage III (n = 3), and stage IV (n = 8), respectively. The result of the χ2 analysis identified a correlation between positive neck (p = 0.01), depth of invasion (p = 0.09), radiation therapy (p = 0.003), and DNM. Groups without DNM showed better prognosis compared to groups with DNM. Regarding positive neck, depth of invasion, and radiation therapy, only depth of invasion showed significance in CSR analysis. CONCLUSION: DNM after surgical treatment of OSCC is a rare event, and few were found in a review of the literature. Also, many prognostic factors have been suggested but controversial. However, in our study, some prognostic factors have been identified to have a significant correlation with the incidence of DNM, and analysis of such factors provides important information predicting neck metastasis and the prognosis.

Clinical Efficacy and Safety of an Automatic Closed-Suction System in Mechanically Ventilated Patients with Pneumonia: A Multicenter, Prospective, Randomized, Non-Inferiority, Investigator-Initiated Trial.

Endotracheal suctioning is an essential but labor-intensive procedure, with the risk of serious complications. A brand new automatic closed-suction device was developed to alleviate the workload of healthcare providers and minimize those complications. We evaluated the clinical efficacy and safety of the automatic suction system in mechanically ventilated patients with pneumonia. In this multicenter, randomized, non-inferiority, investigator-initiated trial, mechanically ventilated patients with pneumonia were randomized to the automatic device (intervention) or conventional manual suctioning (control). The primary efficacy outcome was the change in the modified clinical pulmonary infection score (CPIS) in 3 days. Secondary outcomes were the frequency of additional suctioning and the amount of secretion. Safety outcomes included adverse events or complications. A total of 54 participants, less than the pre-determined number of 102, were enrolled. There was no significant difference in the change in the CPIS over 72 h (-0.13 ± 1.58 in the intervention group, -0.58 ± 1.18 in the control group, p = 0.866), but the non-inferiority margin was not satisfied. There were no significant differences in the secondary outcomes and safety outcomes, with a tendency for more patients with improved tracheal mucosal injury in the intervention group. The novel automatic closed-suction system showed comparable efficacy and safety compared with conventional manual suctioning in mechanically ventilated patients with pneumonia.

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Surface Crystal and Degradability of Shape Memory Scaffold Essentialize Osteochondral Regeneration.

The minimally invasive deployment of scaffolds is a key safety factor for the regeneration of cartilage and bone defects. Osteogenesis relies primarily on cell-matrix interactions, whereas chondrogenesis relies on cell-cell aggregation. Bone matrix expansion requires osteoconductive scaffold degradation. However, chondrogenic cell aggregation is promoted on the repellent scaffold surface, and minimal scaffold degradation supports the avascular nature of cartilage regeneration. Here, a material satisfying these requirements for osteochondral regeneration is developed by integrating osteoconductive hydroxyapatite (HAp) with a chondroconductive shape memory polymer (SMP). The shape memory function-derived fixity and recovery of the scaffold enabled minimally invasive deployment and expansion to fill irregular defects. The crystalline phases on the SMP surface inhibited cell aggregation by suppressing water penetration and subsequent protein adsorption. However, HAp conjugation SMP (H-SMP) enhanced surface roughness and consequent cell-matrix interactions by limiting cell aggregation using crystal peaks. After mouse subcutaneous implantation, hydrolytic H-SMP accelerated scaffold degradation compared to that by the minimal degradation observed for SMP alone for two months. H-SMP and SMP are found to promote osteogenesis and chondrogenesis, respectively, in vitro and in vivo, including the regeneration of rat osteochondral defects using the binary scaffold form, suggesting that this material is promising for osteochondral regeneration.

Analgesic effects of ultrasound-guided preoperative posterior Quadratus Lumborum block in laparoscopic hepatectomy: A prospective double-blinded randomized controlled trial.

STUDY OBJECTIVE: To determine if single-injection bilateral posterior quadratus lumborum block (QLB) with ropivacaine would improve postoperative analgesia in the first 24 h after laparoscopic hepatectomy, compared with 0.9% saline. DESIGN: Prospective, double blinded, randomized controlled trial. SETTING: A single tertiary care center from November 2021 and January 2023. PATIENTS: A total of 94 patients scheduled to undergo laparoscopic hepatectomy due to hepatocellular carcinoma. INTERVENTIONS: Ninety-four patients were randomized into a QLB group (receiving 20 mL of 0.375% ropivacaine on each side, 150 mg in total) or a control group (receiving 20 mL of 0.9% saline on each side). MEASUREMENTS: The primary outcome was the cumulative opioid consumption during the initial 24-h post-surgery. Secondary outcomes included pain scores and intraoperative and recovery parameters. MAIN RESULTS: The mean cumulative opioid consumption during the initial 24-h post-surgery was 30.8 ± 22.4 mg in the QLB group (n = 46) and 34.0 ± 19.4 mg in the control group (n = 46, mean differences: -3.3 mg, 95% confidence interval, -11.9 to 5.4, p = 0.457). The mean resting pain score at 1 h post-surgery was significantly lower in the QLB group than in the control group (5 [4-6.25] vs. 7 [4.75-8], p = 0.035). No significant intergroup differences were observed in the resting or coughing pain scores at other time points or in other secondary outcomes. CONCLUSIONS: Preoperative bilateral posterior QLB did not reduce cumulative opioid consumption during the first 24 h after laparoscopic hepatectomy.

Does coronavirus disease 2019 history alone increase the risk of postoperative pulmonary complications after surgery? Prospective observational study using serology assessment.

BACKGROUND: Concern exists about the increasing risk of postoperative pulmonary complications in patients with a history of coronavirus disease 2019 (COVID-19). OBJECTIVE: We conducted a prospective observational study that compared the incidence of postoperative pulmonary complications in patients with and without a history of COVID-19. METHODS: From August 2022 to November 2022, 244 adult patients undergoing major non-cardiac surgery were enrolled and allocated either to history or no history of COVID-19 groups. For patients without a history of confirming COVID-19 diagnosis, we tested immunoglobulin G to nucleocapsid antigen of SARS-CoV-2 for serology assessment to identify undetected infection. We compared the incidence of postoperative pulmonary complications, defined as a composite of atelectasis, pleural effusion, pulmonary edema, pneumonia, aspiration pneumonitis, and the need for additional oxygen therapy according to a COVID-19 history. RESULTS: After excluding 44 patients without a COVID-19 history who were detected as seropositive, 200 patients were finally enrolled in this study, 100 in each group. All subjects with a COVID-19 history experienced no or mild symptoms during infection. The risk of postoperative pulmonary complications was not significantly different between the groups according to the history of COVID-19 (24.0% vs. 26.0%; odds ratio, 0.99; 95% confidence interval, 0.71-1.37; P-value, 0.92). The incidence of postoperative pulmonary complications was also similar (27.3%) in excluded patients owing to being seropositive. CONCLUSION: Our study showed patients with a history of no or mild symptomatic COVID-19 did not show an increased risk of PPCs compared to those without a COVID-19 history. Additional precautions may not be needed to prevent PPCs in those patients.

W-DRAG: A joint framework of WGAN with data random augmentation optimized for generative networks for bone marrow edema detection in dual energy CT.

Dual-energy computed tomography (CT) is an excellent substitute for identifying bone marrow edema in magnetic resonance imaging. However, it is rarely used in practice owing to its low contrast. To overcome this problem, we constructed a framework based on deep learning techniques to screen for diseases using axial bone images and to identify the local positions of bone lesions. To address the limited availability of labeled samples, we developed a new generative adversarial network (GAN) that extends expressions beyond conventional augmentation (CA) methods based on geometric transformations. We theoretically and experimentally determined that combining the concepts of data augmentation optimized for GAN training (DAG) and Wasserstein GAN yields a considerably stable generation of synthetic images and effectively aligns their distribution with that of real images, thereby achieving a high degree of similarity. The classification model was trained using real and synthetic samples. Consequently, the GAN technique used in the diagnostic test had an improved F1 score of approximately 7.8% compared with CA. The final F1 score was 80.24%, and the recall and precision were 84.3% and 88.7%, respectively. The results obtained using the augmented samples outperformed those obtained using pure real samples without augmentation. In addition, we adopted explainable AI techniques that leverage a class activation map (CAM) and principal component analysis to facilitate visual analysis of the network's results. The framework was designed to suggest an attention map and scattering plot to visually explain the disease predictions of the network.

Effect of high-dose intravenous iron injection on hepatic function in a rat model of cirrhosis.

OBJECTIVE: To investigate the hepatic effects of high-dose intravenous (IV) iron, including those on liver function and the degree of fibrosis, in a rat model of cirrhosis. METHODS: We evenly allocated 25 Sprague-Dawley rats into five groups: normal rats (control group), cirrhotic rats receiving IV normal saline (liver cirrhosis [LC] group), and cirrhotic rats receiving 20, 40, or 80 mg/kg IV ferric carboxymaltose (LC-iron20, LC-iron40, and LC-iron80 group, respectively). Biochemical parameters were compared at 0, 7, 14, 21, and 28 days. The degrees of hepatic fibrosis and iron deposition were evaluated. Inflammatory and oxidative stress markers were also compared. RESULTS: There were no significant differences in the 28-day serum alanine aminotransferase levels among the LC-iron20, LC-iron40, and LC-iron80 groups (69 ± 7, 1003 ± 127, 1064 ± 309, 919 ± 346, and 820 ± 195 IU/L in the control, LC, LC-iron20, LC-iron40, and LC-iron80 groups, respectively). Hepatic iron accumulation increased in a dose-dependent manner, but the degree of hepatic fibrosis was comparable among the groups. The inflammatory and oxidative stress marker levels did not differ significantly according to the IV iron dose. CONCLUSIONS: Administration of IV iron at various high doses appears safe in our rat model of cirrhosis.

Biofabrication of 3D adipose tissue via assembly of composite stem cell spheroids containing adipo-inductive dual-signal delivery nanofibers.

Reconstruction of large 3D tissues based on assembly of micro-sized multi-cellular spheroids has gained attention in tissue engineering. However, formation of 3D adipose tissue from spheroids has been challenging due to the limited adhesion capability and restricted cell mobility of adipocytes in culture media. In this study, we addressed this problem by developing adipo-inductive nanofibers enabling dual delivery of indomethacin and insulin. These nanofibers were introduced into composite spheroids comprising human adipose-derived stem cells (hADSCs). This approach led to a significant enhancement in the formation of uniform lipid droplets, as evidenced by the significantly increased Oil red O-stained area in spheroids incorporating indomethacin and insulin dual delivery nanofibers (56.9 ± 4.6%) compared to the control (15.6 ± 3.5%) with significantly greater gene expression associated with adipogenesis (C/EBPA, PPARG, FABP4, and adiponectin) of hADSCs. Furthermore, we investigated the influence of culture media on the migration and merging of spheroids and observed significant decrease in migration and merging of spheroids in adipogenic differentiation media. Conversely, the presence of adipo-inductive nanofibers promoted spheroid fusion, allowing the formation of macroscopic 3D adipose tissue in the absence of adipogenic supplements while facilitating homogeneous adipogenesis of hADSCs. The approach described here holds promise for the generation of 3D adipose tissue constructs by scaffold-free assembly of stem cell spheroids with potential applications in clinical and organ models.

Dynamic injectable tissue adhesives with strong adhesion and rapid self-healing for regeneration of large muscle injury.

Wounds often necessitate the use of instructive biomaterials to facilitate effective healing. Yet, consistently filling the wound and retaining the material in place presents notable challenges. Here, we develop a new class of injectable tissue adhesives by leveraging the dynamic crosslinking chemistry of Schiff base reactions. These adhesives demonstrate outstanding mechanical properties, especially in regard to stretchability and self-healing capacity, and biodegradability. Furthermore, they also form robust adhesion to biological tissues. Their therapeutic potential was evaluated in a rodent model of volumetric muscle loss (VML). Ultrasound imaging confirmed that the adhesives remained within the wound site, effectively filled the void, and degraded at a rate comparable to the healing process. Histological analysis indicated that the adhesives facilitated muscle fiber and blood vessel formation, and induced anti-inflammatory macrophages. Notably, the injured muscles of mice treated with the adhesives displayed increased weight and higher force generation than the control groups. This approach to adhesive design paves the way for the next generation of medical adhesives in tissue repair.