Cell-based tissue engineered flexor tendon allograft: A canine in vivo study.

This study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue-engineered allograft (Eng-allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re-ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng-allograft, which had been revitalized with autologous bone marrow-derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd-SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng-allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng-allograft group was significantly lower than that of the autograft group with higher graft rupture at the host-graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd-SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts.

Radioresponsive Delivery of Toll-like Receptor 7/8 Agonist for Tumor Radioimmunotherapy Enabled by Core-Cross-Linked Diselenide Nanoparticles.

The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local radiotherapy in vivo remains a significant challenge in order to minimize off-target toxicity, reduce radiation-induced immunosuppression, and maximize synergistic radioimmunotherapy efficacy. In this study, we report the development of core-cross-linked diselenide nanoparticles (dSeNPs) as carriers for radioresponsive delivery of the toll-like receptors 7/8 agonist through systemic administration to achieve combined radioimmunotherapy of tumors. The dSeNPs were fabricated from a ring-opening reaction between 2,2'-diselenidebis(ethylamine) and the ethylene oxide group of an amphiphilic block copolymer. The diselenide bonds were naturally protected in the core of the self-assembled nanostructure, making the dSeNPs extremely stable in the physiological environment. However, they exhibited dose- and time-dependent radiosensitivity, meaning that X-ray irradiation could spatiotemporally control the release of R848 from the dSeNPs. In vivo results showed that local radioresponsive R848 release from dSeNPs greatly improved the synergistic efficacy of combined radioimmunotherapy via the programmed cooperative immune system activation process. This process included macrophage polarization, dendritic cell maturation, and cytotoxic T cell activation. Our findings suggest that core-cross-linked dSeNPs are a promising platform for combined radiotherapy due to their spatiotemporal controllability of radioresponsive drug release.

Optimizing coagulant dosage using deep learning models with large-scale data.

Water treatment plants are facing challenges that necessitate transition to automated processes using advanced technologies. This study introduces a novel approach to optimize coagulant dosage in water treatment processes by employing a deep learning model. The study utilized minute-by-minute data monitored in real time over a span of five years, marking the first attempt in drinking water process modeling to leverage such a comprehensive dataset. The deep learning model integrates a one-dimensional convolutional neural network (Conv1D) and gated recurrent unit (GRU) to effectively extract features and model complex time-series data. Initially, the model predicted coagulant dosage and sedimentation basin turbidity, validated against a physicochemical model. Subsequently, the model optimized coagulant dosage in two ways: 1) maintaining sedimentation basin turbidity below the 1.0 NTU guideline, and 2) analyzing changes in sedimentation basin turbidity resulting from reduced coagulant dosage (5-20%). The findings of the study highlight the effectiveness of the deep learning model in optimizing coagulant dosage with substantial reductions in coagulant dosage (approximately 22% reduction and 21 million KRW/year). The results demonstrate the potential of deep learning models in enhancing the efficiency and cost-effectiveness of water treatment processes, ultimately facilitating process automation.

District-scale surface temperatures generated from high-resolution longitudinal thermal infrared images.

This paper describes a dataset collected by infrared thermography, a non-contact, non-intrusive technique to acquire data and analyze the built environment in various aspects. While most studies focus on the city and building scales, an observatory installed on a rooftop provides high temporal and spatial resolution observations with dynamic interactions on the district scale. The rooftop infrared thermography observatory with a multi-modal platform capable of assessing a wide range of dynamic processes in urban systems was deployed in Singapore. It was placed on the top of two buildings that overlook the outdoor context of the National University of Singapore campus. The platform collects remote sensing data from tropical areas on a temporal scale, allowing users to determine the temperature trend of individual features such as buildings, roads, and vegetation. The dataset includes 1,365,921 thermal images collected on average at approximately 10-second intervals from two locations during ten months.

Targeting STING Activation by Antigen-Inspired MnO2 Nanovaccines Optimizes Tumor Radiotherapy.

Immune checkpoint blockers therapy can improve the radiotherapy-induced immunosuppression by enhancing interferon secretion, but still suffer from low clinical response rate and potential adverse effects. Mn2+ -mediated activation of interferon gene stimulator (STING) pathway provides an alternative for combination radioimmunotherapy of tumor. However, it is still a challenge for specific delivery of Mn2+ to innate immune cells and targeting activation of STING pathway. Herein, a novel antigen-inspired MnO2 nanovaccine is fabricated as Mn2+ source and functionalized with mannose, enabling it to target innate immune cells to activate the STING pathway. Meanwhile, the release of Mn2+ in the intracellular lysosomes can also be for magnetic resonance imaging to monitor the dynamic distribution of nanovaccines in vivo. The targeting activation of STING pathway can enhance radiotherapy-induced immune responses for inhibiting local and distant tumors, and resisting tumor metastasis. The study proposes an optimized radiotherapy strategy through targeting STING activation of antigen-inspired nanovaccines.

Chemotherapy-Sensitized In Situ Vaccination for Malignant Osteosarcoma Enabled by Bioinspired Calcium Phosphonate Nanoagents.

How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously eliciting in situ antitumor immunity. However, targeted chemoimmunotherapy lacks a reliable delivery system. To address this issue, we herein developed a bioinspired calcium phosphonate nanoagent that was synthesized by chemical reactions between Ca2+ and phosphonate residue from zoledronic acid using bovine serum albumin as a scaffold. In addition, methotrexate combination with a phosphorothioate CpG immunomodulator was also loaded for pH-responsive delivery to enable synergistic chemoimmunotherapy of osteosarcoma. The calcium phosphonate nanoagents were found to effectively accumulate in osteosarcoma for nearly 1 week, which is favorable for exerting the vaccination effects in situ by maturing dendritic cells and priming CD8+ T cells to suppress the osteosarcoma progression and pulmonary metastasis through controlled release of the three loaded agents in the acidic tumor microenvironment. The current study may thus offer a reliable delivery platform for achieving targeted chemotherapy-induced in situ antitumor immunity.

Coagulant dosage determination using deep learning-based graph attention multivariate time series forecasting model.

Determination of coagulant dosage in water treatment is a time-consuming process involving nonlinear data relationships and numerous factors. This study provides a deep learning approach to determine coagulant dosage and/or the settled water turbidity using long-term data between 2011 and 2021 to include the effect of various weather conditions. A graph attention multivariate time series forecasting (GAMTF) model was developed to determine coagulant dosage and was compared with conventional machine learning and deep learning models. The GAMTF model (R2 = 0.94, RMSE = 3.55) outperformed the other models (R2 = 0.63 - 0.89, RMSE = 4.80 - 38.98), and successfully predicted both coagulant dosage and settled water turbidity simultaneously. The GAMTF model improved the prediction accuracy by considering the hidden interrelationships between features and the past states of features. The results demonstrate the first successful application of multivariate time series deep learning model, especially, a state-of-the-art graph attention-based model, using long-term data for decision-support systems in water treatment processes.

Steroid-Induced Osteonecrosis of the Femoral Head: Novel Insight Into the Roles of Bone Endothelial Cells in Pathogenesis and Treatment.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a disease characterized by the collapse of the femoral head. SONFH occurs due to the overuse of glucocorticoids (GCs) in patients with immune-related diseases. Among various pathogenesis proposed, the mechanism related to impaired blood vessels is gradually becoming the most convincing hypothesis. Bone endothelial cells including bone microvascular endothelial cells (BMECs) and endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular homeostasis. Therefore, bone endothelial cells are key regulators in the occurrence and progression of SONFH. Impaired angiogenesis, abnormal apoptosis, thrombosis and fat embolism caused by the dysfunctions of bone endothelial cells are considered to be the pathogenesis of SONFH. In addition, even with high disability rates, SONFH lacks effective therapeutic approach. Icariin (ICA, a flavonoid extracted from Epimedii Herba), pravastatin, and VO-OHpic (a potent inhibitor of PTEN) are candidate reagents to prevent and treat SONFH through improving above pathological processes. However, these reagents are still in the preclinical stage and will not be widely used temporarily. In this case, bone tissue engineering represented by co-transplantation of bone endothelial cells and bone marrow mesenchymal stem cells (BMSCs) may be another feasible therapeutic strategy.

Exosomes From M2 Macrophage Promote Peritendinous Fibrosis Posterior Tendon Injury via the MiR-15b-5p/FGF-1/7/9 Pathway by Delivery of circRNA-Ep400.

Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

Biomechanical evaluation of a novel double rip-stop technique with medial row knots for rotator cuff repair: an in vitro study.

AIMS: Many biomechanical studies have shown that the weakest biomechanical point of a rotator cuff repair is the suture-tendon interface at the medial row. We developed a novel double rip-stop (DRS) technique to enhance the strength at the medial row for rotator cuff repair. The objective of this study was to evaluate the biomechanical properties of the DRS technique with the conventional suture-bridge (SB) technique and to evaluate the biomechanical performance of the DRS technique with medial row knots. METHODS: A total of 24 fresh-frozen porcine shoulders were used. The infraspinatus tendons were sharply dissected and randomly repaired by one of three techniques: SB repair (SB group), DRS repair (DRS group), and DRS with medial row knots repair (DRSK group). Specimens were tested to failure. In addition, 3 mm gap formation was measured and ultimate failure load, stiffness, and failure modes were recorded. RESULTS: The mean load to create a 3 mm gap formation in the DRSK and DRS groups was significantly higher than in the SB group. The DRSK group had the highest load to failure with a mean ultimate failure load of 395.0 N (SD 56.8) compared to the SB and DRS groups, which recorded 147.1 N (SD 34.3) and 285.9 N (SD 89.8), respectively (p < 0.001 for both). The DRS group showed a significantly higher mean failure load than the SB group (p = 0.006). Both the DRS and DRSK groups showed significantly higher mean stiffness than the SB group. CONCLUSION: The biomechanical properties of the DRS technique were significantly improved compared to the SB technique. The DRS technique with medial row knots showed superior biomechanical performance than the DRS technique alone.

In Vivo Photoacoustic/Single-Photon Emission Computed Tomography Imaging for Dynamic Monitoring of Aggregation-Enhanced Photothermal Nanoagents.

Emerging nanomedical strategy is to construct a nanoagent that affords not only diagnostic and therapeutic functions but also imaging-guided treatment. It is crucial to understand the in vivo biological processes of nanoagents for improving theranostic function and biosafety. Herein, we report a multimodal photoacoustic/single-photon emission computed tomography (SPECT) imaging technique to dynamically monitor the in vivo behaviors of nanoagents. Near-infrared cypate-induced silk fibroin nanoassembly was chosen as the nanoagent object due to their promise in biocompatibility and aggregation-enhanced photothermal effect. This unique effect makes the nanoagents useful for the integration of photoacoustic imaging and photothermal therapy. Moreover, the nanoagents are also labeled with the radionuclides (99mTc) to render SPECT imaging. Multimodal photoacoustic/SPECT imaging provides real time, noninvasive, sensitive, and whole-body 3D information about nanoagents' distribution in vivo. These results highlight the significance of visualizing the in vivo behaviors of nanoagents and locating the tumor in vivo, substantially benefiting the better treatment planning.