Rapamycin facilitates healing of the tendon-bone interface in an aging rat model of chronic rotator cuff injury.

BACKGROUND: Tendon-bone interface (TBI) healing in chronic rotator cuff injury (CRCI) in older individuals is a common clinical challenge due to cellular senescence, as well as decreased tissue repair and regeneration. Many studies have demonstrated the antiaging, improved tissue repair, and bone regeneration properties of rapamycin (RPM) in multiple age-related diseases. This study aimed to explore the effects of RPM on TBI healing after CRCI in an aging rat model. METHODS: A CRCI model was established in 60 Sprague-Dawley rats (24 months old). Rats were then randomly allocated into the control, 0.1 µg RPM, and 1 µg RPM groups. At 4 and 8 weeks postreconstructive surgery, the supraspinatus tendon-humerus complexes were harvested for biomechanical, microimaging, histological, and immunohistochemical evaluations. RESULTS: Biomechanical testing results demonstrated that the failure load, ultimate strength, and stiffness of the 2 RPM groups were significantly higher than those of the control group at 4 and 8 weeks postoperatively. Microradiographically, both RPM groups had significantly higher values of bone mineral density and the ratio of trabecular bone volume to total volume than controls at each time point. Moreover, the RPM groups had higher histological scores and showed better regenerated TBI, characterized by better organizational tissue, more fibrocartilage cells, and more bone formation. Immunohistochemical evaluations showed that RUNX2-, SOX9-, and SCX-positive cells were significantly more in the 2 RPM groups than in the controls at each time point. CONCLUSIONS: RPM may effectively enhance CRCI healing after reconstruction by facilitating osteogenesis, tenogenesis, and fibrocartilage reformation at the TBI, as well as improving biomechanical properties.

1D Gradient-Weighted Class Activation Mapping, Visualizing Decision Process of Convolutional Neural Network-Based Models in Spectroscopy Analysis.

Being characterized by the self-adaption and high accuracy, the deep learning-based models have been widely applied in the 1D spectroscopy-related field. However, the "black-box" operation and "end-to-end" working style of the deep learning normally bring the low interpretability, where a reliable visualization is highly demanded. Although there are some well-developed visualization methods, such as Class Activation Mapping (CAM) and Gradient-weighted Class Activation Mapping (Grad-CAM), for the 2D image data, they cannot correctly reflect the weights of the model when being applied to the 1D spectral data, where the importance of position information is not considered. Here, aiming at the visualization of Convolutional Neural Network-based models toward the qualitative and quantitative analysis of 1D spectroscopy, we developed a novel visualization algorithm (1D Grad-CAM) to more accurately display the decision-making process of the CNN-based models. Different from the classical Grad-CAM, with the removal of the gradient averaging (GAP) and the ReLU operations, a significantly improved correlation between the gradient and the spectral location and a more comprehensive spectral feature capture were realized for 1D Grad-CAM. Furthermore, the introduction of difference (purity or linearity) and feature contribute in the CNN output in 1D Grad-CAM achieved a reliable evaluation of the qualitative accuracy and quantitative precision of CNN-based models. Facing the qualitative and adulteration quantitative analysis of vegetable oils by the combination of Raman spectroscopy and ResNet, the visualization by 1D Grad-CAM well reflected the origin of the high accuracy and precision brought by ResNet. In general, 1D Grad-CAM provides a clear vision about the judgment criterion of CNN and paves the way for CNN to a broad application in the field of 1D spectroscopy.

Gliotoxin, a natural product with ferroptosis inducing properties.

As one of the mycotoxins produced by Aspergillus fumigatus, gliotoxin has a variety of pharmacological effects, such as anti-tumor, antibacterial, immunosuppressive. Antitumor drugs induce tumor cell death in several forms, including apoptosis, autophagy, necrosis and ferroptosis. Ferroptosis is a recently identified unique form of programmed cell death characterized by iron-dependent accumulation of lethal lipid peroxides, which induces cell death. A large amount of preclinical evidence suggests that ferroptosis inducers may enhance the sensitivity of chemotherapy and the induction of ferroptosis may be an effective therapeutic strategy to prevent acquired drug resistance. In our study, gliotoxin was characterized as a ferroptosis inducer and showed strong anti-tumor activity with IC50 of 0.24 µM and 0.45 µM in H1975 and MCF-7 cells at 72 h, respectively. Gliotoxin may provide a new natural template for the designing of ferroptosis inducers.

6-Heterocyclic carboxylic ester derivatives of gliotoxin lead to LSD1 inhibitors in gastric cancer cells.

Gliotoxin is a representative compound of the epipolythiodioxopiperazine (ETP) class of fungal metabolites. Histone Lysine Specific Demethylase 1 (LSD1) is highly expressed in a variety of cancers. Herein, a series of 6-heterocyclic carboxylic ester derivatives of gliotoxin was designed and synthesized as new LSD1 inhibitors and their biological evaluations in human gastric MGC-803 and HGC-27 cells were carried out. All of the derivatives effectively suppressed the enzymatic activities of LSD1. In particular, compound 4e exhibited excellent LSD1 inhibition with IC50 = 62.40 nM, as well as anti-proliferation against MGC-803 and HGC-27 cells with IC50 values of 0.31 µM and 0.29 µM, respectively. 4e also had a remarkable capacity to inhibit the colony formation, suppress migration and induce the apoptosis of these two cancer cell lines. In sum, our findings identified and characterized the 6-heterocyclic carboxylic ester derivatives of gliotoxin as potent and cellular active LSD1 inhibitors, which may provide a novel chemotype of LSD1 inhibitors for gastric cancer treatment.

Analysis of Therapeutic Effect and Influencing Factors of Ultrasound-Guided Radiofrequency Ablation in the Treatment of Papillary Thyroid Microcarcinoma.

OBJECTIVES: The current study sought to explore the effects of ultrasound (US)-guided radiofrequency ablation (RFA) on papillary thyroid microcarcinoma (PTMC) and influencing factors. METHODS: PTMC patients were assigned to observation (US-guided RFA) and control (surgical operation) groups. A series of operation-related indexes (operation time, intraoperative bleeding, wound closure time, hospital stay, and expenses), visual analogue scale score, lesion size, and thyroid function-related indexes (thyroid-stimulating hormone [TSH], free triiodothyronine*** [FT3], free thyroxine [FT4]), inflammatory factors, and thyroglobulin antibody (TgAb) were assessed and compared. After a 6-month follow-up period, the complications and recurrence were recorded, in addition to analyses of postoperative recurrence cumulative incidence and evaluation of recurrence risk factors. RESULTS: Operation-related indexes of the observation group were relatively decreased compared with the control group. In addition, the lesion volume in the observation group was lower compared to that in the control group at the 6th month after operation, whereas the volume reduction rate was higher. There were no significant differences in regard to thyroid function-related indexes in the observation group before/after operation. After operation, serum TSH levels and inflammatory factors, and TgAb levels were all diminished, while the FT3 and FT4 levels were both elevated in the observation group relative to the control group, and postoperative recurrence cumulative incidence was lower in the observation group. TSH and TgAb were established as the independent risk factors for recurrence after RFA in PTMC patients. CONCLUSIONS: Our findings highlighted that US-guided RFA exhibits better efficacy, safety, and postoperative recovery and lower recurrence risk for PTMC.

Nanolayer-Constructed TiO(OH)2 Microstructures for the Efficiently Selective Removal of Cationic Dyes via an Electrostatic Interaction and Adsorption Mechanism.

Efficient removal of organic dyes from contaminated water has become a great challenge and urgent work due to increasingly serious environmental problems. Here, we have for the first time prepared nanolayer-constructed TiO(OH)2 microstructures which can present negative charge by deprotonation of the hydroxyl group to efficiently and selectively remove cationic dyes from aqueous solution through electrostatic interaction and an attraction mechanism. The nanolayer-constructed TiO(OH)2 microstructures achieve a high adsorption capacity of 257 mg g-1 for methylene blue (MB). The adsorption kinetics, thermodynamics, and isotherms of MB over the TiO(OH)2 microstructures have been studied systemically. The experimental measurements and corresponding analyses demonstrate that the adsorption process of MB on TiO(OH)2 microstructures follows a kinetic model of pseudo-second-order adsorption, agrees well with the Langmuir isotherm mode, and is a spontaneous and exothermic physisorption. Fourier transform infrared (FT-IR) spectra confirm that the prepared TiO(OH)2 microstructures possess hydroxyl group which can deprotonate to present negative charge in solution. Further experimental studies evidently demonstrate that the TiO(OH)2 microstructures also can remove other cationic dyes with positive charge such as basic yellow 1, basic green 4, and crystal violet but cannot adsorb anionic dye of methyl orange (MO) with negative charge in aqueous solution. The measurements for FT-IR spectra and the adsorption of cationic and anionic dyes evidently reveal that the adsorption of cationic dyes over the TiO(OH)2 microstructures is achieved by the electrostatic interaction and attraction between TiO(OH)2 and the dye. This work opens a strategy for the design of new absorbents to efficiently remove organic dyes from aqueous solution through an electrostatic attraction-driven adsorption process.

Treatment of chronic lateral ankle instability by double-band anatomical reconstruction of the anterior talofibular ligament's fibular enthesis. / è·è “å‰éŸ§å¸¦è “éª¨æ­¢ç‚¹åŒæŸè§£å‰–é‡å»ºæ²»ç–—æ ¢æ€§è¸å ³èŠ‚å¤–ä¾§ä¸ç¨³.

OBJECTIVES: Anterior talofibular ligament (ATFL) injury is one of the most common injuries in sports medicine, resulting in chronic lateral ankle instability (CLAI). The patients' daily life may be seriously affected by ankle osteoarthritis and other irreversible damages, if the ATFL injury is not treated in time and drags on. Patients with ATFL injury who show no significant recovery after 3-6 months of conservative treatment should consider surgical treatment as soon as possible to restore ankle stability and function. This study aims to investigate the effect of double-bands anatomical reconstruction of the ATFL's fibular enthesis for the treatment of CLAI. METHODS: A retrospective review was conducted on 67 patients diagnosed with CLAI in the Department of Sports Medicine, Xiangya Hospital, Central South University from January 2015 to January 2018, including 42 males and 25 females, aged from 17 to 41 years old, with disease course of (12.6±3.2) months. Of the 67 patients, 29 left ankles and 38 right ankles were included in this study. Patients suffered from repeated sprains which leaded to pain, swelling and obvious ankle relaxation. There were obvious tenderness at the ATFL insertion and the calcaneal fibular ligament insertion. Both the anterior ankle drawer test and the varus stress test were positive. Other ankle disorders were excluded by X-ray. Preoperative color Doppler ultrasonography and magnetic resonance examination were performed to observe ATFL injury. All the patients had surgical indications and no obvious contraindications, and they were treated with arthroscopic debridement and double-bundle anatomical reconstruction of the AFTL's fibular enthesis under anesthesia. Postoperative routine nursing and standardized rehabilitation exercise were recommended. Outpatient follow-up was conducted at 3, 6, 12, and 24 months postoperatively. American Orthopaedic Foot and Ankle Society (AOFAS) scores, Karlsson Ankle Functional (KAF) score, and the Japanese Society for Surgery of the Foot (JSSF) scale were used to evaluate the clinical outcomes. RESULTS: Intraoperative arthroscopic examination of 67 patients showed inflammatory synovial hyperplasia in 52 cases (77.6%), obvious osteophyte hyperplasia in 12 cases (17.9%), talus osteochondral injury of grade II-III in 23 cases (34.3%), and cartilage injury of grade IV in 5 cases (7.5%). All operations were carried out successfully, and both the anterior ankle drawer test and the varus stress test were negative under anesthesia after surgery. The anchors were in good position. Among them, 3 patients (4.5%) got temporary superficial peroneal nerve palsy and skin numbness at ankle joint after surgery, which gradually recovered within 2 weeks. There were no serious perioperative complications such as infection and suppurative arthritis. Postoperative follow-up was conducted for 12-24 (15.64±3.17) months. At the last follow-up, all patients were walking normally. Most patients had no pain or occasionally mild pain. Ankle function and motion were restored without re-instability. Sixty-four patients (95.5%) worked and exercised as before the surgery. Standing X-ray examination indicated normal joint space without stenosis, and the internal fixation was in good position. Postoperative AOFAS scores (94.78±6.37) were significantly better than the preoperative scores (64.17±12.43, P<0.01). Besides, the KAF scores and the JSSF ankle/hindfoot scale before surgery were significantly increased (KAF: 91.04±11.36 vs 59.74±13.63, P<0.01; JSSF: 95.32±10.21 vs 66.92±14.38, P<0.01). CONCLUSIONS: Arthroscopic debridement and double-bands anatomical reconstruction of the ATFL's fibular enthesis for the treatment of CLAI gains beneficial short-term effects for its minimal invasion and quick recovery.

Periosteum progenitors could stimulate bone regeneration in aged murine bone defect model.

Periosteal stem cells are critical for bone regeneration, while the numbers will decrease with age. This study focused on whether Prx1+ cell, a kind of periosteal stem cell, could stimulate bone regeneration in aged mice. Four weeks and 12 months old Prx1CreER-GFP; Rosa26tdTomato mice were used to reveal the degree of Prx1+ cells participating in the femoral fracture healing procedure. One week, 8 weeks, 12 and 24 months old Prx1CreER-GFP mice were used to analyse the real-time distribution of Prx1+ cells. Twelve months old C57BL/6 male mice (n = 96) were used to create the bone defect model and, respectively, received hydrogel, hydrogel with Prx1- mesenchymal stem cells and hydrogel with Prx1+ cells. H&E staining, Synchrotron radiation-microcomputed tomography and mechanical test were used to analyse the healing results. The results showed that tdTomato+ cells were involved in bone regeneration, especially in young mice. At the same time, GFP+ cells decreased significantly with age. The Prx1+ cells group could significantly improve bone regeneration in the murine bone defect model via directly differentiating into osteoblasts and had better osteogenic differentiation ability than Prx1- mesenchymal stem cells. Our finding revealed that the quantity of Prx1+ cells might account for decreased bone regeneration ability in aged mice, and transplantation of Prx1+ cells could improve bone regeneration at the bone defect site.

Three-dimensional characterization of the microstructure in rabbit patella-patellar tendon interface using propagation phase-contrast synchrotron radiation microtomography.

Understanding the three-dimensional ultrastructure morphology of tendon-to-bone interface may allow the development of effective therapeutic interventions for enhanced interface healing. This study aims to assess the feasibility of propagation phase-contrast synchrotron radiation microtomography (PPC-SRµCT) for three-dimensional characterization of the microstructure in rabbit patella-patellar tendon interface (PPTI). Based on phase retrieval for PPC-SRµCT imaging, this technique is capable of visualizing the three-dimensional internal architecture of PPTI at a cellular high spatial resolution including bone and tendon, especially the chondrocytes lacuna at the fibrocartilage layer. The features on the PPC-SRµCT image of the PPTI are similar to those of a histological section using Safranin-O staining/fast green staining. The three-dimensional microstructure in the rabbit patella-patellar tendon interface and the spatial distributions of the chondrocytes lacuna and their quantification volumetric data are displayed. Furthermore, a color-coding map differentiating cell lacuna in terms of connecting beads is presented after the chondrocytes cell lacuna was extracted. This provides a more in-depth insight into the microstructure of the PPTI on a new scale, particularly the cell lacuna arrangement at the fibrocartilage layer. PPC-SRµCT techniques provide important complementary information to the conventional histological method for characterizing the microstructure of the PPTI, and may facilitate in investigations of the repair mechanism of the PPTI after injury and in evaluating the efficacy of a different therapy.

Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing.

Tendon-bone interface injuries pose a significant challenge in tissue regeneration, necessitating innovative approaches. Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries. In this study, we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions (Mg2+). We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles (Mg-PC) through a self-assembly process and integrated them into a two-component hydrogel. The hydrogel was composed of dopamine-modified hyaluronic acid (Dop-HA) and F127. To ensure controlled release and mitigate the "burst release" effect of Mg2+, we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel. This crosslinking strategy extended the release window of Mg2+ concentrations for up to 56 days. The resulting hydrogel (Mg-PC@Dop-HA/F127) exhibited favorable properties, including injectability, thermosensitivity and shape adaptability, making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites. Furthermore, the hydrogel sustained the release of Mg2+ and Procyanidins, which attracted mesenchymal stem and progenitor cells, alleviated inflammation, and promoted macrophage polarization towards the M2 phenotype. Additionally, it enhanced collagen synthesis and mineralization, facilitating the repair of the tendon-bone interface. By incorporating multilevel metal phenolic networks (MPN) to control ion release, these hybridized hydrogels can be customized for various biomedical applications.

A modular hydrogel bioink containing microsphere-embedded chondrocytes for 3D-printed multiscale composite scaffolds for cartilage repair.

Articular cartilage tissue engineering is being considered an alternative treatment strategy for promoting cartilage damage repair. Herein, we proposed a modular hydrogel-based bioink containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds integrating the micro and macro environment of the native articular cartilage. Gelatin methacryloyl (GelMA)/alginate microsphere was prepared by a microfluidic approach, and the chondrocytes embedded in the microspheres remained viable after being frozen and resuscitated. The modular hydrogel bioink could be printed via the gel-in-gel 3D bioprinting strategy for fabricating the multiscale hydrogel-based scaffolds. Meanwhile, the cells cultured in the scaffolds showed good proliferation and differentiation. Furthermore, we also found that the composite hydrogel was biocompatible in vivo. These results indicated that the modular hydrogel-based bioinks containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds could provide a 3D multiscale environment for enhancing cartilage repairing, which would be encouraging considering the numerous alternative applications in articular cartilage tissue engineering.

CholecTriplet2021: A benchmark challenge for surgical action triplet recognition.

Context-aware decision support in the operating room can foster surgical safety and efficiency by leveraging real-time feedback from surgical workflow analysis. Most existing works recognize surgical activities at a coarse-grained level, such as phases, steps or events, leaving out fine-grained interaction details about the surgical activity; yet those are needed for more helpful AI assistance in the operating room. Recognizing surgical actions as triplets of combination delivers more comprehensive details about the activities taking place in surgical videos. This paper presents CholecTriplet2021: an endoscopic vision challenge organized at MICCAI 2021 for the recognition of surgical action triplets in laparoscopic videos. The challenge granted private access to the large-scale CholecT50 dataset, which is annotated with action triplet information. In this paper, we present the challenge setup and the assessment of the state-of-the-art deep learning methods proposed by the participants during the challenge. A total of 4 baseline methods from the challenge organizers and 19 new deep learning algorithms from the competing teams are presented to recognize surgical action triplets directly from surgical videos, achieving mean average precision (mAP) ranging from 4.2% to 38.1%. This study also analyzes the significance of the results obtained by the presented approaches, performs a thorough methodological comparison between them, in-depth result analysis, and proposes a novel ensemble method for enhanced recognition. Our analysis shows that surgical workflow analysis is not yet solved, and also highlights interesting directions for future research on fine-grained surgical activity recognition which is of utmost importance for the development of AI in surgery.

Efficient pollutant degradation under ultraviolet to near-infrared light irradiation and dark condition using CuSe nanosheets: Mechanistic insight into degradation.

The hydrothermally prepared two-dimensional copper selenide nanosheets (2D CuSe NSs) have been employed for the first time to degrade rhodamine B (RhB) in the presence of hydrogen peroxide (H2O2) under ultraviolet to near-infrared (NIR) light irradiation and dark condition. The experimental measurements demonstrate that 99.7% RhB is degraded under NIR light irradiation for 120 min. Moreover, the experimental tests clearly demonstrate that the 2D CuSe NSs display excellent ability to degrade RhB under dark condition. The different degradation mechanisms under the light irradiation and dark condition have been revealed by the experimental tests through the investigation of H2O2 role and the evaluation of hydroxyl radicals (•OH) and H2O2 concentration during the degradation reaction. Under light irradiation, the H2O2 traps the photogenerated electrons of the CuSe to generate •OH and hydroxide ion (OH-), and the holes react with OH- to produce •OH, making RhB to be degraded efficiently. Under dark conduction, the 2D CuSe NSs react with H2O2 to exhibit Fenton-like process to degrade RhB with a degradation rate of 90.0% within 120 min. This work opens a pathway for developing nanostructures with full-solar-responsive and strong near-infrared photocatalytic activity as well as Fenton-like reaction to efficiently degrade pollutants under light irradiation and dark condition.

Spatio-Temporal Causal Transformer for Multi-Grained Surgical Phase Recognition.

Automatic surgical phase recognition plays a key role in surgical workflow analysis and overall optimization in clinical work. In the complicated surgical procedures, similar inter-class appearance and drastic variability in phase duration make this still a challenging task. In this paper, a spatio-temporal transformer is proposed for online surgical phase recognition with different granularity. To extract rich spatial information, a spatial transformer is used to model global spatial dependencies of each time index. To overcome the variability in phase duration, a temporal transformer captures the multi-scale temporal context of different time indexes with a dual pyramid pattern. Our method is thoroughly validated on the public Cholec80 dataset with 7 coarse-grained phases and the CATARACTS2020 dataset with 19 fine-grained phases, outperforming state-of-the-art approaches with 91.4% and 84.2% accuracy, taking only 24.5M parameters.

Diagnostic Value of Color Doppler Ultrasonography in Subacute Thyroiditis.

In order to explore the clinical effect of color Doppler ultrasonography in the diagnosis of subacute thyroiditis, a method for the diagnosis of subacute thyroiditis by color Doppler ultrasonography was proposed. From November 2019 to November 2020, 90 patients with subacute thyroiditis in our hospital were selected as the experimental group; 90 healthy people were selected as the control group during the same period. Both groups were diagnosed by color Doppler ultrasonography and compared. The experimental results showed that patients with subacute thyroiditis showed mild to moderate enlargement of the involved thyroid gland, and local or diffuse inhomogeneous hypoechoic areas may appear in bilateral or unilateral thyroid glands: irregular edges, unclear boundaries, no "ball feel," mottled changes, and accompanied by tenderness. The blood flow signal around the hypoechoic area is rich, and the internal blood flow signal is less. There was no significant increase in the blood flow velocity of the superior thyroid artery on the affected side. Color Doppler ultrasound not only is simple, economical, and non-invasive but also has a good diagnostic accuracy for subacute thyroiditis, which can provide an important basis for clinical diagnosis and treatment and is worthy of popularization and application.

Effect of secretory leucocyte protease inhibitor on early tendon-to-bone healing after anterior cruciate ligament reconstruction in a rat model.

AIMS: To verify whether secretory leucocyte protease inhibitor (SLPI) can promote early tendon-to-bone healing after anterior cruciate ligament (ACL) reconstruction. METHODS: In vitro: the mobility of the rat bone mesenchymal stem cells (BMSCs) treated with SLPI was evaluated by scratch assay. Then the expression levels of osteogenic differentiation-related genes were analyzed by real-time quantitative PCR (qPCR) to determine the osteogenic effect of SLPI on BMSCs. In vivo: a rat model of ACL reconstruction was used to verify the effect of SLPI on tendon-to-bone healing. All the animals of the SLPI group and the negative control (NC) group were euthanized for histological evaluation, micro-CT scanning, and biomechanical testing. RESULTS: SLPI improved the migration ability of BMSCs and upregulated the expression of genes related to osteogenic differentiation of BMSCs in vitro. In vivo, the SLPI group had higher histological scores at the tendon-bone interface by histological evaluation. Micro-CT showed more new bone formation and bone ingrowth around the grafted tendon in the SLPI group. Evaluation of the healing strength of the tendon-bone connection showed that the SLPI group had a higher maximum failure force and stiffness. CONCLUSION: SLPI can effectively promote early tendon-to-bone healing after ACL reconstruction via enhancing the migration and osteogenic differentiation of BMSCs. Cite this article: Bone Joint Res 2022;11(7):503-512.

Mechanical stimulation promotes enthesis injury repair by mobilizing Prrx1+ cells via ciliary TGF-ß signaling.

Proper mechanical stimulation can improve rotator cuff enthesis injury repair. However, the underlying mechanism of mechanical stimulation promoting injury repair is still unknown. In this study, we found that Prrx1+ cell was essential for murine rotator cuff enthesis development identified by single-cell RNA sequence and involved in the injury repair. Proper mechanical stimulation could promote the migration of Prrx1+ cells to enhance enthesis injury repair. Meantime, TGF-ß signaling and primary cilia played an essential role in mediating mechanical stimulation signaling transmission. Proper mechanical stimulation enhanced the release of active TGF-ß1 to promote migration of Prrx1+ cells. Inhibition of TGF-ß signaling eliminated the stimulatory effect of mechanical stimulation on Prrx1+ cell migration and enthesis injury repair. In addition, knockdown of Pallidin to inhibit TGF-ßR2 translocation to the primary cilia or deletion of Ift88 in Prrx1+ cells also restrained the mechanics-induced Prrx1+ cells migration. These findings suggested that mechanical stimulation could increase the release of active TGF-ß1 and enhance the mobilization of Prrx1+ cells to promote enthesis injury repair via ciliary TGF-ß signaling.

Five-electrode direct current suppressor-detector combiner for ion chromatography: an integration of eluent suppression and resistance detection.

An integration of eluent suppressor and resistance detector is proposed based upon the application of a common anode (or cathode), a common ion-exchange membrane, and two independent constant current sources.

Calcitonin Gene-Related Peptide Influences Bone-Tendon Interface Healing Through Osteogenesis: Investigation in a Rabbit Partial Patellectomy Model.

BACKGROUND: Calcitonin gene-related peptide (CGRP), which has been shown to play an important role in osteogenesis during fracture repair, is also widely distributed throughout the tendon and ligament. Few studies have focused on the role of CGRP in repair of the bone-tendon interface (BTI). PURPOSE: To explore the effect of CGRP expression on BTI healing in a rabbit partial patellectomy model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 60 mature rabbits were subjected to a partial patellectomy and then randomly assigned to CGRP, CGRP-antagonist, and control groups. In the CGRP-antagonist group, the CGRP receptor antagonist BIBN4096BS was administered to block CGRP receptors. The patella-patellar tendon complex was harvested at 8 and 16 weeks postoperatively and subjected to radiographic, microlaser Raman spectroscopy, histologic, and biomechanical evaluation. RESULTS: Radiographic data showed that local CGRP expression improved the growth parameters of newly formed bone, including area and volumetric bone mineral density (P < .05 for both). Raman spectroscopy revealed that the relative bone mineral composition increased in the CGRP group compared with in the control group and the CGRP-antagonist group (P < .05 for both). Histologic testing revealed that the CGRP group demonstrated better integration, characterized by well-developed trabecular bone expansion from the residual patella and marrow cavity formation, at the 8- and 16-week time points. Mechanical testing demonstrated that the failure load, ultimate strength, and stiffness in the CGRP group were significantly higher than those in the control group (P < .05 for all), whereas these parameters in the CGRP-antagonist group were significantly lower compared with those in the control group at 16 weeks after surgery (P < .05 for all). CONCLUSION: Increasing the local concentration of CGRP in the early stages of BTI healing enhanced osteogenesis in a rabbit partial patellectomy model and promoted healing of the BTI injury, whereas treatment using a CGRP antagonist had the opposite effect. However, exogenous CGRP expression did not induce novel bone remolding. CLINICAL RELEVANCE: CGRP may have potential as a new therapy for BTI injuries or may be added to postoperative regimens to facilitate healing.

Recombinant human bone morphogenetic protein-4 enhances tendon-to-bone attachment healing in a murine model of rotator cuff tear.

BACKGROUND: Injuries of tendon-to-bone attachments (TBA) are common clinical challenges. Bone morphogenetic protein-4 (BMP-4) is potent in chondrogenesis. However, studies focusing on the influence of BMP-4 on the healing of TBA are scarce. Thus, this study's objective was to explore the effect of BMP-4 on the healing of TBA in a murine model of rotator cuff tear. METHODS: An injury model of the supraspinatus tendon (SST) insertion was established on a total of 120 mature C57 black (BL)/6 mice (12 weeks old), who were then randomly allocated into 3 groups: BMP-4, noggin (an inhibitor of all BMP activities), and control, At weeks 2 and 4 after surgery, the supraspinatus tendon-humerus complexes (SSTHC) were harvested for microradiographic, histologic, immunofluorescent, and biomechanical evaluations. RESULTS: Radiographic data showed that BMP-4 was able to improve the quality of subchondral bone, manifested as higher bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and lower trabecular spacing (Tb.Sp). Histologically, the BMP-4 group at week-2 and -4 showed a better TBA healing interface, characterized by better organizational integration and remodeling, thicker fibrocartilage layer, and more fibrocartilage cells. Immunofluorescence evaluation demonstrated that the number of SOX 9 positive cells in the BMP-4 group was significantly more than that in the control or noggin groups at postoperative weeks 2 and 4 (P<0.05 for all). Mechanical testing results at postoperative weeks 4 demonstrated the failure load, and stiffness in the BMP-4 group were significantly higher (P<0.05 for both), while in the noggin group were significantly lower (P<0.05 for both), compared to the control group. CONCLUSIONS: The BMP-4 might enhance TBA healing by promoting the regeneration of fibrocartilaginous enthesis and mineralization, while this process was inhibited by noggin. Thus, BMP-4 may be a potential therapy to augment TBA healing and finally lead to more rapid rehabilitation and reduce recurrent injury risk.