Mechanical Robust GO/PVA Hydrogel for Strong and Recyclable Adhesion in Air, Underwater, and Underoil Environments.

Adhesive hydrogels are considered to be promising interfacial adhesive materials for various applications; however, their adhesive strength is significantly reduced when immersed in liquid environments (water and oil) due to obstruction of the liquid layer or swelling in liquid, and they could not always be reused when the failure of the adhesive performance occurred. Herein, a graphite oxide/poly(vinyl alcohol) (GO/PVA) hydrogel with strong adhesion in air and under liquid environments was developed by rationally regulating the interactions of water and dimethyl sulfoxide (DMSO) in the binary liquid system. The strong interaction between water and DMSO allowed the water layer of the GO/PVA hydrogel on the hydrogel surface to act as a shield to repel oil in air, under water, and even when immersed in oil, and it also endowed the obtained hydrogel with antiswelling property when immersed in water and oil. Importantly, the GO/PVA hydrogel could serve as an advanced adhesive to firmly bond different substrates in air, under water, and under oil, and interestingly, its dry and wet adhesive performance was repeatable and recyclable. This work is expected to be an important addition to the field of adhesive soft materials.

IL-1ß-mediated inflammatory responses in intervertebral disc degeneration: Mechanisms, signaling pathways, and therapeutic potential.

Intervertebral disc degeneration (IDD) has been widely recognized as the primary cause of low back pain and is one of the major chronic diseases imposing a severe socioeconomic burden worldwide. IDD is a degenerative process characterized by inflammatory responses, and its underlying pathological mechanisms remain complex. Genetic, developmental, biochemical, and biomechanical factors contribute to the development of IDD. There is a pressing need for an effective non-surgical treatment, mainly due to the lack of comprehensive understanding of the specific mechanisms involved and the effective therapeutic targets for IDD. Recently, interleukin (IL)-1ß has been recognized as an essential inflammatory factor and a key mediator of the inflammatory process in IDD. Current studies have found that IL-1ß is mainly involved in IDD by affecting the metabolism of the extracellular matrix and regulating cell death (RCD), such as apoptosis, pyroptosis, and ferroptosis (a new form of RCD). Although analysis of clinical samples from different laboratories confirmed how IL-1ß is induced in IDD, its specific signal transduction pathway, and the inflammatory role mediated in IDD remains unclear. This review describes the molecules and mechanisms involved in IL-1ß-mediated inflammatory responses, and their roles in resolving the inflammatory process in IDD. Understanding the signaling pathways involved in IL-1ß may lead to a new class of targets that promote remission for IDD patients. This review aims to provide a framework for the treatment of IDD by analyzing the signaling mechanism and function related to IL-1ß, especially in terms of inflammation, matrix metabolism, and cell death regulation.

The mechanisms and functions of TGF-ß1 in tendon healing.

Tendon injury accounts for 30% of musculoskeletal diseases and often leads to disability, pain, healthcare cost, and lost productivity. Following injury to tendon, tendon healing proceeds via three overlapping healing processes. However, due to the structural defects of the tendon itself, the tendon healing process is characterized by the formation of excessive fibrotic scar tissue, and injured tendons rarely return to native tendons, which can easily contribute to tendon reinjury. Moreover, the resulting fibrous scar is considered to be a precipitating factor for subsequent degenerative tendinopathy. Despite this, therapies are almost limited because underlying molecular mechanisms during tendon healing are still unknown. Transforming Growth Factor-ß1 (TGF-ß1) is known as one of most potent profibrogenic factors during tendon healing process. However, blockage TGF-ß1 fails to effectively enhance tendon healing. A detailed understanding of real abilities of TGF-ß1 involved in tendon healing can bring promising perspectives for therapeutic value that improve the tendon healing process. Thus, in this review, we describe recent efforts to identify and characterize the roles and mechanisms of TGF-ß1 involved at each stage of the tendon healing and highlight potential roles of TGF-ß1 leading to the fibrotic response to tendon injury.

The Functions and Mechanisms of Tendon Stem/Progenitor Cells in Tendon Healing.

Tendon injury is one of the prevalent disorders of the musculoskeletal system in orthopedics and is characterized by pain and limitation of joint function. Due to the difficulty of spontaneous tendon healing, and the scar tissue and low mechanical properties that usually develops after healing. Therefore, the healing of tendon injury remains a clinical challenge. Although there are a multitude of approaches to treating tendon injury, the therapeutic effects have not been satisfactory to date. Recent studies have shown that stem cell therapy has a facilitative effect on tendon healing. In particular, tendon stem/progenitor cells (TSPCs), a type of stem cell from tendon tissue, play an important role not only in tendon development and tendon homeostasis, but also in tendon healing. Compared to other stem cells, TSPCs have the potential to spontaneously differentiate into tenocytes and express higher levels of tendon-related genes. TSPCs promote tendon healing by three mechanisms: modulating the inflammatory response, promoting tenocyte proliferation, and accelerating collagen production and balancing extracellular matrix remodeling. However, current investigations have shown that TSPCs also have a negative effect on tendon healing. For example, misdifferentiation of TSPCs leads to a "failed healing response," which in turn leads to the development of chronic tendon injury (tendinopathy). The focus of this paper is to describe the characteristics of TSPCs and tenocytes, to demonstrate the roles of TSPCs in tendon healing, while discussing the approaches used to culture and differentiate TSPCs. In addition, the limitations of TSPCs in clinical application and their potential therapeutic strategies are elucidated.

Inflammation-related signaling pathways in tendinopathy.

Tendon is a connective tissue that produces movement by transmitting the force produced by muscle contraction to the bones. Most tendinopathy is caused by prolonged overloading of the tendon, leading to degenerative disease of the tendon. When overloaded, the oxygen demand of tenocytes increases, and the tendon structure is special and lacks blood supply, which makes it easier to form an oxygen-deficient environment in tenocytes. The production of reactive oxygen species due to hypoxia causes elevation of inflammatory markers in the tendon, including PGE2, IL-1ß, and TNF-α. In the process of tendon healing, inflammation is also a necessary stage. The inflammatory environment formed by cytokines and various immune cells play an important role in the clearance of necrotic material, the proliferation of tenocytes, and the production of collagen fibers. However, excessive inflammation can lead to tendon adhesions and hinder tendon healing. Some important and diverse biological functions of the body originate from intercellular signal transduction, among which cytokine mediation is an important way of signal transduction. In particular, NF-κB, NLRP3, p38/MAPK, and signal transducer and activator of transcription 3, four common signaling pathways in tendinopathy inflammatory response, play a crucial role in the regulation and transcription of inflammatory factors. Therefore, summarizing the specific mechanisms of inflammatory signaling pathways in tendinopathy is of great significance for an in-depth understanding of the inflammatory response process and exploring how to inhibit the harmful part of the inflammatory response and promote the beneficial part to improve the healing effect of the tendon.

Mesenchymal stem cells: An efficient cell therapy for tendon repair (Review).

Tendon injury is a common disorder of the musculoskeletal system caused by overuse or trauma. With increasing incidence of tendon injuries, it is necessary to find an effective treatment. Mesenchymal stem cells (MSCs) are attracting attention because of their high proliferative and self­renewal capacity. These functions of MSCs show promise in treating a variety of diseases, including immune and musculoskeletal system disorder and cardiovascular disease, and show especially satisfactory effects in the treatment of tendon injury. First, since MSCs have multidirectional differentiation potential, they differentiate into specific cells after induction in vivo and in vitro. Furthermore, MSCs have paracrine functions and can secrete biologically active molecules and exosomes such as cytokines, growth factors and chemokines to promote tissue repair and regeneration. In tendon injury, MSCs promote tendon repair through four mechanisms: Decreasing inflammation and promoting neovascularization and cell proliferation and differentiation. They are also involved in extracellular matrix reorganization by promoting collagen production and transforming type III collagen fibers to type I collagen fibers. The present review summarized preclinical experiments with different sources of MSCs and their mechanisms in tendon repair, as well as the limitations of MSCs in current clinical applications and directions that need to be explored in the future.

miRNAs contributing to the repair of tendon injury.

Tendon injury is one of the most common disorders of the musculoskeletal system, with a higher likelihood of occurrence in elderly individuals and athletes. In posthealing tendons, two undesirable consequences, tissue fibrosis and a reduction in mechanical properties, usually occur, resulting in an increased probability of rerupture or reinjury; thus, it is necessary to propose an appropriate treatment. Currently, most methods do not sufficiently modulate the tendon healing process and restore the function and structure of the injured tendon to those of a normal tendon, since there is still inadequate information about the effects of multiple cellular and other relevant signaling pathways on tendon healing and how the expression of their components is regulated. microRNAs are vital targets for promoting tendon repair and can modulate the expression of biological components in signaling pathways involved in various physiological and pathological responses. miRNAs are a type of noncoding ribonucleic acid essential for regulating processes such as cell proliferation, differentiation, migration and apoptosis; inflammatory responses; vascularization; fibrosis; and tissue repair. This article focuses on the biogenesis response of miRNAs while presenting their mechanisms in tendon healing with perspectives and suggestions.

Leaf-Inspired Patterned Organohydrogel Surface for Ultrawide Time-Range Open Biosensing.

Droplet arrays show great significance in biosensing and biodetection because of low sample consumption and easy operation. However, inevitable water evaporation in open environment severely limits their applications in time-consuming reactions. Herein, inspired by the unique water retention features of leaves, it is demonstrated that an open droplet array on patterned organohydrogel surface with water evaporating replenishment (POWER) for ultrawide time-range biosensing, which integrated hydrophilic hydrogel domains and hydrophobic organogel background. The hydrogel domains on the surface can supply water to the pinned droplets through capillary channels formed in the nether organohydrogel bulk. The organogel background can inhibit water evaporation like the wax coating of leaves. Such a unique bioinspired design enables ultrawide time-range biosensing in open environment from a few minutes to more than five hours involving a variety of analytes such as ions, small molecules, and macromolecules. The POWER provides a feasible and open biosensing platform for ultrawide time-range reactions.

Event-Triggered Near-Optimal Control for Unknown Discrete-Time Nonlinear Systems Using Parallel Control.

This article uses parallel control to investigate the problem of event-triggered near-optimal control (ETNOC) for unknown discrete-time (DT) nonlinear systems. First, to achieve parallel control, an augmented nonlinear system (ANS) with an augmented performance index (API) is proposed to introduce the control input into the feedback system. The control stability relationship between the ANS and the original system is analyzed, and it is shown that, by choosing a proper API, optimal control of the ANS with the API can be seen as near-optimal control of the original system with the original performance index (OPI). Second, based on parallel control, a novel event-triggered scheme is proposed, and then a novel ETNOC method is developed using the time-triggered optimal value function of the ANS with the API. The control stability is proved, and an upper bound, which is related to the design parameter, is provided for the actual performance index in advance. Then, to implement the developed ETNOC method for unknown DT nonlinear systems, a novel online learning algorithm is developed without reconstructing unknown systems, and neural network (NN) and adaptive dynamic programming (ADP) techniques are employed in the developed algorithm. The convergence of the signals in the closed-loop system (CLS) is shown using the Lyapunov approach, and the assumption of boundedness of input dynamics is not required. Finally, two simulations justify the theoretical conjectures.

STAT3 expression in patients with fragility fractures and its effect on the biological function of osteoblasts.

To determine the expression of signal transducer and activator of transcription 3 (STAT3) in patients with fragility fractures (FFs) and its effect on the biological function of osteoblasts. The study included 32 patients with FFs who were diagnosed and treated in the research group and 30 concurrent healthy individuals in the control group. We observed STAT3 mRNA expression in the patients with FFs and controls and altered STAT3 mRNA to detect changes in the proliferation, invasion, and apoptosis of osteoblasts. The patients with FFs presented higher serum STAT3 mRNA expression than the controls (P < 0.05). We plotted receiver operating characteristic curves based on the STAT3 mRNA expression and found that the area under the curve for STAT3 mRNA was 0.856 (P < 0.05). Transfection of STAT3 mRNA mimics resulted in increased STAT3 mRNA expression, inhibited cell proliferation as detected by an MTT assay, and increased apoptosis rate, which was determined using flow cytometry with human fetal osteoblastic cell line 1.19 cells. STAT3 mRNA expression was elevated in the serum of patients with FFs and can be used as a biomarker for the diagnosis of the disease. Regulating STAT3 mRNA can inhibit the proliferation and induce the osteoblasts apoptosis.

The Design and Characterization of a Strong Bio-Ink for Meniscus Regeneration.

The meniscus is vital to the mechanical function of the knee, while it is frequently harmed because it bears a heavy load. A strong bio-ink for meniscus regeneration was prepared for the future meniscal tissue engineering. The prepared bio-ink consists of poly (vinyl alcohol) and decellularized extracellular matrix (PVA/dECM). The mechanical properties and the rheological features were explored to evaluate the effects of freezing/thawing cycles and alkaline treatment process. The printability was verified using a three-dimensional printer. The endothelial cells were employed to assess the biocompatibility. Finally, a 12-week rabbit meniscus defect model was established to evaluate the meniscus regeneration capability. We found that the bio-ink by soaking in alkaline for 40 min and 20 freezing/thawing cycles demonstrated excellent mechanical properties. The Young's modulus reached 0.49 MPa and the stress limitation was 2.9 MPa. The results also showed good printability and biocompatibility of the proposed bio-ink in vitro. The PVA/dECM hydrogel healed the meniscus defect after 12 weeks of implantation. The articular cartilage and subchondral bone exhibited normal microstructure and composition. These results suggested that the PVA/dECM hydrogel could be a promising solution to repair meniscal lesions with preventive effects against degenerative meniscal tears and post-traumatic arthritis.

Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis.

Bone metastatic breast cancer has severely threatened the survival and life quality of patients. Due to the suboptimal efficacy of anti-metastatic chemotherapeutic drugs and the complicated bone marrow microenvironments, effective treatment of metastatic breast cancer remains challenging for traditional clinical approaches. In this work, we developed a mesoporous nanoplatform (m-CuS-PEG) with the co-loading of CuS nanodots and a chemotherapeutic drug cisplatin for the combined photothermal-chemotherapy of bone-metastasized breast cancer. The CuS nanodots were decorated onto mesoporous silica (m-SiO2) surface with dendritic mesoporous channels, into which the cisplatin was accommodated. The carboxyl-terminated poly (ethylene glycol) (PEG) was further functionalized onto the surface to obtain the functional nanoplatform m-CuS-PEG. The drug release of the loaded cisplatin exhibited pH- and thermal-dual responsive manner. The attached CuS nanodots rendered the mesoporous nanoplatform with high photothermal conversion ability. Upon irradiation with a near-infrared laser in the second near-infrared (NIR-II) window, m-CuS-PEG dispersions exhibited rapid temperature elevation and high photostability. The results revealed that m-CuS-PEG had excellent biocompatibility. The cisplatin-loaded m-CuS-PEG not only showed superior cancer cell-killing effects, but also significantly inhibit the growth of metastatic tumors. The tumor-induced bone destruction was also dramatically attenuated by the mesoporous nanoplatform-mediated combined therapy. Overall, the developed functional nanoplatform integrates photothermal therapy and efficient chemotherapeutic drug delivery to offer an alternative approach for combating breast cancer bone metastasis.

Programmable Microparticle Array for In Situ Modification and Multiple miRNA Detection.

Simultaneous detection of multiple miRNAs of one disease can greatly reduce misdiagnosis and improve the detection rate, which is helpful for early cancer diagnosis. Here, a programmable microparticle-array-based acoustic microchip for in situ simultaneous multiple miRNAs detection is developed. On this microchip, the multiple probes-labeled microparticle array can be procedurally arranged in a microfluidic reaction chamber when four orthogonally piezoelectric transducers are applied. The probes-labeled microparticle array offers a platform for full molecular contact under dynamic ultrasonic streaming, and the array supplies a multipoint data correction to reduce the false positive of the detection results for more precisely visible fluorescence multiple target miRNAs sensing. We employed miRNA-21, miRNA-210, and miRNA-155 as specific biomarkers of pancreatic cancer and successfully finished the multiple miRNAs simultaneous detection in the microchip with a detection limit of 139.1, 179.9, and 111.4 pM, respectively. Such a device is programmable by adjusting the imputing frequency and voltage, and target biomarkers can be easily collected when the ultrasound force is released for further analysis, which shows great potential in multiple miRNAs enrichment and simultaneous detection for cancer clinical diagnosis.

miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6.

Vascular calcification is a prominent manifestation of advanced atherosclerosis. Tumor necrosis factor-receptor-associated factors (TRAFs) were reported to participate in atherosclerosis development. In this study, the role and mechanism of TRAF6 in vascular calcification were explored. To induce the vascular calcification, oxidized low-density lipoprotein (Ox-LDL) was applied to treat vascular smooth muscle cells (VSMCs). TRAF6 protein expression in VSMCs was assessed by western blotting. Osteogenic differentiation of VSMCs was assessed by alkaline phosphatase activity analysis. Mineral deposition in VSMCs was evaluated by von Kossa staining. VSMC proliferation, migration, apoptosis, inflammation, and reactive oxygen species (ROS) generation were detected using cell counting kit-8, Transwell, flow cytometry, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), and dichlorodihydrofluorescein diacetate staining, respectively. Luciferase reporter assay was utilized to identify the binding relationship between miR-146-5p and TRAF6 in VSMCs. We found that Ox-LDL administration induced the calcification of VSMCs and elevated the TRAF6 level. TRAF6 knockdown restrained VSMC calcification, proliferation, migration, inflammation, and ROS generation caused by Ox-LDL. Mechanically, TRAF6 was targeted by miR-146-5p in VSMCs. Furthermore, TRAF6 overexpression offset the inhibitory effects of miR-146-5p upregulation on vascular calcification in VSMCs under the Ox-LDL condition. Overall, miR-146-5p restrains the calcification of VSMCs by suppressing TRAF6.

Covalent immobilization of VEGF on allogeneic bone through polydopamine coating to improve bone regeneration.

Objective: Promoting bone regeneration and repairing in bone defects is of great significance in clinical work. Using a simple and effective surface treatment method to enhance the osteogenic ability of existing bone scaffold is a promising method. In this article, we study the application of catecholic amino acid 3,4-dihydroxyphenylalanine (DOPA) surface coating chelated with vascular endothelial growth factor (VEGF) on allogeneic bone. Method: Allogeneic bone is immersed in DOPA solution and DOPA form polydopamine (PDA) with good adhesion. Electron microscopy is used to characterize the surface characteristics of allogeneic bone. MC3T3-E1 cells were tested for biocompatibility and osteogenic signal expression. Finally, a 12-week rabbit bone defect model was established to evaluate bone regeneration capability. Results: We found that the surface microenvironment of DOPA bonded allogeneic bone was similar to the natural allogeneic bone. VEGF loaded allografts exhibited satisfying biocompatibility and promoted the expression of osteogenic related signals in vitro. The VEGF loaded allografts healed the bone defect after 12 weeks of implantation that continuous and intact bone cortex was observed. Conclusion: The PDA coating is a simple surface modification method and has mild properties and high adhesion. Meanwhile, the PDA coating can act on the surface modification of different materials. This study provides an efficient surface modification method for enhancing bone regeneration by PDA coating, which has a high potential for translational clinical applications.

A Promising Candidate in Tendon Healing Events-PDGF-BB.

Tendon injuries are one of the most common musculoskeletal disorders for which patients seek medical aid, reducing not only the quality of life of the patient but also imposing a significant economic burden on society. The administration of growth factors at the wound site is a feasible solution for enhancing tendon healing. Platelet-derived growth factor-BB (PDGF-BB) has a well-defined safety profile compared to other growth factors and has been approved by the Food and Drug Administration (FDA). The purpose of this review is to summarize the role of PDGF-BB in tendon healing through a comprehensive review of the published literature. Experimental studies suggest that PDGF-BB has a positive effect on tendon healing by enhancing inflammatory responses, speeding up angiogenesis, stimulating tendon cell proliferation, increasing collagen synthesis and increasing the biomechanics of the repaired tendon. PDGF-BB is regarded as a promising candidate in tendon healing. However, in order to realize its full potential, we still need to carefully consider and study key issues such as dose and application time in the future, so as to explore further applications of PDGF-BB in the tendon healing process.

Biological response of extracorporeal shock wave therapy to tendinopathy in vivo (review).

Tendinopathy is a degenerative disease of the tendons caused by prolonged overstretching or overuse of the tendons. It accounts for a large proportion of musculoskeletal disorders which can occur in all age groups. The management of tendinopathy is typically conservative. In clinical practice, when other conservative treatments fail, extracorporeal shock wave therapy (ESWT) is normally used as an efficient alternative to surgical management. Several basic studies have shown that ESWT with lower energy flux densities can produce some biological responses in vivo to tendinopathy and may accelerate the initiation of the healing process in injured tendons. ESWT has a positive impact on the interactive chain of biological response, enhancing the signaling pathways of angiogenesis through mechanical conduction, and promoting cell proliferation and collagen formation. Finally, it helps tissue regeneration by controlling inflammation. The purpose of this review is to summarize the biological responses generated by ESWT in tendinopathy through a comprehensive review of the published literature. Although ESWT has been used clinically for the treatment of tendinopathies for nearly decades, less is known about the experimental studies of its biological effects on tendon tissue. Further studies on the biological response of ESWT for tendon injuries in vivo are needed in the future in order to provide better management to patients.

A "cell-free treatment" for tendon injuries: adipose stem cell-derived exosomes.

Tendon injuries are widespread and chronic disorders of the musculoskeletal system, frequently caused by overload of the tendons. Currently, the most common treatment for tendon injuries is "cell-free therapy", of which exosomes, which can treat a host of diseases, including immune disorders, musculoskeletal injuries and cardiovascular diseases, are one kind. Among the many sources of exosomes, adipose-derived stem cell exosomes (ASC-Exos) have better efficacy. This is attributed not only to the ease of isolation of adipose tissue, but also to the high differentiation capacity of ASCs, their greater paracrine function, and immunomodulatory capacity compared to other exosomes. ASC-Exos promote tendon repair by four mechanisms: promoting angiogenesis under hypoxic conditions, reducing the inflammatory response, promoting tendon cell migration and proliferation, and accelerating collagen synthesis, thus accelerating tendon healing. This review focuses on describing studies of preclinical experiments with various exosomes, the characteristics of ASC-Exos and their mechanisms of action in tendon healing, as well as elaborating the limitations of ASC-Exos in clinical applications.

The Functions and Mechanisms of Basic Fibroblast Growth Factor in Tendon Repair.

Tendon injury is a disorder of the musculoskeletal system caused by overuse or trauma, which is characterized by pain and limitations in joint function. Since tendon healing is slowly and various treatments are generally ineffective, it remains a clinically challenging problem. Recent evidences suggest that basic fibroblast growth factor (bFGF) not only plays an important role in tendon healing, but also shows a positive effect in laboratory experimentations. The purpose of this review is to summarize the effects of bFGF in the tendon healing. Firstly, during the inflammatory phase, bFGF stimulates the proliferation and differentiation of vascular endothelial cells to foster neovascularization. Furthermore, bFGF enhances the production of pro-inflammatory factors during the early phase of tendon healing, thereby accelerating the inflammatory response. Secondly, the cell proliferation phase is accompanied by the synthesis of a large number of extracellular matrix components. bFGF speeds up tendon healing by stimulating fibroblasts to secrete type III collagen. Lastly, the remodeling phase is characterized by the transition from type III collagen to type I collagen, which can be promoted by bFGF. However, excessive injection of bFGF can cause tendon adhesions as well as scar tissue formation. In future studies, we need to explore further applications of bFGF in the tendon healing process.

Effect of Angiogenesis in Bone Tissue Engineering.

The reconstruction of large skeletal defects is still a tricky challenge in orthopedics. The newly formed bone tissue migrates sluggishly from the periphery to the center of the scaffold due to the restrictions of exchange of oxygen and nutrition impotent cells osteogenic differentiation. Angiogenesis plays an important role in bone reconstruction and more and more studies on angiogenesis in bone tissue engineering had been published. Promising advances of angiogenesis in bone tissue engineering by scaffold designs, angiogenic factor delivery, in vivo prevascularization and in vitro prevascularization are discussed in detail. Among all the angiogenesis mode, angiogenic factor delivery is the common methods of angiogenesis in bone tissue engineering and possible research directions in the future.