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Chronic diabetic wounds are the most common complication for diabetic patients. Due to high oxidative stress levels affecting the entire healing process, treating diabetic wounds remains a challenge. Here, we present a strategy for continuously regulating oxidative stress microenvironment by the catalyst-like magnesium-gallate metal-organic framework (Mg-GA MOF) and developing sprayable hydrogel dressing with sodium alginate/chitosan quaternary ammonium salts to treat diabetic wounds. Chitosan quaternary ammonium salts with antibacterial properties can prevent bacterial infection. The continuous release of gallic acid (GA) effectively eliminates reactive oxygen species (ROS), reduces oxidative stress, and accelerates the polarization of M1-type macrophages to M2-type, shortening the transition between inflammation and proliferative phase and maintaining redox balance. Besides, magnesium ions adjuvant therapy promotes vascular regeneration and neuronal formation by activating the expression of vascular-associated genes. Sprayable hydrogel dressings with antibacterial, antioxidant, and inflammatory regulation rapidly repair diabetic wounds by promoting neurovascular network reconstruction and accelerating re-epithelialization and collagen deposition. This study confirms the feasibility of catalyst-like MOF-contained sprayable hydrogel to regulate the microenvironment continuously and provides guidance for developing the next generation of non-drug diabetes dressings.

Abstract Segmental bone defects, arising from factors such as trauma, tumor resection, and congenital malformations, present significant clinical challenges that often necessitate complex reconstruction strategies. Hydrogels loaded with multiple osteogenesis-promoting components have emerged as promising tools for bone defect repair. While the osteogenic potential of the Piezo1 agonist Yoda1 has been demonstrated previously, its hydrophobic nature poses challenges for effective loading onto hydrogel matrices.In this study, we address this challenge by employing Yoda1-pretreated bone marrow-derived mesenchymal stem cell (BMSCs) exosomes (Exo-Yoda1) alongside exosomes derived from BMSCs (Exo-MSC). Comparatively, Exo-Yoda1-treated BMSCs exhibited enhanced osteogenic capabilities compared to both control groups and Exo-MSC-treated counterparts. Notably, Exo-Yoda1-treated cells demonstrated similar functionality to Yoda1 itself. Transcriptome analysis revealed activation of osteogenesis-associated signaling pathways, indicating the potential transduction of Yoda1-mediated signals such as ErK, a finding validated in this study. Furthermore, we successfully integrated Exo-Yoda1 into gelatin methacryloyl (GelMA)/methacrylated sodium alginate (SAMA)/β-tricalcium phosphate (β-TCP) hydrogels. These Exo-Yoda1-loaded hydrogels demonstrated augmented osteogenesis in subcutaneous ectopic osteogenesis nude mice models and in rat skull bone defect model. In conclusion, our study introduces Exo-Yoda1-loaded GELMA/SAMA/β-TCP hydrogels as a promising approach to promoting osteogenesis. This innovative strategy holds significant promise for future widespread clinical applications in the realm of bone defect reconstruction. Graphical Abstract

Managing bone defects remains a formidable clinical hurdle, primarily attributed to the inadequate orchestration of vascular reconstruction and osteogenic differentiation in both spatial and temporal dimensions. This challenge persists due to the constrained availability of autogenous grafts and the limited regenerative capacity of allogeneic or synthetic bone substitutes, thus necessitating continual exploration and innovation in the realm of functional and bioactive bone graft materials. While synthetic scaffolds have emerged as promising carriers for bone grafts, their efficacy is curtailed by deficiencies in vascularization and osteoinductive potential. Nitric oxide (NO) plays a key role in revascularization and bone tissue regeneration, yet studies related to the use of NO for the treatment of bone defects remain scarce. Herein, we present a pioneering approach leveraging a photothermal-responsive system to augment NO release. This system comprises macromolecular mPEG-P nanoparticles encapsulating indocyanine green (ICG) (NO-NPs@ICG) and a mPEG-PA-PP injectable thermosensitive hydrogel carrier. By harnessing the synergistic photothermal effects of near-infrared radiation and ICG, the system achieves sustained NO release, thereby activating the soluble guanylate cyclase (SGC)-cyclic guanosine monophosphate (cGMP) signaling pathway both in vitro and in vivo. This orchestrated cascade culminates in the facilitation of angiogenesis and osteogenesis, thus expediting the reparative processes in bone defects. In a nutshell, the NO release-responsive system elucidated in this study presents a pioneering avenue for refining the bone tissue microenvironment and fostering enhanced bone regeneration.

Abstract Arthritis is a chronic disease whose etiology is difficult to pinpoint, and the difficulty of arthritis detection and subsequent treatment causes enormous distress to patients. In recent years, thanks to advances in medicine and detection, a variety of treatment modalities for arthritis have emerged. The combination of emerging detection technologies with different anti‐inflammatory medications and even advances in surgical techniques have all played a positive role in the treatment of arthritis. In the present work, we have collected relevant literature on fluorescence (FL) imaging and phototherapy of arthritis in recent years, intending to reveal the advantages and potential application value of FL imaging and phototherapy for researchers. Meanwhile, due to the shortcomings of FL imaging and phototherapy in the diagnosis and treatment of arthritis, we advocate overcoming these difficulties in future research.

Magnesium phosphate bone cement has become a widely used orthopedic implant due to the advantages of fast-setting and high early strength. However, developing magnesium phosphate cement possessing applicable injectability, high strength, and biocompatibility simultaneously remains a significant challenge. Herein, we propose a strategy to develop high-performance bone cement and establish a trimagnesium phosphate cement (TMPC) system. The TMPC exhibits high early strength, low curing temperature, neutral pH, and excellent injectability, overcoming the critical limitations of recently studied magnesium phosphate cement. By monitoring the hydration pH value and electroconductivity, we demonstrate that the magnesium-to-phosphate ratio could manipulate the components of hydration products and their transformation by adjusting the pH of the system, which will influence the hydration speed. Further, the ratio could regulate the hydration network and the properties of TMPC. Moreover, in vitro studies show that TMPC has outstanding biocompatibility and bone-filling capacity. The facile preparation properties and these advantages of TMPC render it a potential clinical alternative to polymethylmethacrylate and calcium phosphate bone cement. This study will contribute to the rational design of high-performance bone cement.

There is a continuing need for artificial bone substitutes for bone repair and reconstruction, Magnesium phosphate bone cement (MPC) has exceptional degradable properties and exhibits promising biocompatibility. However, its mechanical strength needs improved and its low osteo-inductive potential limits its therapeutic application in bone regeneration. We functionally modified MPC by using a polymeric carboxymethyl chitosan-sodium alginate (CMCS/SA) gel network. This had the advantages of: improved compressive strength, ease of handling, and an optimized interface for bioactive bone in-growth. The new composites with 2% CMCS/SA showed the most favorable physicochemical properties, including mechanical strength, wash-out resistance, setting time, injectable time and heat release. Biologically, the composite promoted the attachment and proliferation of osteoblast cells. It was also found to induce osteogenic differentiation in vitro, as verified by expression of osteogenic markers. In terms of molecular mechanisms, data showed that new bone cement activated the Wnt pathway through inhibition of the phosphorylation of β-catenin, which is dependent on focal adhesion kinase. Through micro-computed tomography and histological analysis, we found that the MPC-CMCS/SA scaffolds, compared with MPC alone, showed increased bone regeneration in a rat calvarial defect model. Overall, our study suggested that the novel composite had potential to help repair critical bone defects in clinical practice.

Abstract To solve the problem of tendon adhesion after an operation, an anti‐adhesion membrane is designed, which can inhibit the exogenous healing of tendons and promote endogenous healing. Here, poly[3(S)‐methyl‐morpholine‐2,5‐dione‐co‐lactic acid] P(MMD‐co‐LA) containing alanine units is obtained by melt ring‐opening polymerization (ROP). It can effectively reduce the production of acidic degradation products that cause aseptic inflammation. Then a kind of oriented P(MMD‐co‐LA)/deferoxamine (DFO) anti‐adhesion membrane with good mechanical properties, cell adhesion properties, and induced macrophage polarization properties is constructed by electrospinning. In vitro and in vivo studies have shown that oriented fibrous membranes can down‐regulate the expression of inflammatory cytokines. In addition, the fibrous membrane can up‐regulate the expression of angiogenesis‐related genes, namely HIF1‐α, SDF‐1α, and VEGF, by releasing DFO in situ, thus promoting the revascularization of tendon defects and providing nutritional support for endogenous tendon healing. This method provides a new barrier strategy to reduce tendon adhesion through anti‐inflammation combined with vascularization to inhibit exogenous tendon healing while promoting tendon endogenous healing. The results provide essential insights into the corresponding regulation of the tendon healing microenvironment.

Abstract Clinical work and research on diabetic wound repair remain challenging globally. Although various conventional wound dressings have been continuously developed, the efficacy is unsatisfactory. The effect of drug delivery is limited by the depth of penetration. The sustained release of biomolecules from biological wound dressings is a promising treatment approach to wound healing. An assortment of cell-derived exosomes (exos) have been proved to be instrumental in tissue regeneration, and researchers are dedicated to developing biomolecules carriers with unique properties. Herein, we reported a methacrylate gelatin (GelMA) microneedles (MNs) patch to achieve transdermal and controlled release of exos and tazarotene. Our MNs patch comprising GelMA/PEGDA hydrogel has distinctive biological features that maintain the biological activity of exos and drugs in vitro. Additionally, its unique physical structure prevents it from being tightly attached to the skin of the wound, it promotes cell migration, angiogenesis by slowly releasing exos and tazarotene in the deep layer of the skin. The full-thickness cutaneous wound on a diabetic mouse model was carried out to demonstrate the therapeutic effects of GelMA/PEGDA@T + exos MNs patch. As a result, our GelMA/PEGDA@T + exos MNs patch presents a potentially valuable method for repairing diabetic wound in clinical applications. Graphic Abstract

The abundant neurovascular network in the periosteal fibrous layer is essential for regulating bone homeostasis and repairing bone defects. However, the majority of the current studies only focus on the structure or function, and most of them merely involve osteogenesis and angiogenesis, lacking an in-depth study of periosteal neurogenesis. In this study, a photothermal double-layer biomimetic periosteum with neurovascular coupling was proposed. The outer layer of biomimetic periosteum is a conventional electrospinning membrane to prevent soft tissue invasion, and the inner layer is an oriented nanofiber membrane to promote cell recruitment and angiogenesis. From the perspective of functional bionics, based on the whitlockite (WH) similar to bone composition, we doped Nd (the trivalent form of neodymium element) in it as the inducing element of photothermal response to prepare photothermal whitlockite (Nd@WH). The sustained release of Mg2+ in Nd@WH can effectively promote the up-regulation of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). The release of Ca2+ and PO43− ions and photothermal osteogenesis jointly promote bone regeneration. Under the combined effect of structure and function, the formation of nerves, blood vessels, and related collagens greatly simulates the microenvironment of extracellular matrix and periosteum regeneration and ultimately promotes bone regeneration. In this study, physical and chemical characterization proved that the bionic periosteum has good flexibility and operability. The in vitro cell experiment and in vivo calvarial defect model verified that PPCL/Nd@WH biomimetic periosteum had excellent bone tissue regeneration function compared with other groups. Finally, PPCL/Nd@WH provides a new idea for the design of bionic periosteum.

In spite of the considerable achievements in the field of regenerative medicine in the past several decades, osteochondral defect regeneration remains a challenging issue among diseases in the musculoskeletal system because of the spatial complexity of osteochondral units in composition, structure and functions. In order to repair the hierarchical tissue involving different layers of articular cartilage, cartilage-bone interface and subchondral bone, traditional clinical treatments including palliative and reparative methods have showed certain improvement in pain relief and defect filling. It is the development of tissue engineering that has provided more promising results in regenerating neo-tissues with comparable compositional, structural and functional characteristics to the native osteochondral tissues. Here in this review, some basic knowledge of the osteochondral units including the anatomical structure and composition, the defect classification and clinical treatments will be first introduced. Then we will highlight the recent progress in osteochondral tissue engineering from perspectives of scaffold design, cell encapsulation and signaling factor incorporation including bioreactor application. Clinical products for osteochondral defect repair will be analyzed and summarized later. Moreover, we will discuss the current obstacles and future directions to regenerate the damaged osteochondral tissues.

Wallerian degeneration after peripheral nerve injury (PNI), that is, the autonomous degeneration of distal axons, leads to an imbalance of iron homeostasis and easily induces oxidative stress caused by iron overload. Inspired by the process of nerve degeneration and regeneration, the design of a functional electrospinning scaffold with iron chelating ability exhibited the importance of reconstructing a suitable microenvironment. Here, an electrospinning scaffold based on deferoxamine and poly(3(S)-methyl-morpholine-2,5-dione-co-lactone) (PDPLA/DFO) was constructed. This work aims to explore the promotion of nerve regeneration by the physiological regulation of the scaffold. In vitro, PDPLA/DFO films mitigated the reduction of glutathione and the inactivation of Glutathione peroxidase 4 caused by iron overload. In addition, they decreased reactive oxygen species, relieve the stress of the endoplasmic reticulum and mitochondria, and reduce cell apoptosis. In vivo, PDPLA/DFO conduits constructed the anti-inflammatory microenvironment and promoted cell survival by alleviating iron overload and organelle stress. In conclusion, PDPLA/DFO guidance conduits targeted the distal iron overload and promoted nerve regeneration. It provides novel ideas for designing nerve conduits targeting the distal microenvironment.

Chitosan (CS) is a type of natural polysaccharide, widely used as a biomaterial on account of its great biocompatibility and the multitudes of functional groups on the long chitosan chain, making it easy for property augmentations. Nevertheless, the lack of workability and mechanical capacity limits the applications. Herein, electrospinning was chosen to fabricate oriented chitosan/polyethylene oxide (PEO) nanofibres decorated by integrin-targeting polypeptides (RGD, Arg-Gly-Asp), which is essential for cell adhesion. At the same time, porous PLGA-PEG membranes were taken as a shell of the composite film, which can provide mechanical support for the scaffold. Adequate topological anisotropic information from oriented nanofibres helps the scaffold simulate the natural axon structure, which can induce accelerated regeneration of neurotmesis. Moreover, β-Tricalcium Phosphate (β-TCP) nanoparticles were brought into nanofibers to neutralize the acidic environment produced by the degeneration of PLGA-PEG. Cell viability tests at the in vitro level and dorsal root ganglion (DRG, 1-day sucking SD rat) co-culture detection proved that the scaffold possesses excellent biocompatibility while guiding oriented regeneration of damaged nerves. In this study, a CS-RGD/PEO/β-TCP/PLGA-PEG porous composite scaffold with low cytotoxicity was fabricated. The scaffold can not only lead to the oriented growth of nerves but also has selectivity, which can help nutrient exchange while inhibiting the invasion of fibrous tissue.

Vascularisation and mineralisation are indispensable conditions for bone repair materials. The introduction of magnesium ions into calcium phosphate-based materials can give them angiogenic and mineralising capabilities. However, the optimum calcium to magnesium ratio has yet to be determined. Microspheres have received much attention from researchers due to their flexibility, non-agglomeration and other advantages. We prepared calcium-magnesium phosphate biphasic microspheres (CMBS) using the water-in-oil emulsion cross-linking method to achieve osteogenic differentiation and vascularisation. The simultaneous use of the sacrificial template method and heat treatment endow the microspheres with a rich micro-pore structure. In addition, we investigated the compounding ratio of calcium phosphate to magnesium phosphate and determined the optimal compounding ratio (Ca/Mg = 3/1–1/1) for this material. The prepared microspheres promoted the attachment, proliferation and directed differentiation of bone marrow mesenchymal stromal cells (BMSCs) and human umbilical vein cells (HUVECs). CMBS-I (Ca/Mg = 3/1) and CMBS-II (Ca/Mg = 1/1) microspheres showed the best promotion effect among all groups. These microspheres were implanted under the skin of Sprague- Dawley (SD) rats, and the composite microspheres significantly induced vascular regeneration compared to pure phase microspheres.

An ideal scaffold should have good biocompatibility and osteogenic differentiation properties and provide interconnected porous networks for cell penetration and nutrient and waste transportation. To improve the biological activity of hydrogels, with nano-β-tricalcium phosphate (TCP) as a model, we successfully designed β-TCP nanoparticle/hydrogel encapsulated scaffolds, which improved the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) and focused on the osteogenic differentiation mechanism of the β-TCP nanoparticle-mediated microenvironment and phosphorus. Results showed that β-TCP nanoparticles affected phosphorylated ERK1/2 and BMP-2 signalling molecules in BMSCs through ATP metabolism. Addition of an ATP inhibitor (NEM) and SLC20a1 inhibitor (Foscarnet), significantly inhibited expression of phosphorylated ERK1/2 and BMP-2. This study also provides an understanding of the positive role of β-TCP nanoparticles and β-TCP nanoparticle/hydrogel-encapsulated scaffolds in the bone repair field.

The mesoporous hydroxyapatite (HAP) powder was synthesized by using the microemulsion (hexadecyltrimethyl ammonium bromide (CTAB)/cyclohexane/n-octyl alcohol) system. The optimal ratios of concentrations of CTAB, cyclohexane and n-octyl alcohol in the microemulsion on morphology of the HAP were studied. The effects of pHs and calcination temperatures on the phase composition of the HAP powder were discussed. The phase composition, morphology, mesoporous structure and the optical density (OD) were characterized and confirmed by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), N2 adsorption–desorption isotherms and Multiskan Spectrum, respectively. We further investigated the effect of the HAP powder with meso-structure on the proliferation of bone marrow mesenchymal stem cells (BMSCs) and MC3T3 in vitro, and in vitro study of drug release of mesoporous HAP powder. Through the optimized microemulsion system (CTAB 25 g/L/cyclohexane 125 mL/L/n-octyl alcohol 250 mL/L) at pH of 11.0, the mesoporous HAP was formed. The specific surface area of the HAP powder product is 13.62 m2/g with an average pore size of 19.56 nm after calcinating at 850 °C. Keywords: Hydroxyapatite, Mesoporous, Microemulsion, Cells, pH, Calcinating

Magnesium phosphate-based bone cements (MPBCs) have been widely applied in orthopedic and dental fields owing to their excellent self-setting ability and high strength. However, their lack of macroporosity and poor drug release properties restrict their use. In this study, we incorporated various degrees of cross-linking of gelatine microspheres (GM) into MPBC and improved the physicochemical and biocompatible properties, biodegradation and drug release behaviour of the composites. Diclofenac sodium (DS) was utilized as a model drug. Through experiments and observations, we found that the GM induced an adjustable setting time (12 min–16 min), high compression strength (23 MPa–58 MPa), abundant macropores (30.2%–37.8%) and sustained DS release with the double exponential biphasic kinetic model (more than 2 months) into the MPBC composites. Moreover, the sustained release of magnesium and calcium ions had a synergistic effect with GM on the proliferation, osteogenesis differentiation, mineralization ability and gene expression (COL I, OPN, and Runx2) of MC3T3-E1 cells. Subcutaneous implantation and histological analyses indicated that the MPBC-GM composites activated angiogenesis without inducing severe inflammatory reactions. In brief, we prepared biocompatible MPBC composites with adjustable physicochemical properties, formation of macropores, degradation and drug release behaviour.

Abstract One hundred fifty to 300-nm-sized monodisperse iron oxide (Fe3O4) hollow microspheres were synthesized by the one-pot hydrothermal method. The morphology and crystal structure of the as-prepared hollow microspheres was characterized by scanning electron microscopy, X-ray diffraction, transmission electron microscopy, and high-resolution transmission electron microscopy, while the magnetic property was investigated by vibrating sample magnetometer. We found that the particle size of the hollow microspheres was related to the amount of sodium citrate, polyacrylamide (PAM), and urea. The hollow structure of Fe3O4 microspheres has high magnetization saturation values ranging in 49.10–75.41 emu/g.

Chemical substances containing citrate such as calcium citrate, citrate esters and citric acid exhibit anti-oxidant and anti-inflammatory properties in different cells and tissues. However, data on the anti-oxidant and anti-inflammatory properties and mechanisms of action of citrate are insufficient. In this study, we systematically evaluated the anti-oxidant capacity of citrate using chemical, cellular and animal assays. Citrate showed a stable molecular structure and did not directly react with oxides. Citrate exerted protective and anti-apoptotic effects on BMSCs and also showed significant inhibitory effects on the oxidative stress and inflammatory reactions in the rat air pouch model. By using proteomics, we found that PPARγ contributed to the upregulation of various free radical scavenging proteins and the downregulation of diverse components of the inflammatory responses. Citrate-regulated global PPARγ expression was evidenced by the significant increase expression of PPARγ in PC12 cell line. Our results provide novel insights into the role of citrate in regulating cellular redox signaling and the function of PPARγ signaling in this process and also provide basic molecular cell biology information to improve the applications of biomaterials or stem cells as treatments for oxidative stress-induced degenerative diseases and inflammatory diseases. Keywords: Anti-oxidant, Citrate, Oxidative stress, Stem cells, ITRAQ

Abstract Neuroma formation after amputation as a long‐term deficiency leads to spontaneous neuropathic pain that reduces quality of life of patients. To prevent neuroma formation, capping techniques are implemented as effective treatments. However, an ideal, biocompatible material covering the nerves is an unmet clinical need. In this study, biocompatible characteristics presented by the poly(D,L‐lactic acid)/arginylglycylaspartic acid (RGD peptide) modification of poly{(lactic acid)‐co‐ [(glycolic acid)‐alt‐(L‐lysine)]} (PRGD/PDLLA) are evaluated as a nerve conduit. After being capped on the rat sciatic nerve stump in vivo, rodent behaviors and tissue structures are compared via autotomy scoring and histological analyses. The PRGD/PDLLA capped group gains lower autotomy score and improves the recovery, where inflammatory infiltrations and excessive collagen deposition are defeated. Transmission electron microscopy images of the regeneration of myelin sheath in both groups show that abnormal myelination is only present in the uncapped rats. Changes in related genes (MPZ, MBP, MAG, and Krox20) are monitored quantitative real‐time polymerase chain reaction (qRT‐PCR) for mechanism investigation. The PRGD/PDLLA capping conduits not only act as physical barriers to inhibit the invasion of inflammatory infiltration in the scar tissue but also provide a suitable microenvironment for promoting nerve repairing and avoiding neuroma formation during nerve recovery.