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Hydrogels are widely used as debriding agents on account of providing a moist environment for wound healing, however the lack of mechanical strength, angiogenesis and antibacterial property limits their applications. In this study, we synthesized novel divalent ion cross-liking hydrogels (copper, zinc, strontium and calcium) and compared the mechanical performance, swelling ratio, antibacterial properties and biocompatibility in vitro and vivo . Thereinto, among the four divalent ions cross-linked hydrogels, copper ion crosslinking exhibited the maximum breaking strength, while strontium and zinc ion cross-linked hydrogels exhibited an excellent mechanical strength. In addition, the swelling ratio and pore size of no-ion cross-linked hydrogels was larger than ion cross-kinked hydrogels. In vitro , the improvements on wound healing after hydrogel application were evaluated by histological and molecular assays by detecting VEGF and TGF-β expression. In vitro and in vivo study results showed that zinc cross-kinked hydrogel had a spectrum of antibacterial activities, cell viability, mechanical strength and the ability of wound closure by promoting fibroblasts migration, vascularization, collagen deposition and the formation of granulation tissue. [ABSTRACT FROM AUTHOR]

Herein, a polyacrylic acid sol-gel method was presented to synthesize rare earth doped calcium phosphate nanocrystals (RE-CaP) as cell bioimaging agent. The effects of calcination temperature, calcination time and PAA concentration on phase composition, morphology, size and luminescence were discussed. In addition, the hemolysis, cytotoxicity, cell uptake and cell imaging of resulting RE-CaP nanocrystals were investigated. Results show that the increases in calcination temperature and time promote the transformation of product from impure crystalline phase (CaCO 3 , CaO) to pure CaP phase. The rise of calcination temperature results in significant enhancement of luminescence intensity. PAA concentration does not influence the crystalline phase composition and its increase leads to a little increase in luminescence intensity. In addition, the co-doping of Gd 3+ improves the luminescence intensity of Eu 3+ emissions. This method achieves the doping of Eu 3+ ions in the crystallographic Ca 2+ I and Ca 2+ II sites of HAP with a preferable occupation at Ca 2+ II site. The resulting RE-CaP nanocrystals (PAA: 0.6 mg/mL, Eu/Gd = 2:1.5, 600 °C, 3 h) show good biocompatibility and can be easily uptaken by cancer cells. The internalized nanocrystals show stable and strong red luminescence under visible wavelengths excitation. In summary, PAA sol-gel method can be used to synthesize biocompatible RE-CaP luminescent nanomaterials for cell bioimaging. [ABSTRACT FROM AUTHOR]

[Display omitted] • Lipoic acid modifies chitosan into a soluble form (LAMC) that can form a hydrogel under UV light without a photoinitiator. • The LAMC hydrogel exhibits strong adhesion, making it effective in adhering to the wound and preventing detachment. • LAMC hydrogel is cell-friendly, and the hydrogel loaded with exosomes shows respectable skin wound repair effects. Diabetic wounds are challenging to heal due to high glucose levels, and oxidative stress, impaired immune response and delayed angiogenesis. Hydrogel dressings capable of adapting and improving multiple microenvironments have broad prospects for application in clinical diabetes wound healing. In this study, we developed a photocrosslinked chitosan hydrogel using the antioxidant molecule "lipoic acid", eliminating the need for additional photoinitiators. The obtained hydrogel exhibited respectable adhesion (adhesion strengths to iron, wood and skin are 0.045 MPa, 0.049 MPa and 0.041 MPa, respectively), photo-induced self-healing, and responsiveness to pH, H 2 O 2 and glucose. Notably, as compared to conventional injectable methacrylated chitosan hydrogel, LAMC hydrogels displayed the abilities to regulate the wound environment, such as reducing oxidative stress, blood sugar levels, and pH, and creating a favorable microenvironment for wound healing. Exosome-loaded LAMC hydrogels enabled targeted exosome release based on glucose concentration, pH, and H 2 O 2 to promote angiogenesis and accelerate healing. Our study offers a novel method for preparing injectable chitosan hydrogels and introduces a new strategy for developing drug-delivery systems that effectively promote diabetic wound healing, potentially transforming current therapeutic approaches. [ABSTRACT FROM AUTHOR]

• 3D-printed dual-ion chronological release functional platform was successfully prepared. • The platform can realize the chronological release of magnesium and zinc ions. • The controlled release of magnesium ion can significantly promote the early reconstruction of neurovascular network. • Early neuro-vascularization network reconstruction is important for eventual bone regeneration. Critical-sized bone defects remain an unsolved challenge because of the failure to induce early reconstruction of the neuro-vascularization network. Nerve and vascular regeneration begin immediately after the occurrence of bone defect and play a key role in the subsequent osteogenic differentiation. In this study, a 3D-printed alpha-tricalcium phosphate scaffolds with dual-ion chronological release functional platform consisted of magnesium containing gelatin microspheres and zinc-doped bioglass was designed to reconstruct neuro-vascularization network for critical-sized bone defect regeneration. Our results demonstrated that magnesium containing gelatin microspheres could regulate the release rate of Mg2+ and achieve early complete release of Mg2+. The controlled release of Mg2+ can effectively enhance the vascularization of human umbilical vein endothelial cells and the ability of nerve regeneration of PC12 cells in vitro and also avoid the potential inhibition of high concentration of Mg2+ on bone formation in late osteogenesis. Moreover, zinc-doped bioglass ensured the long-term release of Zn2+, thereby promoting the activity and osteogenic differentiation of bone marrow mesenchymal stem cells. In rat calvarial critical-sized defect models, 3D-printed alpha-tricalcium phosphate scaffolds with dual-ion chronological release functional platform could significantly enhance neuro-vascularization network density and exhibited excellent performance in promoting new bone formation. Consequently, the 3D-printed alpha-tricalcium phosphate scaffolds with dual-ion chronological release functional platform has the potential to be used as bone grafts for repairing critical-sized bone defects and provides guidance for the design of repair materials. [ABSTRACT FROM AUTHOR]

Biocompatible, biodegradable and stimuli-responsive nanomaterials can be used as drug carriers and to achieve controlled drug delivery, which is crucial for treating tumors and lowering drug side effects. Calcium phosphate (CaP) nanoparticles and poly(acrylic acid) (PAA) hydrogels can be used as biocompatible and pH-responsive drug carriers. In this study, based on the ultrasound effect, PAA/CaP hybrid nanogels (approximately 100 nm, PDI < 0.2) are obtained via the cross-linking of CaP nanoparticles and PAA molecules between the Ca 2 + ions and –COOH groups. The PAA/CaP hybrid nanogels show good stability in biological media as well as no hemolysis and no cytotoxicity to L02 cells. Moreover, the PAA/CaP hybrid nanogels display an enhanced loading capacity (approximately 32%) for doxorubicin hydrochloride (DOX) compared to pure CaP nanoparticles (approximately 7.5%) and a pH-controlled drug release due to their dissolution in acidic environment. DOX can be delivered into cancer cells by the PAA/CaP hybrid nanogels, which show an inhibitory effect comparable to that of free DOX, although the inhibitory effect is delayed due to the slow release of DOX from the carriers. In vivo , the PAA/CaP hybrid nanogels cannot avoid the capture by the reticuloendothelial system; however, they show passive tumor targeting ability. In brief, the biocompatible, biodegradable and pH-responsive PAA/CaP hybrid nanogels have the potential to act as drug carriers for controlled drug release. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) decreases people's both physical and psychological levels. The rehabilitation of SCI is still a clinical challenging process owing to the inflammatory environment for cell survival. Herein, we designed a dopamine-modified chitosan hydrogel to improve poor microenvironment of spinal cord injury. Dopamine modified chitosan hydrogel was fabricated by crosslinking with citric acid (CS-CA-DA), which address the insufficient mechanical properties. In vitro analysis showed that dopamine modification improved the cell survival and cell adhesion. Moreover, implantation of CS-CA-DA hydrogel alone into rat injured spinal cord helped improving cell survivals, modulating immunity, promoting macrophage polarization to the M2 phenotype and promoting axonal regeneration in vivo in brutal areas of SCI. This strategy of modified chitosan with dopamine undergoing a high mechanical properties, excellent cell compatibility and antioxidant performance, providing a new insight into repairing spinal cord injury. The preparation process of CS-CA-DA hydrogel and physicochemical structure and multifunctional properties of CS-CA-DA hydrogel. [Display omitted] [ABSTRACT FROM AUTHOR]

For the treatment of infected bleeding wounds, we compounded methacrylate anhydride dopamine (DAMA) and Zn-doped whitlockite nanoparticles (Zn-nWH) into methacrylate anhydride quaternized chitosan (QCSMA) to obtain a multifunctional hydrogel dressing (QCSMA/DAMA/Zn-nWH) with hemostasis, disinfection and wound healing promotion. QCSMA/DAMA/Zn-nWH exhibited good adhesion (0.031 MPa) and DPPH scavenging ability (94%), favorable biocompatibility (hemolysis ratio < 2%, no cytotoxicity), and showed a low BCI value (< 13%) in vitro coagulation test and could activate coagulation pathway. In addition, QCSMA/DAMA/Zn-nWH had excellent hemostatic effect (129 ± 22 s, 27 ± 5 mg) in vivo compared with the control (571 ± 15 s, 147 ± 31 mg) and CCS (354 ± 27 s, 110 ± 46 mg). Meanwhile, QCSMA/DAMA/Zn-nWH showed excellent antibacterial properties (> 90% against S. aureus and E. coli) and could promote collagen deposition, reduce inflammatory expression and promote wound healing. All results indicate that these multifunctional hydrogel dressings have great potential in clinical hemostasis and anti-infection healing. Preparation of QCSMA/DAMA/Zn-nWH hydrogel dressing through mixing the methacrylate anhydride quaternized chitosan (QCSMA), methacrylate anhydride dopamine (DAMA) and Zn-doped whitlockite nanoparticles (Zn-nWH) via photo-polymerization and the coordination of metal ions with the catechol group of dopamine. The hydrogel dressing has excellent adhesion antibacterial and antioxidation properties, which can quickly achieve incompressible liver hemostasis, and promote the infected full-thickness skin defect wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Reconstruction of the microenvironment at the site of injury plays an important role in tissue regeneration and functional recovery. With calcium magnesium phosphate (MCPC) as a model, the effects of MCPC on the vascularization and neurotization in the process of wound regeneration were investigated. Herein, a series of MCPC/hydrogels with different concentrations (0–4%) of MCPC were synthesized. The results showed that MCPC could stimulate the migration behavior of vascular endothelial cells (HUVECs) and up-regulate the expression of VEGF and HIF-1α genes. Further in vivo results revealed that MCPC/hydrogels significantly improved wound healing and blood vessel formation. In addition, we demonstrated that MCPC/hydrogels could also largely accelerate the regeneration of nerves, which would finally contribute to wound healing due to the proper release of magnesium and calcium ions. This research also provides an insight toward the positive role of MCPC in vascular and nerve reconstruction during wound healing. [ABSTRACT FROM AUTHOR]

Biphasic ceramic microspheres promote osteogenic differentiation and angiogenesis. [Display omitted] • The biphasic microspheres are composed of calcium phosphate and magnesium phosphate. • The surface morphology, internal structure and protein adhesion ability of the biphasic microspheres could be adjusted with the change of sintering temperature. • The biphasic microspheres showed good viability and stimulation on the proliferation, osteogenic differentiation, mineralization ability of BMSCs. • Biphasic microspheres have a robust promoting effect on angiogenesis. 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. [ABSTRACT FROM AUTHOR]

Novel GSH/enzyme-responsive anti-hyperthyroidism prodrugs were developed for transdermal delivery of 2-sulfonyl-1-methylimidazole and enhancing the therapeutic effect. [Display omitted] • Novel prodrugs for transdermal delivery of methimazole (MMI) were synthesized. • The prodrugs showed a transdermal effect significantly higher than parent MMI. • GSH-triggerd drug release behavior was confirmed. • A significant inhibition on lactoperoxidase (LPO) was observed. • The prodrugs will be useful in improvement of transdermal delivery of MMI. Novel GSH/enzyme-responsive anti-hyperthyroidism prodrugs designed for transdermal delivery of 2-sulfonyl-1- methylimidazole (MMI) were synthesized by a Michael addition reaction of MMI with propiolic acid (PA) followed by esterification with three long chain fatty alcohols and their structures were characterized by 1H NMR, 13C NMR and mass spectrometry. Their maximum steady state flux through rat skin in the PG/W solution was found to be more than 37-times faster than that of MMI. The result may be attributed to the improved lipophilicity of prodrug and rapid bioconversion. The prodrugs were hydrolyzed by esterase on passing through the skin and appeared mainly as intermediate MMI-PA in the receiver compartment and accompanied by a small amount of MMI and intact prodrug. The prodrugs did not release any MMI in the media without GSH or with 100 µM GSH, while the obvious MMI release could be observed within 6.4 h in the media containing 2 mM and 10 mM GSH, and their maximum cumulative release rates reached 95.07% for lauryl alcohol ester prodrug (MMI-PA-OLa). MMI-PA-OLa exhibited a significant inhibition effect on lactoperoxidase (LPO) after being incubated in millimolar GSH media, whose inhibition rate was very similar to that of free MMI with an equivalent dose. These results suggested that MMI-PA-OLa could pass efficiently through the skin and release MMI in response to the intracellular environment. [ABSTRACT FROM AUTHOR]

Facilitating angiogenesis, reducing the formation of glial scar tissue, and the occurrence of a strong inflammatory response are of great importance for the repair of central nerve damage. In our previous study, a temperature-sensitive hydrogel grafted with bioactive isoleucine-lysine-valine-alanine-valine (IKVAV) peptide was prepared and it showed regular three-dimensional porous structure, rapid (de)swelling performance and good biological activity. Therefore, in this study, we used this hydrogel scaffold to treat for SCI to study the effect of it to facilitate angiogenesis, inhibit the differentiation and adhesion of keratinocytes, and further reduce the formation of glial scar tissue. The results reveal that the peptide hydrogel scaffold achieved excellent performance and can also promote the expression of angiogenic factors and reduce the secretion of pro-inflammatory factors to a certain extent. Particularly, it can also inhibit the formation of glial scar tissue and repair damaged tissue. The proposed strategy for developing this hydrogel scaffold provides a new insight into designing biomaterials for a broad range of applications in the tissue engineering of the central nervous system (CNS). [Display omitted] • The PNPP-IKVAV scaffold can be conducive to angiogenesis. • The PNPP-IKVAV scaffold can inhibit the formation of glial scar tissue and improve functional recovery of damaged tissues. • The PNPP-IKVAV scaffold can enhance neuron differentiation in neural stem cells effectively. [ABSTRACT FROM AUTHOR]

Delayed injured nerve regeneration remains a clinical problem, partly ascribing to the lack of regulation of regenerative microenvironment, topographical cues, and blood nourishment. Functional electrospun conduits have been established as an efficacious strategy to facilitate nerve regeneration by providing structural guidance, regulating the regenerative immune microenvironment, and improving vascular regeneration. However, the synthetic polymers conventionally used to fabricate electrospinning scaffolds, such as poly(L-lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), can cause aseptic inflammation due to acidic degradation products. Therefore, a poly[3(S)-methyl-morpholine-2,5-dione- co -lactic] [P(MMD- co -LA)] containing alanine units with good mechanical properties and reduced acid degradation products, was obtained by melt ring-opening polymerization (ROP). Here, we aimed to explore the effect of oriented nanofiber/Deferoxamine (DFO, a hydrophilic angiogenic drug) scaffold in the rapid construction of a favorable regenerative microenvironment, including cell bridge, polarized vascular system, and immune microenvironment. In vitro studies have shown that the scaffold can sustainably release DFO, which accelerates the migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as the expression of genes related to angiogenesis. The physical clues provided by the arranged nanofibers can regulate the polarization of macrophages and reduce the expression of inflammatory factors. Furthermore, the in vivo results demonstrated a higher M2 polarization level of the oriented nanofibrous scaffold treatment group with reducedinflammation reaction in the injured nerve. Moreover, the in-situ release of DFO up-regulated the expression of HIF1-α and SDF-1α genes, as well as the expression of HIF1-α′s target gene VEGF, further promoting revascularization and enhancing nerve regeneration at the defect site. The obtained results provide essential insights on accelerating the creation of the nerve regeneration microenvironment by combining the physiological processes of nerve regeneration with topographical cues and chemical signal induction. [ABSTRACT FROM AUTHOR]

The difficulty of wound healing in patients with diabetes mellitus remains a considerable challenge for clinical and scientific research. To address the problem of poor healing that affects chronic wounds in patients with diabetes, we developed an injectable self-healing hydrogel based on chitosan (CS), hyaluronic acid (HA), and kalium γ-cyclodextrin metal organic frameworks (K-γ-CD-MOFs) loaded α-lipoic acid (α-LA) with antibacterial activity and antioxidant performance. In vitro analysis showed that the hydrogel could promote cell proliferation and migration on the basis of Cell Counting Kit-8 (CCK-8) assay and Transwell experiments. Moreover, the addition of α-LA allowed the reversal of oxidative stress-induced cell damage. In vivo analyses were performed involving a full-thickness wound model in diabetic Sprague–Dawley (SD) rats. The hydrogel dressing significantly promoted the wound healing process with better granulation tissue formation and more collagen deposition because of its multifunctional traits, suggesting that it can be an excellent treatment for chronic full-thickness skin wound healing. • QCS-OHA hydrogel with Injectable, self-healing antibacterial properties are obtained. • QCS-OHA hydrogel combined with (K-γ-CD-MOFs) achieves sustained drug release. • QCS-OHA-α-LA hydrogel has vascularization and antioxidant effects for promoting wound healing. [ABSTRACT FROM AUTHOR]

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. Unlabelled Image • Macroporous magnesium phosphate-based bone cements (MPBCs) with sustained drug release was constructed by cross-linked gelatine microspheres (GM). • With the change of cross-linking extent, the setting time and compression strength, degradation behaviour, drug release ability of MPBC-GM composites will be adjustable for clinical application. • MPBC-GM composites showed good viability and stimulatory effect on the proliferation, osteogenesis differentiation, mineralization ability and gene expression (COL I, OPN, and Runx2) of MC3T3-E1 cells. • MPBC-GM composites showed a strong potential promotion on the angiogenesis. [ABSTRACT FROM AUTHOR]

Natural polymers and synthetic polymers have been extensively studied as scaffold materials, with the former offering advantages such as biocompatibility, biodegradability, and structural similarity to the natural extracellular matrix (ECM). However, the use of natural polymers in extrusion-based 3D printing has been limited by their poor mechanical properties and challenging rheological properties. In this study, gelatin and sodium alginate were utilized as scaffold materials, with the addition of Ca 2+ and Mg 2+ components to enhance their physical and chemical properties, and influence early cell behavior. Subsequently, these materials were fabricated into scaffolds using 3D printing. Our results demonstrated that the addition of Ca 2+ and Mg 2+ could improve the compactness of the 3D network structure, mechanical strength, swelling properties and degradation properties of methacrylated gelatin/methacrylated sodium alginate (GelMA/SAMA) composite hydrogel. In vitro cell tests revealed that the GelMA/SAMA composite hydrogel exhibited negligible cytotoxicity and promoted early cell viability, particularly with the higher concentration of Mg 2+ in the material. Notably, the extrusion 3D printing process successfully produced GelMA/SAMA scaffolds. These results collectively indicate that GelMA/SAMA composite scaffolds hold promise as potential biomaterials for tissue engineering applications.

Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis, is fabricated. Mechanistically, only outside M1 macrophages are accumulated high concentrations of citrate, in contrast, M2 macrophages consume massive citrate. Therefore, citrate-functionalized scaffolds exert more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate can block glycolysis-related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. These studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) guided by Fenton chemistry and iron-containing materials can induce ferroptosis as a prospective cancer treatment method, but the inefficient Fe 3+ /Fe 2+ conversion restricts the monotherapeutic performances. Here, an iron-based nanoplatform (Fe 3 O 4 -SRF@FeTA) including a magnetic core and a reductive film is developed for combined CDT and photothermal therapy (PTT) through ferroptosis augmentation. The inner iron oxide core serves as a photothermal transducer, a magnet-responsive module, and an iron reservoir for CDT. The coated Fe 3+ -tannic acid film (FeTA) provides extra iron and reductants for Fe 3+ /Fe 2+ conversion acceleration, and functions as a door keeper for the pH- and light-responsive release of the embedded ferroptosis inducer sorafenib (SRF). The in vitro results demonstrate that the iron-based nanocomplexes promote the production of lipid peroxide through the amplified Fenton activity, and downregulate glutathione involved in lipid peroxide repair system through the responsively released SRF. Upon accumulation in tumor by magnetic targeting and sequential laser irradiation locoregionally, Fe 3 O 4 -SRF@FeTA nanocomplexes present prominent in vivo anticancer efficacy by leveraging PTT and CDT-enhanced ferroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Predicting protein binding with the material surface still remains a challenge. Here, a novel approach, platypus dual perception neural network (Platyper), was developed to describe the interactions in protein-surface systems involving bioceramics with BMPs. The resulting model integrates a graph convolutional neural network (GCN) based on interatomic potentials with a convolutional neural network (CNN) model based on images of molecular structures. This dual-vision approach, inspired by the platypus's adaptive sensory system, addresses the challenge of accurately predicting the complex binding and unbinding dynamics in steered molecular dynamics (SMD) simulations. The model's effectiveness is demonstrated through its application in predicting surface interactions in protein-ligand systems. Notably, Platyper improves computational efficiency compared to classical SMD-based methods and overcomes the limitations of GNN-based methods for large-scale atomic simulations. The incorporation of heat maps enhances model's interpretability, providing valuable insights into its predictive capabilities. Overall, Platyper represents a promising advancement in the accurate and efficient prediction of protein-surface interactions in the context of bioceramics and growth factors.

Dynamic covalent bond hydrogels have demonstrated significant application potential in biomedical fields for their dynamic reversibility. However, the contradiction between the stability and dynamics of the hydrogel restricts its application. Here, utilizing silver sulfadiazine (AgSD) as a catalyst, hyaluronic acid-based hydrogels are constructed through imine bond crosslinking and incorporated disulfide bonds within the same crosslinking chain. It is found that AgSD can accelerate the formation of imine crosslinking bonds to improve the stability of hydrogels, thereby shortening the gelation time by ≈36.9 times, enhancing compression strength and adhesion strength by ≈2.4 times and 1.7 times, respectively, while inhibiting swelling and degradation rates to ≈2.1 times and 3.7 times. Besides, AgSD can coordinate with disulfide bonds to enhance the dynamics of hydrogel, enhancing the hydrogel self-healing efficiency by ≈2.3 times while reducing the relaxation time by ≈25.1 times. Significantly, AgSD imparts remarkable antibacterial properties to the hydrogel, thereby effectively facilitating the healing of bacterial infected wounds. Consequently, introducing AgSD enables hydrogels to possess concurrent stability, dynamics, and antibacterial properties. This strategy of regulating hydrogels by introducing AgSD provides a valuable reference for the application of dynamic covalent bonds., (© 2024 Wiley‐VCH GmbH.)

Bone cement is widely used in clinical with optimistic filling and mechanical properties. However, the setting time of bone cement is difficult to accurately control, and the existing bone cements exhibit limited therapeutic functionalities. In response to these challenges, we designed and synthesized Nd-doped whitlockite (Nd-WH), endowing bone cement with photothermal-responsive and fluorescence imaging capabilities. The doping amount and photothermal properties of Nd-doped whitlockite were studied, and the composite bone cement was prepared. The results showed that the setting time of bone cement could be regulated by near infrared irradiation, and the multiple functions of promoting osteogenic differentiation, antibacterial and anti-tumor could be realized by adjusting the power and irradiation time of near infrared. By incorporating Nd-doped whitlockite and bone cement, we developed an all-in-one strategy to achieve setting time control, enhanced osteogenic ability, tumor cell clearance, bacterial clearance, and bone tissue regeneration. The optimized physical and mechanical properties of composite bone cement ensure adaptability and plasticity. In vitro and in vivo experiments validated the effectiveness of this bone cement platform for bone repair, tumor cell clearance and bacterial clearance. The universal methods to regulate the setting time and function of bone cement by photothermal effect has potential in orthopedic surgery and is expected to be a breakthrough in the field of bone defect repair. Further research and clinical validation are needed to ensure its safety, efficacy and sustainability. STATEMENT OF SIGNIFICANCE: Bone cement is a valuable clinical material. However, the setting time of bone cement is difficult to control, and the therapeutic function of existing bone cement is limited. Various studies have shown that the bone repair capacity of bone cements can be enhanced by synergistic stimulatory effects in vivo and ex vivo. Unfortunately, most of the existing photothermal conversion materials are non-degradable and poorly biocompatible. This study provides a bone-like photothermal conversion material with photothermal response and fluorescence imaging properties, and constructed a platform for integrated regulation of the setting time of bone cement and diversification of its functions. Therefore, it helps to design multi-functional bone repair materials that are more convenient and effective in clinical operation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The regenerative microenvironment after peripheral nerve injury is imbalanced and difficult to rebalance, which is mainly affected by inflammation, oxidative stress, and inadequate blood supply. The difficulty in remodeling the nerve regeneration microenvironment is the main reason for slow nerve regeneration. Traditional drug treatments have certain limitations, such as difficulty in penetrating the blood-nerve barrier and lack of pleiotropic effects. Therefore, there is an urgent need to build multifunctional nerve grafts that can effectively regulate the regenerative microenvironment and promote nerve regeneration. Nitric oxide (NO), a highly effective gas transmitter with diatomic radicals, is an important regulator of axonal growth and migration, synaptic plasticity, proliferation of neural precursor cells, and neuronal survival. Moreover, NO provides potential anti-inflammation, anti-oxidation, and blood vessel promotion applications. However, excess NO may cause cell death and neuroinflammatory cell damage. The prerequisite for NO treatment of peripheral nerve injury is that it is gradually released over time. In this study, we constructed an injectable NO slow-release system with two main components, including macromolecular NO donor nanoparticles (mPEG-P(MSNO-EG) nanoparticles, NO-NPs) and a carrier for the nanoparticles, mPEG-PA-PP injectable temperature-sensitive hydrogel. Due to the multiple physiological regulation of NO and better physiological barrier penetration, the conduit effectively regulates the inflammatory response and oxidative stress of damaged peripheral nerves, promotes nerve vascularization, and nerve regeneration and docking, accelerating the nerve regeneration process. STATEMENT OF SIGNIFICANCE: The slow regeneration speed of peripheral nerves is mainly due to the destruction of the regeneration microenvironment. Neural conduits with drug delivery capabilities have the potential to improve the microenvironment of nerve regeneration. However, traditional drugs are hindered by the blood nerve barrier and cannot effectively target the injured area. NO, an endogenous gas signaling molecule, can freely cross the blood nerve barrier and act on target cells. However, excessive NO can lead to cell apoptosis. In this study, a NO sustained-release system was constructed to regulate the microenvironment of nerve regeneration through various pathways and promote nerve regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The healing of scalded wounds faces many challenges such as chronic inflammation, oxidative stress, wound infection, and difficulties in vascular and nerve regeneration. Treating a single problem cannot effectively coordinate the complex regenerative microenvironment of scalded wounds, limiting the healing and functional recovery of the skin. Therefore, there is a need to develop a multi-effect treatment plan that can adaptively address the issues at each stage of wound healing. In this study, we propose a scheme for on-demand release of hydrogen sulfide (H 2 S) based on the concentration of reactive oxygen species (ROS) in the wound microenvironment. This is achieved by encapsulating peroxythiocarbamate (PTCM) in the ROS-responsive polymer poly(ethylene glycol)-poly(L-methionine) (PMet) to form nanoparticles, which are loaded into a thermosensitive injectable hydrogel, F127-poly(L-aspartic acid- N -hydroxysuccinimide) (F127-P(Asp-NHS)), to create a scald dressing. The H 2 S released by the hydrogel dressing on demand regulates the wound microenvironment by alleviating infection, reducing oxidative stress, and remodeling inflammation, thereby accelerating the healing of full-thickness scalded wounds. This hydrogel dressing for the adaptive release of H 2 S has great potential in addressing complex scalded wounds associated with infection and chronic inflammation.

Spinal cord injury (SCI) often leads to cell death, vascular disruption, axonal signal interruption, and permanent functional damage. Currently, there are no clearly effective therapeutic options available for SCI. Considering the inhospitable SCI milieu typified by ischemia, hypoxia, and restricted neural regeneration, a novel injectable hydrogel system containing conductive black phosphorus (BP) nanosheets within a lipoic acid-modified chitosan hydrogel matrix (LAMC) is explored. The incorporation of tannic acid (TA)-modified BP nanosheets (BP@TA) into the LAMC hydrogel matrix significantly improved its conductivity. Further, by embedding a bicyclodextrin-conjugated tazarotene drug, the hydrogel showcased amplified angiogenic potential in vitro. In a rat model of complete SCI, implantation of LAMC/BP@TA hydrogel markedly improved the recovery of motor function. Immunofluorescence evaluations confirmed that the composite hydrogel facilitated endogenous angiogenesis and neurogenesis at the injury site. Collectively, this work elucidates an innovative drug-incorporated hydrogel system enriched with BP, underscoring its potential to foster vascular and neural regeneration., (© 2024 Wiley‐VCH GmbH.)

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., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

The periosteum, rich in neurovascular networks, bone progenitor cells, and stem cells, is vital for bone repair. Current artificial periosteal materials face challenges in mechanical strength, bacterial infection, and promoting osteogenic differentiation and angiogenesis. To address these issues, we adjusted the electrospinning ratio of poly-ε-caprolactone and chitosan and incorporated Zn doping whitlockite with polydopamine coating into a nanofiber membrane. After a series of characterizations, optimal results were achieved with a poly-ε-caprolactone: chitosan ratio of 8:1 and 5% nanoparticle content. In vitro cell experiments and in vivo calvarial defect models, the sustained release of Mg 2+ and Ca 2+ promoted vascularization and new bone formation, respectively, while the release of Zn 2+ was conducive to antibacterial and cooperated with Mg 2+ to promote neurovascularization. Consequently, this antibacterial bionic periosteum with an angiogenesis-neurogenesis coupling effect demonstrates a promising potential for bone repair applications.

Polyethylene terephthalate (PET) artificial ligaments, renowned for their superior mechanical properties, have been extensively adopted in anterior cruciate ligament (ACL) reconstruction surgeries. However, the inherent bio-inertness of PET introduces formidable barriers to graft-bone integration, a critical aspect of rehabilitation. Previous interventions, ranging from surface roughening to chemical modifications, have aimed to address this challenge; however, consistently effective techniques for inducing graft-bone integration remain scarce. Our study employed advanced surface-coating methodologies to introduce strontium-doped hydroxyapatite (SrHA) onto PET ligaments. Detailed scanning electron microscopy (SEM) examinations revealed a uniform and integrative coating of SrHA on PET fibers. Furthermore, spectroscopic analysis confirmed the steady release of strontium ions from the coated surface under physiological conditions. In-depth cellular studies proved that extracellular strontium emanating from SrHA-coated PET (PET@SrHA) ligaments actively steers the M2 macrophage polarization. Additionally, macrophages (Mφs) manifested a heightened secretion of prohealing cytokines when exposed to PET@SrHA. Subsequent investigations showed that these cytokines acted as mediators, activating integrin signaling pathways among macrophages, vascular endothelial cells, and osteoblasts. As a direct consequence, an increased rate of angiogenesis and osteogenic differentiation was observed, vital for graft-bone integration following ACL reconstruction with PET@SrHA ligaments. From a biochemical standpoint, our results pinpoint strontium ions as influential immunomodulators, sculpting the graft-bone interface's immune environment. This insight presents the SrHA-coating technique as a viable therapeutic strategy, holding sound promise for improving angiogenesis and osseointegration outcomes during ACL reconstruction using PET-based grafts.

Sonodynamic therapy (SDT), an emerging cancer treatment with significant potential, offers the advantages of non-invasiveness and deep tissue penetrability. The method involves activating sonosensitizers with ultrasound to generate reactive oxygen species (ROS) capable of eradicating cancer cells, addressing the challenge faced by photodynamic therapy (PDT) where conventional light sources struggle to penetrate deep tissues, impacting treatment efficacy. This study addresses prevalent challenges in numerous nanodiagnostic and therapeutic agents, such as intricate synthesis, poor repeatability, low stability, and high cost, by introducing a streamlined one-step assembly method for nanoparticle preparation. Specifically, the sonosensitizer Chlorin e6 (Ce6) and the chemotherapy drug erlotinib are effortlessly combined and self-assembled under sonication, yielding carrier-free nanoparticles (EC-NPs) for non-small cell lung cancer (NSCLC) treatment. The resulting EC-NPs exhibit optimal drug loading capacity, a simplified preparation process, and robust stability both in vitro and in vivo , owing to their carrier-free characteristics. Under the synergistic treatment of sonodynamic therapy and chemotherapy, EC-NPs induce an excess of reactive oxygen in tumor tissue, prompting apoptosis of cancer cells and reducing their proliferative capacity. Both in vitro and in vivo experiments demonstrate superior therapeutic effects of EC-NPs under ultrasound conditions compared to free Ce6. In summary, our research findings highlight that the innovatively designed carrier-free sonosensitizer EC-NPs present a therapeutic option with commendable efficacy and minimal side effects.

Diabetic wounds are a difficult medical challenge. Excessive secretion of matrix metalloproteinase-9 (MMP-9) in diabetic wounds further degrades the extracellular matrix and growth factors and causes severe vascular damage, which seriously hinders diabetic wound healing. To solve these issues, a double-network porous hydrogel composed of poly (methyl methacrylate-co-acrylamide) (p(MMA-co-AM)) and polyvinyl alcohol (PVA) was constructed by the high internal phase emulsion (HIPE) technique for the delivery of potassium sucrose octasulfate (PSO), a drug that can inhibit MMPs, increase angiogenesis and improve microcirculation. The hydrogel possessed a typical polyHIPE hierarchical microstructure with interconnected porous morphologies, high porosity, high specific surface area, excellent mechanical properties and suitable swelling properties. Meanwhile, the p(MMA-co-AM)/PVA@PSO hydrogel showed high drug-loading performance and effective PSO release. In addition, both in vitro and in vivo studies showed that the p(MMA-co-AM)/PVA@PSO hydrogel had good biocompatibility and significantly accelerated diabetic wound healing by inhibiting excessive MMP-9 in diabetic wounds, increasing growth factor secretion, improving vascularization, increasing collagen deposition and promoting re-epithelialization. Therefore, this study provided a reliable therapeutic strategy for diabetic wound healing, some theoretical basis and new insights for the rational design and preparation of wound hydrogel dressings with high porosity, high drug-loading performance and excellent mechanical properties., (© The Author(s) 2024. Published by Oxford University Press.)

The multifaceted process of nerve regeneration following damage remains a significant clinical issue, due to the lack of a favorable regenerative microenvironment and insufficient endogenous biochemical signaling. However, the current nerve grafts have limitations in functionality, as they require a greater capacity to effectively regulate the intricate microenvironment associated with nerve regeneration. In this regard, we proposed the construction of a functional artificial scaffold based on a "two-pronged" approach. The whole system was developed by encapsulating Tazarotene within nanomicelles formed through self-assembly of reactive oxygen species (ROS)-responsive amphiphilic triblock copolymer, all of which were further loaded into a thermosensitive injectable hydrogel. Notably, the hydrogel exhibits obvious temperature sensitivity at a concentration of 6 wt %, and the nanoparticles possess concentration-dependent H 2 O 2 -response capability with a controlled release profile in 48 h. The combined strategy promoted the repair of injured peripheral nerves, attributed to the dual role of the materials, which mainly involved providing structural support, modulating the immune microenvironment, and enhancing angiogenesis. Overall, this study opens up intriguing prospects in tissue engineering.

Bone infection is one of the most devastating orthopedic outcomes, and overuse of antibiotics may cause drug-resistance problems. Photothermal therapy(PTT) is a promising antibiotic-free strategy for treating infected bone defects. Considering the damage to normal tissues and cells caused by high-temperature conditions in PTT, this study combines the antibacterial property of Cu to construct a multi-functional Cu 2 O@MXene/alpha-tricalcium phosphate (α-TCP) scaffold support with internal and external sandwiching through 3D printing technology. On the "outside", the excellent photothermal property of Ti 3 C 2 MXene is used to carry out the programmed temperature control by the active regulation of 808 nm near-infrared (NIR) light. On the "inside", endogenous Cu ions gradually release and the release accumulates within the safe dose range. Specifically, programmed temperature control includes brief PTT to rapidly kill early bacteria and periodic low photothermal stimulation to promote bone tissue growth, which reduces damage to healthy cells and tissues. Meanwhile, Cu ions are gradually released from the scaffold over a long period of time, strengthening the antibacterial effect of early PTT, and promoting angiogenesis to improve the repair effect. PTT combined with Cu can deliver a new idea forinfected bone defects through in vitro and vivo application., (© 2023 Wiley-VCH GmbH.)

Pathological bacterial infection poses a serious threat to public health security. The excessive use of antibiotics has resulted in a serious decline in treatment effect and bacterial resistance. For the treatment of infected wounds, we compounded dopamine-assisted exfoliated molybdenum disulfide (MoS 2 @PDA) into lipoic acid modified chitosan (LAMC) to obtain a composite hydrogel dressing (LAMC-MoS 2 @PDA). LAMC-MoS 2 @PDA hydrogels exhibited excellent photothermal conversion ability and the LAMC-MoS 2 @PDA2 group (0.3 wt%) has a photothermal conversion efficiency of 26.29 %. Meanwhile, they showed good biocompatibility and ROS scavenging activity in vitro. Photothermal therapy usually utilizes photothermal agents to convert near-infrared light into heat energy for bacterial cell membrane destruction and bacterial protein inactivation. Under the near-infrared light irradiation, the antibacterial ratio of LAMC-MoS 2 @PDA hydrogels against Staphylococcus aureus and Escherichia coli reached nearly 100 %, and the morphology of the bacteria showed obvious contraction and cleavage. The hydrogels also showed an excellent antibacterial effect and wound healing promotion in the infected wound of rats. In particular, the LAMC-MoS 2 @PDA2 (+) group (with NIR) showed almost complete wound closure after 14 days, indicating that the LAMC-MoS 2 @PDA hydrogels have great potential in clinical anti-infected treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Peripheral nerve regeneration is a complex physiological process. Single-function nerve scaffolds often struggle to quickly adapt to the imbalanced regenerative microenvironment, leading to slow nerve regeneration and limited functional recovery. In this study, we demonstrate a "pleiotropic gas transmitter" strategy based on endogenous reactive oxygen species (ROS), which trigger the on-demand H 2 S release at the defect area for transected peripheral nerve injury (PNI) repair through concurrent neuroregeneration and neuroprotection processing. This H 2 S delivery system consists of an H 2 S donor (peroxyTCM) encapsulated in a ROS-responsive polymer (mPEG-PMet) and loaded into a temperature-sensitive poly (amino acid) hydrogel (mPEG-PA-PP). This multi-effect combination strategy greatly promotes the regeneration of PNI, attributed to the physiological effects of H 2 S. These effects include the inhibition of inflammation and oxidative stress, protection of nerve cells, promotion of angiogenesis, and the restoration of normal mitochondrial function. The adaptive release of pleiotropic messengers to modulate the tissue regeneration microenvironment offers promising peripheral nerve repair and tissue engineering opportunities.

As a superior alternative to sutures, tissue adhesives have been developed significantly in recent years. However, existing tissue adhesives struggle to form fast and stable adhesion between tissue interfaces, bond weakly in wet environments and lack bioactivity. In this study, a degradable and bioactive citrate-based polyurethane adhesive is constructed to achieve rapid and strong tissue adhesion. The hydrophobic layer was created with polycaprolactone to overcome the bonding failure between tissue and adhesion layer in wet environments, which can effectively improve the wet bonding strength. This citrate-based polyurethane adhesive provides rapid, non-invasive, liquid-tight and seamless closure of skin incisions, overcoming the limitations of sutures and commercial tissue adhesives. In addition, it exhibits biocompatibility, biodegradability and hemostatic properties. The degradation product citrate could promote the process of angiogenesis and accelerate wound healing. This study provides a novel approach to the development of a fast-adhering wet tissue adhesive and provides a valuable contribution to the development of polyurethane-based tissue adhesives., (© The Author(s) 2023. Published by Oxford University Press.)

Clinical treatment of osteosarcoma encounters great challenges of postsurgical tumor recurrence and extensive bone defect. To develop an advanced artificial bone substitute that can achieve synergistic bone regeneration and tumor therapy for osteosarcoma treatment, a multifunctional calcium phosphate composite enabled by incorporation of bioactive FePSe 3 -nanosheets within the cryogenic-3D-printed α-tricalcium phosphate scaffold (TCP-FePSe 3 ) is explored. The TCP-FePSe 3 scaffold exhibits remarkable tumor ablation ability due to the excellent NIR-II (1064 nm) photothermal property of FePSe 3 -nanosheets. Moreover, the biodegradable TCP-FePSe 3 scaffold can release selenium element to suppress tumor recurrence by activating of the caspase-dependent apoptosis pathway. In a subcutaneous tumor model, it is demonstrated that tumors can be efficiently eradicated via the combination treatment with local photothermal ablation and the antitumor effect of selenium element. Meanwhile, in a rat calvarial bone defect model, the superior angiogenesis and osteogenesis induced by TCP-FePSe 3 scaffold have been observed in vivo. The TCP-FePSe 3 scaffold possesses improved capability to promote the repair of bone defects via vascularized bone regeneration, which is induced by the bioactive ions of Fe, Ca, and P released during the biodegradation of the implanted scaffolds. The TCP-FePSe 3 composite scaffolds fabricated by cryogenic-3D-printing illustrate a distinctive strategy to construct multifunctional platform for osteosarcoma treatment., (© 2023 Wiley-VCH GmbH.)

Poly(amide-imide) (PAI), serving as a synthetic polymer, has been widely used in industry for excellent mechanical properties, chemical resistance and high thermal stability. However, lack of suitable cell niche and biological activity limited the further application of PAI in biomedical engineering. Herein, silicon modified L-phenylalanine derived poly(amide-imide) (PAIS) was synthesized by introducing silica to L-phenylalanine derived PAI to improve physicochemical and biological performances. The influence of silicon amount on physicochemical, immune, and angiogenic performances of PAIS were systemically studied. The results show that PAIS exerts excellent hydrophilic, mechanical, biological activity. PAIS shows no effects on the number of macrophages, but can regulate macrophage polarization and angiogenesis in a dose-dependent manner. This study advanced our understanding of silicon modification in PAI can modulate cell responses via initiating silicon concentration regulation. The acquired knowledge will provide a new strategy to design and optimize biomedical PAI in the future., (© 2023 Wiley Periodicals LLC.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Implantable electrochemical sensor holds great promise in the real-time monitoring of dopamine (DA) to regulate body function. However, the real application of these sensors is limited by the weak current signal of DA in the human body and the poor compatibility of the on-chip microelectronic devices. In this work, a SiC/graphene composite film was fabricated using laser chemical vapor deposition (LCVD) and employed as a DA sensor. The graphene in the porous nanoforest-like SiC framework offered efficient channels for electronic transmission, leading to an enhanced electron transfer rate and consequently an increased current response for DA detection. The three-dimensional (3D) porous network also facilitated the exposure of more catalytic active sites toward DA oxidation. Besides, the wide distribution of graphene in the nanoforest-like SiC films reduced the interfacial resistance of the charge transfer. The SiC/graphene composite film exhibited excellent electrocatalytic activity toward DA oxidation with a low detection limit of 0.11 μM and a high sensitivity of 0.86 μA·μM -1 ·cm -2 . The film electrode also showed a wide linear response for DA in 0.5-78 μM, along with good selectivity, repeatability, and reproducibility. Furthermore, the cell counting kit-8 (CCK-8) and live-dead assays revealed that the film is also biocompatible for biomedical applications. Therefore, the nanoforest-like SiC/graphene composite film via the CVD process enables a promising candidate for an integrated miniature DA biosensor with high detection performance.

Three-dimensional (3D) printed bioactive scaffolds have been widely used in the field of bone tissue engineering. However, its in vivo visualization and bacterial inflammation are intractable issues during the surgery and treatment. Herein, we first synthesized an aggregation-induced emission-active luminogen (AIEgen) named 4BC with efficient reactive oxygen species (ROS) generation. Then, a series of 3D bioactive scaffolds loaded with 4BC were fabricated by a precipitation adsorption method, namely 4BC @scaffolds, which showed good in situ imaging performance for the implanted scaffolds by using simple UV light irradiation. Among them, the 4BC @TMP scaffold composed of trimagnesium phosphate (TMP) had excellent bactericidal ability for Escherichia coli and Staphylococcus aureus in vitro and resisted bacterial inflammation in vivo through photodynamic action. H&E and immunofluorescence staining were performed to further evaluate the inhibitory effect of bacterial inflammation in vivo. This work verified that AIEgen-based 3D scaffolds are promising bioactive frameworks for bioimaging and antibacterial applications.

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 Mg 2+ in Nd@WH can effectively promote the up-regulation of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). The release of Ca 2+ and PO 4 3- 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Magnetic iron oxide nanoparticles have shown great research value in the field of nerve regeneration because of their characteristics of satisfactory material properties and their ability to be stimulated by an external magnetic field to enhance the function of all aspects. Nevertheless, the impact of magnetic iron oxide nanoparticles on nerve regeneration regulated by macrophage polarization has not been well studied, and it is also not clear whether the introduction of the magnetic field has a further effect. Therefore, mesoporous hollow Fe 3 O 4 nanoparticles (MHFPs) were synthesized. We selected an alternating magnetic field (AMF) because it may confer a stronger effect on MHFPs as compared to a static magnetic field, and then explored the field's ability to induce macrophage polarization. Furthermore, the effects of this regulation on other neuro-associated cells were also explored. Our results suggest that MHFPs can efficiently induce polarization of macrophages at the concentration of 40 μg mL -1 , upregulate the expression of related genes and cytokines, and further promote the proliferation of neural stem cells and the subsequent migration of vascular endothelial cells. These effects were significantly enhanced after the application of an AMF. This work also showed that the internalization of particles is the starting point for polarization regulation.

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Unrestricted usage of antibiotics has accelerated the emergence of new strains of microorganisms with antimicrobial resistance (AMR) and the development of therapeutic technologies that do not rely only on antibiotics. Herein, mesoporous hollow Fe 3 O 4 nanoparticles (MHFPs) were synthesized by a one-pot hydrothermal method, and the feasibility and possible mechanism of using alternating magnetic field (AMF) with MHFPs to kill Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were explored. The presence of the AMF (2.5 kW, 210 kHz) combined with the MHFPs resulted in a dramatic decrease in colony forming units (CFU) for E. coli and S. aureus in 25 min compared with the pure MHFPs at concentrations of 500, 800 and 1000 μg mL -1 . Macroscopic hyperthermia was proved not to be the sole reason for the phenomenon. Visible membrane damage was demonstrated by live/dead staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) assays. Besides, the permeability and integrity changes of the cell membrane were then quantitatively confirmed by measuring the relative electrical conductivity. In addition, bacterial biofilms were significantly dispersed in the presence of MHFPs and AMF. These results suggested that under the mediation of AMF, MHFPs can potentially serve as an efficient nonantibiotic therapeutic platform to disperse bacterial biofilms and inactivate bacteria by damaging the cell membrane of the bacteria.

In recent years, the magnesium phosphate cements showed impressive advantages for their setting property, mechanical strength, and resorption rate in laboratory investigation. While it remained a big challenge to develop the magnesium phosphate cements with ideal self-setting properties, sufficient mechanical strength, excellent biocompatibility, and osteoinductivity for clinical application. In our work, we prepared the magnesium calcium phosphate cement (MCPC) using the MgO, KH 2 P 2 O 4 , and Ca(H 2 PO 4 ) 2 particles with the citric acid added. The citric acid was adopted to modify the setting time and compressive strength of the MCPC, which were investigated by the X-ray diffractometer and scanning electron microscopy. The cytocompatibility and osteoinductivity of the modified cements were evaluated by the MC3T3-E1 cells proliferation and morphology, alkaline phosphatase assay, alizarin red staining and western blot assay. The results demonstrated that the citric acid modified MCPC was featured of satisfactory setting time, ideal mechanical strength, good cytocompatibility and osteoinductivity, indicating its potential application for bone regeneration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Studies have showed that nanoparticles have a certain anti-cancer activity and can inhibit many kinds of cancer cells. β-tricalcium phosphate nanoparticles (nano-β-TCP) displays better biodegradation, but the application and mechanism of nano-β-TCP in anti-cancer activity are still not clear. Purpose: The objective of this study was to synthesize nano-β-TCP and investigate its inhibitory properties and mechanism on hepatocellular carcinoma (HepG2) cells in vitro and in vivo. Methods: Nano-β-TCP was synthesized using ethanol-water system and characterized. The effects of nano-β-TCP on cell viability, cell uptake, intracellular oxidative stress (ROS), cell cycle and apoptosis were also investigated with HepG2 cells and human hepatocyte cells (L-02). Intratumoral injection of nano-β-TCP was performed on the xenograft liver cancer model to explore the inhibitory effect and mechanism of nano-β-TCP on liver tumors. Results: In vitro results revealed that nano-β-TCP caused reduced cell viability of HepG2 cells in a time-and dose-dependent manner. Nano-β-TCP was internalized through endocytosis and degraded in cells, resulting in obvious increase of the intracellular Ca 2+ and PO 4 3- ions. Nano-β-TCP induced cancer cells to produce ROS and induced apoptosis of tumor cells by an apoptotic signaling pathways both in extrinsic and intrinsic pathway. In addition, nano-β-TCP blocked cell cycle of HepG2 cells in G0/G1 phase and disturbed expression of some related cyclins. In vivo results showed that 40 mg/kg of nano-β-TCP had no significant toxic side effects, but could effectively suppress hepatocellular carcinoma growth. Conclusion: These findings revealed the anticancer effect of nano-β-TCP and also clarified the mechanism of its inhibitory effect on hepatocellular carcinoma., Competing Interests: The authors declare no conflicts of interest in this work.

Inorganic phosphate cements have become prevalent as bone filling materials in clinical applications, owing to beneficial properties such as self-setting, biodegradability and osteoconductivity. However, the further development of phosphate cements with higher strength and improved cytocompatibility is expected. In this paper, we reported the preparation of a novel magnesium phosphate based cement (MPBC), which has similar compositions with magnesium phosphate cement (MPC) but Ca(H 2 PO 4 ) 2 ·H 2 O and citric acid were additionally added to modulate the performance. The physicochemical and biological properties of MPBC were investigated, the influences of the added Ca(H 2 PO 4 ) 2 ·H 2 O and citric acid on the performances of MPBC were analyzed, and the differences of performance between MPBC and MPC were discussed. Experimental results show that the setting time and compressive strength of MPBC were effectively enhanced by the addition of citric acid. In vitro biological degradation indicates that about 15 wt% of MPBC was reduced in 4 weeks. Compared with MPC, MPBC has weaker alkalinity and less dissolution of phosphate, leading to better suitability for cell proliferation and adhesion. These results suggest that as a bone filling material, MPBC shows better performance than MPC in many key indicators and has promising application prospects., (Copyright © 2018. Published by Elsevier Ltd.)