An injectable hydrogel dressing for controlled release of hydrogen sulfide pleiotropically mediates the wound microenvironment.

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 (H2S) 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 H2S 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 H2S has great potential in addressing complex scalded wounds associated with infection and chronic inflammation.

Mg-gallate metal-organic framework-based sprayable hydrogel for continuously regulating oxidative stress microenvironment and promoting neurovascular network reconstruction in diabetic wounds.

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.

Corrigendum to "Design and fabrication of high-performance self-setting trimagnesium phosphate" [Bioact. Mater. 28 (2023) 348-357].

[This corrects the article DOI: 10.1016/j.bioactmat.2023.05.019.].

Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.

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.

One Stone Three Birds: Silver Sulfadiazine Modulates the Stability and Dynamics of Hydrogels for Infected Wound Healing.

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.

Injectable Hydrogel System Incorporating Black Phosphorus Nanosheets and Tazarotene Drug for Enhanced Vascular and Nerve Regeneration in Spinal Cord Injury Repair.

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.

Photothermal antibacterial MoS2 composited chitosan hydrogel for infectious wound healing.

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 (MoS2@PDA) into lipoic acid modified chitosan (LAMC) to obtain a composite hydrogel dressing (LAMC-MoS2@PDA). LAMC-MoS2@PDA hydrogels exhibited excellent photothermal conversion ability and the LAMC-MoS2@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-MoS2@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-MoS2@PDA2 (+) group (with NIR) showed almost complete wound closure after 14 days, indicating that the LAMC-MoS2@PDA hydrogels have great potential in clinical anti-infected treatment.

An injectable and adaptable hydrogen sulfide delivery system for modulating neuroregenerative microenvironment.

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 H2S release at the defect area for transected peripheral nerve injury (PNI) repair through concurrent neuroregeneration and neuroprotection processing. This H2S delivery system consists of an H2S 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 H2S. 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.

IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice.

Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in the fibrotic hearts. Increased IRX2 expression is mainly derived from cardiac fibroblast (CF) during the angiotensin II (Ang II)-induced fibrotic response. Using two CF-specific Irx2-knockout mouse models, we show that deletion of Irx2 in CFs protect against pathological fibrotic remodelling and improve cardiac function in male mice. In contrast, Irx2 gain of function in CFs exaggerate fibrotic remodelling. Mechanistically, we find that IRX2 directly binds to the promoter of the early growth response factor 1 (EGR1) and subsequently initiates the transcription of several fibrosis-related genes. Our study provides evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis.

Design and fabrication of high-performance injectable self-setting trimagnesium phosphate.

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.

A Gelatin-Based Composite Hydrogel with a "One Stone, Two Birds" Strategy for Photothermal Antibacterial and Vascularization of Infected Wounds.

Bacterial infection, prolonged inflammation, and insufficient angiogenesis are the main challenges for effective wound repair. In this work, we developed a stretchable, remodeling, self-healing, and antibacterial multifunctional composite hydrogel for infected wound healing. The hydrogel was prepared using tannic acid (TA) and phenylboronic acid-modified gelatin (Gel-BA) through hydrogen bonding and borate ester bonds and incorporated iron-containing bioactive glasses (Fe-BGs) with uniform spherical morphologies and amorphous structures to achieve GTB composite hydrogels. On one hand, the chelation of Fe3+ in Fe-BGs with TA endowed the hydrogel with good photothermal synergistic antibacterial ability; on the other hand, the bioactive Fe3+ and Si ions contained in Fe-BGs can recruit cells and synergistically promote blood vessel formation. In vivo animal experiments showed that the GTB hydrogels remarkably accelerated infected full-thickness skin wound healing by improving granulation tissue formation, collagen deposition, and the formation of nerves and blood vessels while decreasing inflammation. This hydrogel with a dual synergistic effect and ″one stone, two birds″ strategy holds immense potential for wound dressing applications.

A One-Stone-Two-Birds Strategy for Osteochondral Regeneration Based on a 3D Printable Biomimetic Scaffold with Kartogenin Biochemical Stimuli Gradient.

Osteochondral defect (OCD) regeneration remains challenging because of the hierarchy of the native tissue including both the articular cartilage and the subchondral bone. Constructing an osteochondral scaffold with biomimetic composition, structure, and biological functionality is the key to achieve its high-quality repair. In the present study, an injectable and 3D printable bilayered osteochondral hydrogel based on compositional gradient of methacrylated sodium alginate, gelatin methacryloyl, and ß-tricalcium phosphate (ß-TCP), as well as the biochemical gradient of kartogenin (KGN) in the two well-integrated zones of chondral layer hydrogel (CLH) and osseous layer hydrogel (OLH) is developed. In vitro and subcutaneous in vivo evaluations reveal that apart from the chondrogenesis of the embedded bone mesenchymal stem cells induced by CLH with a high concentration of KGN, a low concentration of KGN with ß-TCP in the OLH synergistically achieves superior osteogenic differentiation by endochondral ossification, instead of the intramembranous ossification using OLH with only ß-TCP. The biomimetic construct leveraging KGN as the only biochemical inducer can facilitate cartilage and subchondral bone restoration in the in vivo osteochondral defect. This one-stone-two-birds strategy opens up a new facile approach for OCD regeneration by exploiting the biological functions of the bioactive drug molecule KGN.

Micropatterned photothermal double-layer periosteum with angiogenesis-neurogenesis coupling effect for bone regeneration.

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 PO4 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.

Mesoporous bioglass capsule composite injectable hydrogels with antibacterial and vascularization promotion properties for chronic wound repair.

Building an angiogenesis microenvironment and inhibiting wound infection are of great significance for chronic wound repair. In this paper, polydopamine-encapsulated mesoporous bioglass (MBG@PDA) capsules were constructed to realize the integration of angiogenesis and infection inhibition through the formation of a composite hydrogel with modified hyaluronic acid (HAMA) to promote wound healing. The experiments showed that the composite hydrogel had good adhesion and toughness and promoted the migration of fibroblasts to accelerate the epithelialization process. In addition, in the composite hydrogel, MBG@PDA could release Mg2+ to promote the proliferation and migration of vascular endothelial cells for angiogenesis. At the same time, MBG@PDA in the composite hydrogel could facilitate the long-term release of drugs to inhibit the growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) for reducing the possibility of wound infection. Finally, the results of in vivo experiments showed that a multifunctional dressing could repair wounds more quickly by promoting angiogenesis and reducing the pathological areas. In summary, the construction of these composite hydrogels can provide a repair method in the wound-repair field.

Photothermal Hydrogel Encapsulating Intelligently Bacteria-Capturing Bio-MOF for Infectious Wound Healing.

Chronic wounds are characterized by long-term inflammation and persistent infection, which make them difficult to heal. Therefore, an urgent desire is to develop a multifunctional wound dressing that can prevent wound infection and promote wound healing by creating a favorable microenvironment. In this study, a curcumin-based metal-organic framework (QCSMOF-Van), loaded with vancomycin and coated with quaternary ammonium salt chitosan (QCS), was prepared. Multifunctional composite hydrogels were conveniently synthesized by combining methacrylic anhydride modified gelatin and methacrylic anhydride modified oxidized sodium alginate with QCSMOF-Van through radical polymerization and Schiff base reaction. It is important to note that the QCSMOF-Van could capture bacteria through the positive charges on the surface of QCS. In this process, due to the synergistic effect of broad-spectrum antibacterial Zn2+ and vancomycin, the metabolism of bacteria was well inhibited, and the efficient capturing and rapid killing of bacteria were achieved. The QCSMOF-Van hydrogels could precisely regulate the balance of M1/M2 phenotypes of macrophages, thereby promoting the regeneration of nerves and blood vessels, which promotes the rapid healing of chronic wounds. This advanced cascade management strategy for tissue regeneration highlights the potential of multifunctional composite hydrogels in chronic wound dressings.

Mesoporous hollow Fe3O4 nanoparticles regulate the behavior of neuro-associated cells through induction of macrophage polarization in an alternating magnetic field.

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 Fe3O4 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.

Iron oxide nanoparticles with photothermal performance and enhanced nanozyme activity for bacteria-infected wound therapy.

Metal-based nanomaterials usually have broad-spectrum antibacterial properties, low biological toxicity and no drug resistance due to their intrinsic enzyme-like catalytic properties and external field (magnetic, thermal, acoustic, optical and electrical) responsiveness. Herein, iron oxide (Fe3O4) nanoparticles (IONPs) synthesized by us have good biosafety, excellent photothermal conversion ability and peroxidase-like catalytic activity, which can be used to construct a photothermal-enzymes combined antibacterial treatment platform. IONPs with peroxide-like catalytic activity can induce H2O2 to catalyze the production of •OH in a slightly acidic environment, thus achieving certain bactericidal effects and increasing the sensitivity of bacteria to heat. When stimulated by near-infrared light, the photothermal effect could destroy bacterial cell membranes, resulting in cleavage and inactivation of bacterial protein, DNA or RNA. Meanwhile, it can also improve the catalytic activity of peroxidase-like and promote IONPs to catalyze the production of more •OH for killing bacteria. After IONPs synergistic treatment, the antibacterial rate of Escherichia coli and Staphylococcus aureus reached nearly 100%. It also has an obvious killing effect on bacteria in infected wounds of mice and can effectively promote the healing of S. aureus-infected wounds, which has great application potential in clinical anti-infection treatment.

Folic acid-functionalized L-cys/ZnS:O nanoparticles for homologous targeting and photodynamic therapy of tumor cells.

The combination of photodynamic therapy (PDT) and fluorescence imaging provides a promising approach to theranostics. However, traditional photosensitizers (PSs) have low water solubility and lack active targeting ability. Our ingenious design used L-cys/ZnS:O (LZS) nanoparticles (NPs) modified with folic acid (FA), allowing them to easily enter tumor cells and accurately gather around the nucleus of cancer cells. L-Cysteine were used as intermediates, ZnS:O quantum dots and FA could be connected by a solid-state method and a coupling reaction. In doing so, the cytotoxicity of LZS NPs was further reduced, while the hydrophilicity and dispersibility were improved. Moreover, the as-synthesized FA@LZS NPs had a higher generation of reactive oxygen species (ROS) than commercial Ce6, and they killed HepG2 cells specifically in vitro. These findings give a clear way for the development of advanced PSs with homologous labeling functions. A template for NPs or other fluorophores modified by targeting groups is also provided.

A multifunctional chitosan hydrogel dressing for liver hemostasis and infected wound healing.

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.