Construction of bupivacaine-loaded gelatin-based hydrogel delivery system for sciatic nerve block in mice.

Peripheral nerve blockade (PNB) is a common treatment to relieve postoperative pain. However, local anesthetics alone have a short duration of action and severe side effects during postoperative analgesia. In order to overcome these limitations, the present study reported an injectable hydrogel with a drug slow-release profile for regional nerve blockade. The injectable hydrogel was prepared by crosslinking with gelatin and NHS-PEG-NHS, which was degradable in the physiological environment and displayed sustainable release of anesthetics locally, thus improving the disadvantage of the high toxicity of local anesthetics. In this regard, we conducted a series of in vitro characterizations and proved that the hydrogel has a porous three-dimensional mesh structure with high drug loading capability, and sustainable drug release profile. And cytotoxicity experiments confirmed the good biocompatibility of the hydrogel. It was shown that using the animal sciatic nerve block model, the analgesic effect was greatly improved in vivo, and there was no obvious evidence of permanent inflammation or nerve damage in the block site's sections. This locally slow-release platform, combined with local anesthetics, is therefore a promising contender for long-acting analgesia.

Thermosensitive hydrogel with programmed dual-octenidine release combating biofilm for the treatment of apical periodontitis.

The utilization of intracanal medicaments is an indispensable procedure in root-canal treatment. However, the conventional intracanal medicaments still need improvement regarding antimicrobial efficacy and ease of clinical operation. To address the above issues, OCT/PECT@OCT + ALK composite hydrogel characterized by programming sequential release of dual antimicrobial agents has been proposed. Thanks to the self-assemble ability of amphiphilic copolymer poly(ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT), dual hydrophilic and hydrophobic antimicrobial agents could be easily encapsulated in the hydrogel system and tailored for sequential drug release for a better antibiofilm effect. The hydrophilic octenidine (Octenidine dihydrochloride, OCT-HCl) is encapsulated in the hydrophilic part of hydrogel for instantaneous elevating the drug concentration through bursting release, and the hydrophobic octenidine (Octenidine, OCT) is further loaded into the PECT nanoparticles to achieve a slower and sustained-release profile. Additionally, calcium hydroxide (Ca(OH)2) was incorporated into the system and evenly dispersed among PECT nanoparticles to create an alkaline (ALK) environment, synergistically enhancing the antibiofilm effect with higher efficiency and prolonged duration. The antibiofilm effect has been demonstrated in root-canal models and apical periodontitis rats, exhibiting superior performance compared to clinically used Ca(OH)2 paste. This study demonstrates that OCT/PECT@OCT + ALK composite thermosensitive hydrogel is a potential intracanal medicament with excellent antibiofilm effect and clinical operability.

Bioactive microgel-coated electrospun membrane with cell-instructive interfaces and topology for abdominal wall defect repair.

Current mesh materials used for the clinical treatment of abdominal defects struggle to balance mechanical properties and bioactivity to support tissue remodeling. Therefore, a bioactive microgel-coated electrospinning membrane was designed with the superiority of cell-instructive topology in guiding cell behavior and function for abdominal wall defect reconstruction. The electrostatic spinning technique was employed to prepare a bioabsorbable PLCL fiber membrane with an effective mechanical support. Additionally, decellularized matrix (dECM)-derived bioactive microgels were further coated on the fiber membrane through co-precipitation with dopamine, which was expected to endow cell-instructive hydrophilic interfaces and topological morphologies for cell adhesion. Moreover, the introduction of the dECM into the microgel promoted the myogenic proliferation and differentiation of C2C12 cells. Subsequently, in vivo experiments using a rat abdominal wall defect model demonstrated that the bioactive microgel coating significantly contributed to the reconstruction of intact abdominal wall structures, highlighting its potential for clinical application in promoting the repair of soft tissue defects associated with abdominal wall damage. This study presented an effective mesh material for facilitating the reconstruction of abdominal wall defects and contributed novel design concepts for the surface modification of scaffolds with cell-instructive interfaces and topology.

dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing.

Due to its highly insidious and rapid progression, deep tissue pressure injury (DTPI) is a clinical challenge. Our previous study found that DTPI may be a skeletal muscle injury dominated by macrophage immune dysfunction due to excessive iron accumulation. Decellularized extracellular matrix (dECM) hydrogel promotes skeletal muscle injury repair. However, its role in polarizing macrophages and regulating iron metabolism in DTPI remains unclear. Here, porcine dECM hydrogel was prepared, and its therapeutic function and mechanism in repairing DTPI were investigated. The stimulus of dECM hydrogel toward RAW264.7 cells resulted in a significantly higher percentage of CD206+ macrophages and notably decreased intracellular divalent iron levels. In mice DTPI model, dECM hydrogel treatment promoted M1 to M2 macrophage conversion, improved iron metabolism and reduced oxidative stress in the early stage of DTPI. In the remodeling phase, the dECM hydrogel remarkably enhanced revascularization and accelerated skeletal muscle repair. Furthermore, the immunomodulation of dECM hydrogels in vivo was mainly involved in the P13k/Akt signaling pathway, as revealed by GO and KEGG pathway analysis, which may ameliorate the iron deposition and promote the healing of DTPI. Our findings indicate that dECM hydrogel is promising in skeletal muscle repair, inflammation resolution and tissue injury healing by effectively restoring macrophage immune homeostasis and normalizing iron metabolism.

Biodegradable Cardiac Occluder with Surface Modification by Gelatin-Peptide Conjugate to Promote Endogenous Tissue Regeneration.

Transcatheter intervention has been the preferred treatment for congenital structural heart diseases by implanting occluders into the heart defect site through minimally invasive access. Biodegradable polymers provide a promising alternative for cardiovascular implants by conferring therapeutic function and eliminating long-term complications, but inducing in situ cardiac tissue regeneration remains a substantial clinical challenge. PGAG (polydioxanone/poly (l-lactic acid)-gelatin-A5G81) occluders are prepared by covalently conjugating biomolecules composed of gelatin and layer adhesive protein-derived peptides (A5G81) to the surface of polydioxanone and poly (l-lactic acid) fibers. The polymer microfiber-biomacromolecule-peptide frame with biophysical and biochemical cues could orchestrate the biomaterial-host cell interactions, by recruiting endogenous endothelial cells, promoting their adhesion and proliferation, and polarizing immune cells into anti-inflammatory phenotypes and augmenting the release of reparative cytokines. In a porcine atrial septal defect (ASD) model, PGAG occluders promote in situ tissue regeneration by accelerating surface endothelialization and regulating immune response, which mitigate inflammation and fibrosis formation, and facilitate the fusion of occluder with surrounding heart tissue. Collectively, this work highlights the modulation of cell-biomaterial interactions for tissue regeneration in cardiac defect models, ensuring endothelialization and extracellular matrix remodeling on polymeric scaffolds. Bioinspired cell-material interface offers a highly efficient and generalized approach for constructing bioactive coatings on medical devices.

Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration.

Excessive reactive oxygen species (ROS) at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle, leading to delayed wound healing and regeneration. Here, a novel bioactive, anti-fouling, flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate (EGCG)-copper (Cu) capsules (termed as EGCG-Cu@CBgel) is engineered for burn wound management, which is dedicated to synergistically exerting ROS-scavenging, immune metabolic regulation and pro-angiogenic effects. EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis, effectively relieving oxidative damages and blocking proinflammatory signal transduction. Importantly, EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase, alleviate accumulation of pyruvate and convert it to acetyl coenzyme A (CoA), whereby inhibits glycolysis and normalizes tricarboxylic acid (TCA) cycle. Additionally, metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo. Meanwhile, copper ions (Cu2+) released from the hydrogel facilitate angiogenesis. EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure, weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure. Overall, this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin, and highlights the importance of immunometabolism modulation in tissue repair and regeneration.

An anti-inflammatory chondroitin sulfate-poly(lactic-co-glycolic acid) composite electrospinning membrane for postoperative abdominal adhesion prevention.

Postoperative abdominal adhesion is a very common and serious complication, resulting in pain, intestinal obstruction and heavy economic burden. Post-injury inflammation that could activate the coagulation cascade and deposition of fibrin is a major cause of adhesion. Many physical barrier membranes are used to prevent abdominal adhesion, but their efficiency is limited due to the lack of anti-inflammatory activity. Here, an electrospinning membrane composed of poly(lactic-co-glycolic acid) (PLGA) providing support and mechanical strength and chondroitin sulfate (CS) conferring anti-inflammation activity is fabricated for preventing abdominal adhesion after injury. The PLGA/CS membrane shows a highly dense fiber network structure with improved hydrophilicity and good cytocompatibility. Importantly, the PLGA/CS membrane with a mass ratio of CS at 20% provides superior anti-adhesion efficiency over a native PLGA membrane and commercial poly(D, L-lactide) (PDLLA) film in abdominal adhesion trauma rat models. The mechanism is that the PLGA/CS membrane could alleviate the local inflammatory response as indicated by the promoted percentage of anti-inflammatory M2-type macrophages and decreased expression of pro-inflammatory factors, such as IL-1ß, TNF-α and IL-6, resulting in the suppression of the coagulation system and the activation of the fibrinolytic system. Furthermore, the deposition of fibrin at the abdominal wall was inhibited, and the damaged abdominal tissue was repaired with the treatment of the PLGA/CS membrane. Collectively, the PLGA/CS electrospinning membrane is a promising drug-/cytokine-free anti-inflammatory barrier for post-surgery abdominal adhesion prevention and a bioactive composite for tissue regeneration.

Bioinspired, Anticoagulative, 19 F MRI-Visualizable Bilayer Hydrogel Tubes as High Patency Small-Diameter Vascular Grafts.

The clinical patency of small-diameter vascular grafts (SDVGs) (ID < 6 mm) is limited, with the formation of mural thrombi being a major threat of this limitation. Herein, a bilayered hydrogel tube based on the essential structure of native blood vessels is developed by optimizing the relation between vascular functions and the molecular structure of hydrogels. The inner layer of the SDVGs comprises a zwitterionic fluorinated hydrogel, avoiding the formation of thromboinflammation-induced mural thrombi. Furthermore, the position and morphology of the SDVGs can be visualized via 19 F/1 H magnetic resonance imaging. The outer poly(N-acryloyl glycinamide) hydrogel layer of SDVGs provides matched mechanical properties with native blood vessels through the multiple and controllable intermolecular hydrogen-bond interactions, which can withstand the accelerated fatigue test under pulsatile radial pressure for 380 million cycles (equal to a service life of 10 years in vivo). Consequently, the SDVGs exhibit higher patency (100%) and more stable morphology following porcine carotid artery transplantation for 9 months and rabbit carotid artery transplantation for 3 months. Therefore, such a bioinspired, antithrombotic, and visualizable SDVG presents a promising design approach for long-term patency products and great potential of helping patients with cardiovascular diseases.

Extracellular Matrix/Glycopeptide Hybrid Hydrogel as an Immunomodulatory Niche for Endogenous Cardiac Repair after Myocardial Infarction.

The treatment of myocardial infarction (MI) remains a substantial challenge due to excessive inflammation, massive cell death, and restricted regenerative potential, leading to maladaptive healing process and eventually heart failure. Current strategies of regulating inflammation or improving cardiac tissue regeneration have limited success. Herein, a hybrid hydrogel coassembled by acellular cardiac extracellular matrix (ECM) and immunomodulatory glycopeptide is developed for endogenous tissue regeneration after MI. The hydrogel constructs a niche recapitulating the architecture of native ECM for attracting host cell homing, controlling macrophage differentiation via glycopeptide unit, and promoting endotheliocyte proliferation by enhancing the macrophage-endotheliocyte crosstalk, which coordinate the innate healing mechanism for cardiac tissue regeneration. In a rodent MI model, the hybrid hydrogel successfully orchestrates a proreparative response indicated by enhanced M2 macrophage polarization, increased angiogenesis, and improved cardiomyocyte survival, which alleviates infarct size, improves wall thicknesses, and enhances cardiac contractility. Furthermore, the safety and effectiveness of the hydrogel are demonstrated in a porcine MI model, wherein proteomics verifies the regulation of immune response, proangiogenesis, and accelerated healing process. Collectively, the injectable composite hydrogel serving as an immunomodulatory niche for promoting cell homing and proliferation, inflammation modulation, tissue remodeling, and function restoration provides an effective strategy for endogenous cardiac repair.

Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma.

Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.

ROS scavenging and immunoregulative EGCG@Cerium complex loaded in antibacterial polyethylene glycol-chitosan hydrogel dressing for skin wound healing.

The elevation of oxidative stress and inflammatory response after injury remains a substantial challenge that can deteriorate the wound microenvironment and compromise the success of wound healing. Herein, the assembly of naturally derived epigallocatechin-3-gallate (EGCG) and Cerium microscale complex (EGCG@Ce) was prepared as reactive oxygen species (ROS) scavenger, which was further loaded in antibacterial hydrogels as wound dressing. EGCG@Ce shows superior antioxidation capacity towards various ROS including free radical, O2- and H2O2 through superoxide dismutase-like or catalase-mimicking catalytic activity. Importantly, EGCG@Ce could provide mitochondrial protective effect against oxidative stress damages, reverse the polarization of M1 macrophages and reduce the secretion of pro-inflammatory cytokines. Furtherly, EGCG@Ce was loaded into the PEG-chitosan hydrogel with dynamic, porous, injectable and antibacterial properties as wound dressing, which accelerated the regeneration of both epidermal layer and dermis, resulting in improved healing process of full-thickness skin wounds in vivo. Mechanistically, EGCG@Ce re-shaped the detrimental tissue microenvironment and augmented the pro-reparative response through reducing ROS accumulation, alleviating inflammatory response, enhancing the M2 macrophage polarization and angiogenesis. Collectively, antioxidative and immunomodulatory metal-organic complex-loaded hydrogel is a promising multifunctional dressing for the repair and regeneration of cutaneous wounds without additional drugs, exogenous cytokines, or cells. STATEMENT OF SIGNIFICANCE: (1) We reported an effective antioxidant through self-assembly coordination of EGCG and Cerium for managing the inflammatory microenvironment at the wound site, which not only showed high catalytic capacity towards multiple ROS, but also could provide mitochondrial protective effect against oxidative stress damage, reverse the polarization of M1 macrophages and downregulate pro-inflammatory cytokines. EGCG@Ce was further loaded into porous and bactericidal PEG-chitosan (PEG-CS) hydrogel as a versatile wound dressing, which accelerated wound healing and angiogenesis. (2) The applicability of alleviating sustainable inflammation and regulating macrophage polarization through ROS scavenging is a promising strategy for tissue repair and regeneration without additional drugs, cytokines, or cells.

Versatile Hydrogel Dressing with Skin Adaptiveness and Mild Photothermal Antibacterial Activity for Methicillin-Resistant Staphylococcus Aureus-Infected Dynamic Wound Healing.

Bacterial infection often induces chronic repair of wound healing owing to aggravated inflammation. Hydrogel dressing exhibiting intrinsic antibacterial activity may substantially reduce the use of antibiotics for infected wound management. Hence, a versatile hydrogel dressing (rGB/QCS/PDA-PAM) exhibiting skin adaptiveness on dynamic wounds and  mild photothermal antibacterial activity is developed for safe and efficient infected wound treatment. Phenylboronic acid-functionalized graphene (rGB) and oxadiazole-decorated quaternary carboxymethyl chitosan (QCS) are incorporated into a polydopamine-polyacrylamide (PDA-PAM) network with multiple covalent and noncovalent bonds, which conferred the hydrogel with flexible mechanical properties, strong tissue adhesion and excellent self-healing ability on the dynamic wounds. Moreover, the glycocalyx-mimicking phenylboronic acid on the surface of rGB enables the hydrogel to specifically capture bacteria. The enhanced membrane permeability of QCS enhanced bacterial vulnerability to photothermal therapy（PTT）, which is demonstrated by efficient mild PTT antibacteria against methicillin-resistant Staphylococcus aureus in vitro and in vivo at temperatures of <49.6 °C. Consequently, the hydrogel demonstrate accelerated tissue regeneration on MRSA-infected wound in vivo, with an intact epidermis, abundant collagen deposition and prominent angiogenesis. Therefore, rGB/QCS/PDA-PAM is a versatile hydrogel dressing exhibiting inherent antibacterial activity and has considerable potential in treating wounds infected with drug-resistant bacteria.

Nanogels co-loading paclitaxel and curcumin prepared in situ through photopolymerization at 532 nm for synergistically suppressing breast tumors.

Combined chemotherapy plays an increasingly important and practical role in the clinical treatment of malignant tumor. In this study, paclitaxel (PTX) and curcumin (Cur) are simultaneously encapsulated into nanogels (termed as NG-PC) in situ by microemulsion photopolymerization at 532 nm for synergistically suppressing breast tumors. NG-PC with a size of 180 nm and a low polydispersity index (PDI < 0.2) presents a controlled and cumulative release of PTX and Cur within 90 h. Moreover, NG-PC displays a remarkable killing effect against 4T1 and MCF-7 cells. In vivo antitumor evaluation on 4T1 tumor-bearing mice demonstrates that NG-PC has significantly higher ability to inhibit tumor growth, inducing necrosis, apoptosis and suppression of proliferation than that of a single drug. Our research provides a facile method to prepare a nano-drug delivery platform with excellent drug co-loading ability and synergistic antitumor effect.

Flexible and Zwitterionic Fluorinated Hydrogel Scaffold with High Fluorine Content for Noninvasive 19 F Magnetic Resonance Imaging under Ultrahigh Scanning Resolution.

The imaging of hydrogel scaffolds by 19 F magnetic resonance imaging (MRI) represents an attractive tool for straightforward and noninvasive monitoring of their morphology and in vivo fate. However, their further applications are significantly limited by a dilemma of insufficient signal resolution with low 19 F content, and/or hydrophobic aggregation of fluorine moieties-induced signal attenuation with high 19 F content. Herein, a novel label-free fluorinated hydrogel (PFCB) is fabricated with high fluorine content to realize noninvasive monitoring through 19 F MRI under ultrahigh scanning resolution (1 mm of scanning thickness). The integration of a zwitterionic unit into each fluorine moiety completely overcame the hydrophobic aggregation-induced signal attenuation, manifesting as high 19 F content and imaging performance. Importantly, 3D reconstruction of the PFCB hydrogel in vivo can be facilely and accurately performed with background free signals, providing detailed biological information of the implanted hydrogel. Additionally, PFCB hydrogel showed adjustable and high mechanical performance, and exhibited minimum foreign body reaction after implantation. As a proof of concept, PFCB hydrogel could be further applied as gel electrodes and wireless flexible sensors for healthcare monitoring. Overall, such label-free fluorinated PFCB hydrogel is an ideal flexible scaffold for eventual clinical applications integrating 19 F MRI-guided unequivocally 3D reconstruction and healthcare monitoring.

Bioinspired and Inflammation-Modulatory Glycopeptide Hydrogels for Radiation-Induced Chronic Skin Injury Repair.

Clinical wound management of radiation-induced skin injury (RSI) remains a great challenge due to acute injuries induced by excessive reactive oxygen species (ROS), and the concomitant repetitive inflammatory microenvironment caused by an imbalance in macrophage homeostasis. Herein, a cutaneous extracellular matrix (ECM)-inspired glycopeptide hydrogel (GK@TAgel ) is rationally designed for accelerating wound healing through modulating the chronic inflammation in RSI. The glycopeptide hydrogel not only replicates ECM-like glycoprotein components and nanofibrous architecture, but also displays effective ROS scavenging and radioprotective capability that can reduce the acute injuries after exposure to irradiation. Importantly, the mannose receptor (MR) in GK@TAgel exhibits high affinity and bioactivity to drive the M2 macrophage polarization, thereby overcoming the persistent inflammatory microenvironment in chronic RSI. The repair of RSI in mice demonstrates that GK@TAgel significantly reduces the hyperplasia of epithelial, promotes appendage regeneration and angiogenesis, and decreased the proinflammatory cytokine expression, which is superior to the treatment of commercial radioprotective drug amifostine. Collectively, the ECM-mimetic hydrogel dressing can protect the tissue from irradiation and heal the chronic wound in RSI, holding great potential in clinical wound management and tissue regeneration.

ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus-infected chronic skin wound healing.

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment-responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.

Titanium alloy composited with dual-cytokine releasing polysaccharide hydrogel to enhance osseointegration via osteogenic and macrophage polarization signaling pathways.

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling. However, the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants, resulting in a high occurrence rate of implant loosening or failure in osteological therapy. In this study, extracellular matrix-mimetic polysaccharide hydrogel co-delivering BMP-2 and interleukin (IL)-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect. Notably, it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect toward osteogenesis. The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells (hBMSCs). The repair of large-scale femur defect in rat indicated that the dual-cytokine-delivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype, resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine. Collectively, this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing. The biomimetic hydrogel-metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration, holding great promise in treating orthopedic diseases.

Biomimetic glycopeptide hydrogel coated PCL/nHA scaffold for enhanced cranial bone regeneration via macrophage M2 polarization-induced osteo-immunomodulation.

The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GRgel) self-assembled by ß-sheet RADA16-grafted glucomannan was designed to mimic the glycoprotein composition and the fibrillar architecture of natural extracellular matrix (ECM), which was non-covalently composited with 3D-printed polycaprolactone/nano hydroxyapatite (PCL/nHA) scaffold for cranial bone regeneration. The glycopeptide hydrogel significantly promoted the proliferation, osteogenic differentiation of bone mesenchymal stem cells (BMSCs), which was further augmented by GRgel-induced macrophage M2-phonotype polarization and the effective M2 macrophage-BMSC crosstalk. The repair of critical-size skull bone defect in rat indicated a superior efficacy of PCL/nHA@GRgel implant on bone regeneration and osseointegration, with an average bone area of 83.3% throughout the defect location at 12 weeks post treatment. Furthermore, the osteo-immunomodulatory GRgel induced a reparative microenvironment similar with that in normal cranium, as characterized by an increased percentage of anti-inflammatory M2 macrophages and osteoblasts, and high-level vascularization. Collectively, the composite scaffold developed here with macrophage polarization-mediated osteo-immunomodulation may represent a promising implant for expediting in situ bone regeneration by providing biochemical and osteoinductive cues at the injured tissue.

Polarization of tumor-associated macrophages by TLR7/8 conjugated radiosensitive peptide hydrogel for overcoming tumor radioresistance.

Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application, which is mainly caused by the aggravation of immunosuppressive tumor microenvironment (ITM). Especially tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance. Herein, the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel (Smac-TLR7/8 hydrogel) to regulate TAMs repolarization from M2 type into M1 type, thus modulating the ITM and overcoming the radioresistance. The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology, porous structure and excellent biocompatibility. Upon γ-ray radiation, Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type. Notably, combined with radiotherapy, TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion, activate antitumor immune response and effectively inhibit tumor growth. Moreover, TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors, thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes (TILs) and decreasing Treg cells in two different immune activity tumor mice models. Overall, this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance, thus improving the efficacy of radiotherapy and immunotherapy.