Intrinsically bioactive multifunctional Poly(citrate-curcumin) for rapid lung injury and MRSA infection therapy

Dysregulated inflammation after trauma or infection could result in the further disease and delayed tissue reconstruction.The conventional anti-inflammatory drug treatment suffers to the poor bioavailability and side effects.Herein,we developed an amphiphilic multifunctional poly(citrate-polyglycol-curcumin)(PCGC)nano oligomer with the robust anti-inflammatory activity for treating acute lung injury(ALI)and Methicillin-resistant staphylococcus aureus(MRSA)infected wound.PCGC demonstrated the sustained curcumin release,inherent photoluminescence,good cellular compatibility,hemocompatibility,robust antioxidant activity and enhanced cellular uptake.PCGC could efficiently scavenge nitrogen-based free radicals,oxygen-based free radicals,and intracellular oxygen species,enhance the endothelial cell migration and reduce the expression of pro-inflammatory factors through the NF-κB signal pathway.Combined the anti-inflammation and antioxidant properties,PCGC can shortened the inflammatory process.In animal model of ALI,PCGC was able to reduce the pulmonary edema,bronchial cell infiltration,and lung inflammation,while exhibiting rapid metabolic behavior in vivo.The MRSA-infection wound model showed that PCGC significantly reduced the expression of pro-inflammatory factors,promoted the angiogenesis and accelerated the wound healing.The transcriptome sequencing and molecular mechanism studies further demonstrated that PCGC could inhibit multiple inflammatory related pathways including TNFAIP3,IL-15RA,NF-κB.This work demonstrates that PCGC is efficient in resolving inflammation and promotes the prospect of application in inflammatory diseases as the drug-loaded therapeutic system.

Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor

Osteoarthritis(OA),a common degenerative disease,is characterized by high disability and imposes substantial economic impacts on individuals and society.Current clinical treatments remain inadequate for effectively managing OA.Organoids,miniature 3D tissue structures from directed differentiation of stem or progenitor cells,mimic native organ structures and functions.They are useful for drug testing and serve as active grafts for organ repair.However,organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth.Hydrogel microspheres,with tunable physical and chemical properties,show promise in cartilage tissue engineering by replicating the natural microenvironment.Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration,we developed a novel RGD-SF-DNA hydrogel microsphere(RSD-MS)via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA.The RSD-MSs exhibited uniform size,porous surface,and optimal swelling and degradation properties.In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells(BMSCs)proliferation,adhesion,and chondrogenic differentiation.Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis.Moreover,in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors(COPs)significantly enhanced cartilage regeneration.In conclusion,RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids,offering an innovative strategy and material choice for cartilage regeneration and tissue engineering.

AI-enabled organoids:Construction,analysis,and application

Organoids,miniature and simplified in vitro model systems that mimic the structure and function of organs,have attracted considerable interest due to their promising applications in disease modeling,drug screening,personalized medicine,and tissue engineering.Despite the substantial success in cultivating physiologically relevant organoids,challenges remain concerning the complexities of their assembly and the difficulties associated with data analysis.The advent of AI-Enabled Organoids,which interfaces with artificial intelligence(AI),holds the potential to revolutionize the field by offering novel insights and methodologies that can expedite the development and clinical application of organoids.This review succinctly delineates the fundamental concepts and mechanisms underlying AI-Enabled Organoids,summarizing the prospective applications on rapid screening of construction strategies,cost-effective extraction of multiscale image features,streamlined analysis of multi-omics data,and precise preclinical evaluation and application.We also explore the challenges and limitations of interfacing organoids with AI,and discuss the future direction of the field.Taken together,the AI-Enabled Organoids hold significant promise for advancing our understanding of organ development and disease progression,ultimately laying the groundwork for clinical application.

Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting Hoxa7/MAPK signaling axis

Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secretion of the senescence-associated secretory phenotype(SASP),which bring difficulties for bone repair.Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells(O-BMSCs)was considered as effective strategy for bone regeneration in aging microenvironment.Magnesium(Mg)ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.In this study,Akermanite biocreamics(Akt)containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro.Moreover,the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway.Furthermore,the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats.The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis.The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.

Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair

Segmental bone defects,stemming from trauma,infection,and tumors,pose formidable clinical challenges.Traditional bone repair materials,such as autologous and allogeneic bone grafts,grapple with limitations including source scarcity and immune rejection risks.The advent of nucleic acid nanotechnology,particularly the use of DNA hydrogels in tissue engineering,presents a promising solution,attributed to their biocompatibility,biodegradability,and programmability.However,these hydrogels,typically hindered by high gelation temperatures(~46◦C)and high construction costs,limit cell encapsulation and broader application.Our research introduces a novel polymer-modified DNA hydrogel,developed using nucleic acid nanotechnology,which gels at a more biocompatible temperature of 37◦C and is cost-effective.This hydrogel then incorporates tetrahedral Framework Nucleic Acid(tFNA)to enhance osteogenic mineralization.Furthermore,considering the modifiability of tFNA,we modified its chains with Aptamer02(Apt02),an aptamer known to foster angiogenesis.This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells(BMSCs)and angiogenesis in human umbilical vein endothelial cells(HUVECs),with cell sequencing confirming their targeting efficacy,respectively.In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation.This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction,marking a significant advancement in tissue engineering and regenerative medicine.

Adipose-derived mesenchymal stem cells(MSCs)are a superior cell source for bone tissue engineering

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most promising seed cells for bone tissue engineering.As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat,MSCs can be isolated from numerous tissues and exhibit varied differentiation potential.To identify an optimal progenitor cell source for bone tissue engineering,we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources,including immortalized mouse embryonic fibroblasts(iMEF),immortalized mouse bone marrow stromal stem cells(imBMSC),immortalized mouse calvarial mesenchymal progenitors(iCAL),and immortalized mouse adipose-derived mesenchymal stem cells(iMAD).We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro,whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair.Transcriptomic analysis revealed that,while each MSC line regulated a distinct set of target genes upon BMP9 stimulation,all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt,TGF-β,PI3K/AKT,MAPK,Hippo and JAK-STAT pathways.Collectively,our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.

Double hits with bioactive nanozyme based on cobalt-doped nanoglass for acute and diabetic wound therapies through anti-inflammatory and pro-angiogenic functions

Regeneration of pathological wounds,such as diabetic ulcers,poses a significant challenge in clinical settings,despite the widespread use of drugs.To overcome clinical side effects and complications,drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events.This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass(namely,CoNZ),which exhibits high enzymatic/catalytic activity while releasing therapeutic ions.Cobalt oxide“Co3O4”tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS.Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process,promoting neovascularization,matrix deposition,and epithelial lining while reducing pro-inflammatory signs.Notably,CoNZ was highly effective in treating pathological wounds(streptozotocin-induced diabetic wounds).Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events.In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ.CoNZ-promoted angiogenesis was attributed to the release of cobalt ions,as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1α.Finally,we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine.Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound,indicating the potential of CoNZ as a novel drug-free therapeutic approach.

A bioactive composite hydrogel dressing that promotes healing of both acute and chronic diabetic skin wounds

Mesenchymal stem cell derived exosomes(MSC-Exos)demonstrate beneficial effects on wound healing via anti-inflammatory and angiogenic properties.Chitosan(CS)exhibits excellent biocompatibility and accelerates cellular migration,adhesion,and proliferation.The ions released from bioactive glass(BG)and titanium dioxide(TiO_(2))nanoparticles exhibit sustained angiogenic and antibacterial potency.In this study,CMCS-CEBT hydrogel was synthesized from exosomes encapsulated carboxymethyl chitosan(CMCS),chitosan nanoparticles(CS-NPs),BG,and TiO_(2)nanoparticles for a preliminary evaluation of its impacts on the treatment of full-thickness skin defects,diabetic wounds,and burn skin injury due to burns.In vitro analysis indicated that the hydrogel exhibits excellent cell compatibility,stimulates endothelial cell adhesion and proliferation,and presents anti-inflammatory,angiogenic,and antibacterial activities.In vivo,the composite hydrogel dressing accelerated a wound healing acceleration effect,stimulated angiogenesis,and increased collagen deposition and the expression of anti-inflammatory factors.This innovative composite hydrogel dressing as a potential clinical therapy,utilizing bioactive materials,holds promise as a potential clinical therapy that aims to facilitate the regeneration of acute and chronically damaged skin tissue.

Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments

Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challenge to treatment.In this study,inspired by the innate immune,immune cell mobilized hydrogel microspheres were constructed by microfluidic methods and load chemokines,macrophage antibodies and engineered cell membrane vesicles(sEVs)via covalent and non-covalent junctions.The immune cell mobilized hydrogel microspheres,based on a mixture of streptavidin grafted hyaluronic acid methacrylate(HAMA-SA)and Chondroitin sulfate methacrylate(ChSMA)microspheres(HCM),can recruit,capture and reprogram proinflammatory macrophages in the joint cavity to improve the joint inflammatory microenvironment.In vitro experiments demonstrated that immune cell mobilized hydrogel microspheres had excellent macrophage recruitment,capture,and reprogramming abilities.Pro-inflammatory macrophages can be transformed into anti-inflammatory macrophages with an efficiency of 88.5%.Animal experiments also revealed significant reduction in synovial inflammation and cartilage matrix degradation of OA.Therefore,the immune cell mobilized hydrogel microspheres may be an effective treatment of OA inflammation for the future.

Decellularized extracellular matrix biomaterials for regenerative therapies:Advances,challenges and clinical prospects

Tissue engineering and regenerative medicine have shown potential in the repair and regeneration of tissues and organs via the use of engineered biomaterials and scaffolds.However,current constructs face limitations in replicating the intricate native microenvironment and achieving optimal regenerative capacity and functional recovery.To address these challenges,the utilization of decellularized tissues and cell-derived extracellular matrix(ECM)has emerged as a promising approach.These biocompatible and bioactive biomaterials can be engineered into porous scaffolds and grafts that mimic the structural and compositional aspects of the native tissue or organ microenvironment,both in vitro and in vivo.Bioactive dECM materials provide a unique tissue-specific microenvironment that can regulate and guide cellular processes,thereby enhancing regenerative therapies.In this review,we explore the emerging frontiers of decellularized tissue-derived and cell-derived biomaterials and bio-inks in the field of tissue engineering and regenerative medicine.We discuss the need for further improvements in decellularization methods and techniques to retain structural,biological,and physicochemical characteristics of the dECM products in a way to mimic native tissues and organs.This article underscores the potential of dECM biomaterials to stimulate in situ tissue repair through chemotactic effects for the development of growth factor and cell-free tissue engineering strategies.The article also identifies the challenges and opportunities in developing sterilization and preservation methods applicable for decellularized biomaterials and grafts and their translation into clinical products.

Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer

Surgical resection remains the prefer option for bladder cancer treatment.However,the effectiveness of surgery is usually limited for the high recurrence rate and poor prognosis.Consequently,intravesical chemotherapy synergize with immunotherapy in situ is an attractive way to improve therapeutic effect.Herein,a combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system was developed.GEM loaded PLEL hydrogel was intravesical instilled to kill tumor cells directly,then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses synergize with GEM.The results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior in response to physiological temperature and presented sustained drug release,and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo.Hence,this combined treatment with PLEL hydrogel system has great potential and suggests a clinically-relevant and valuable option for bladder cancer.

Biofabrication methods for reconstructing extracellular matrix mimetics

In the human body,almost all cells interact with extracellular matrices(ECMs),which have tissue and organ-specific compositions and architectures.These ECMs not only function as cellular scaffolds,providing structural support,but also play a crucial role in dynamically regulating various cellular functions.This comprehensive review delves into the examination of biofabrication strategies used to develop bioactive materials that accurately mimic one or more biophysical and biochemical properties of ECMs.We discuss the potential integration of these ECM-mimics into a range of physiological and pathological in vitro models,enhancing our understanding of cellular behavior and tissue organization.Lastly,we propose future research directions for ECM-mimics in the context of tissue engineering and organ-on-a-chip applications,offering potential advancements in therapeutic approaches and improved patient outcomes.

Decellularized heart extracellular matrix alleviates activation of hiPSC-derived cardiac fibroblasts

Human induced pluripotent stem cell derived cardiac fibroblasts(hiPSC-CFs)play a critical role in modeling human cardiovascular diseases in vitro.However,current culture substrates used for hiPSC-CF differentiation and expansion,such as Matrigel and tissue culture plastic(TCPs),are tissue mismatched and may provide pathogenic cues.Here,we report that hiPSC-CFs differentiated on Matrigel and expanded on tissue culture plastic(M-TCP-iCFs)exhibit transcriptomic hallmarks of activated fibroblasts limiting their translational potential.To alleviate pathogenic activation of hiPSC-CFs,we utilized decellularized extracellular matrix derived from porcine heart extracellular matrix(HEM)to provide a biomimetic substrate for improving hiPSC-CF phenotypes.We show that hiPSC-CFs differentiated and expanded on HEM(HEM-iCFs)exhibited reduced expression of hallmark activated fibroblast markers versus M-TCP-iCFs while retaining their cardiac fibroblast phenotype.HEM-iCFs also maintained a reduction in expression of hallmark genes associated with pathogenic fibroblasts when seeded onto TCPs.Further,HEM-iCFs more homogenously integrated into an hiPSC-derived cardiac organoid model,resulting in improved cardiomyocyte sarcomere development.In conclusion,HEM provides an improved substrate for the differentiation and propagation of hiPSC-CFs for disease modeling.

Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis

Mitochondria are crucial in sustaining and orchestrating cellular functions.Capitalizing on this,we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury(SCI).In our study,we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region.Sourced from IL-10-induced Mertkhi bone marrow-derived macrophages,we conjugated a peptide sequence,cations-cysteine-alanine-glutamine-lysine(CAQK),with the mitochondria,optimizing its targeting affinity for the injury site.Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris,curtailed lipid buildup,ameliorated mitochondrial dysfunction,and attenuated pro-inflammatory profiles in macrophages,both in vitro and in vivo.The intravenously delivered mitochondrial compounds targeted the SCI epicenter,with macrophages being the primary recipients.Critically,they promoted tissue regeneration and bolstered functional recovery in SCI mice.This study heralds a transformative approach to mitochondrial transplantation in SCI,spotlighting the modulation of macrophage activity,phagocytosis,and phenotype.

Advancing neural regeneration via adaptable hydrogels:Enriched with Mg^(2+)and silk fibroin to facilitate endogenous cell infiltration and macrophage polarization

Peripheral nerve injury is a complex and challenging medical condition due to the limited ability of nerves to regenerate, resulting in the loss of both sensory and motor function. Hydrogels have emerged as a promising biomaterial for promoting peripheral nerve regeneration, while conventional hydrogels are generally unable to support endogenous cell infiltration due to limited network dynamics, thereby compromising the therapeutic outcomes. Herein, we present a cell adaptable hydrogel containing a tissue-mimetic silk fibroin network and a dynamically crosslinked bisphosphonated-alginate network. The dynamic network of this hydrogel can respond to cell-generated forces to undergo the cell-mediated reorganization, thereby effectively facilitating the rapid infiltration of Schwann cells and macrophages, as well as the ingrowth of axons. We further show that the magnesium ions released from the hydrogel not only promote neurite outgrowth but also regulate the polarization of macrophages in a sequential manner, contributing to the formation of a regenerative microenvironment. Therefore, this hydrogel effectively prevents muscle atrophy and promotes the regeneration and functional recovery of nerve defects of up to 10 mm within 8 weeks. The findings from this study demonstrate that adaptable hydrogels are promising inductive biomaterials for enhancing the therapeutic outcomes of peripheral nerve injury treatments.

Developing natural polymers for skin wound healing

Natural polymers are complex organic molecules that occur in the natural environment and have not been subjected to artificial synthesis.They are frequently encountered in various creatures,including mammals,plants,and microbes.The aforementioned polymers are commonly derived from renewable sources,possess a notable level of compatibility with living organisms,and have a limited adverse effect on the environment.As a result,they hold considerable significance in the development of sustainable and environmentally friendly goods.In recent times,there has been notable advancement in the investigation of the potential uses of natural polymers in the field of biomedicine,specifically in relation to natural biomaterials that exhibit antibacterial and antioxidant characteristics.This review provides a comprehensive overview of prevalent natural polymers utilized in the biomedical domain throughout the preceding two decades.In this paper,we present a comprehensive examination of the components and typical methods for the preparation of biomaterials based on natural polymers.Furthermore,we summarize the application of natural polymer materials in each stage of skin wound repair.Finally,we present key findings and insights into the limitations of current natural polymers and elucidate the prospects for their future development in this field.

A tough,antibacterial and antioxidant hydrogel dressing accelerates wound healing and suppresses hypertrophic scar formation in infected wounds

Wound management is an important issue that places enormous pressure on the physical and mental health of patients,especially in cases of infection,where the increased inflammatory response could lead to severe hypertrophic scars(HSs).In this study,a hydrogel dressing was developed by combining the high strength and toughness,swelling resistance,antibacterial and antioxidant capabilities.The hydrogel matrix was composed of a double network of polyvinyl alcohol(PVA)and agarose with excellent mechanical properties.Hyperbranched polylysine(HBPL),a highly effective antibacterial cationic polymer,and tannic acid(TA),a strong antioxidant molecule,were added to the hydrogel as functional components.Examination of antibacterial and antioxidant properties of the hydrogel confirmed the full play of the efficacy of HBPL and TA.In the in vivo studies of methicillin-resistant Staphylococcus aureus(MRSA)infection,the hydrogel had shown obvious promotion of wound healing,and more profoundly,significant suppression of scar formation.Due to the common raw materials and simple preparation methods,this hydrogel can be mass produced and used for accelerating wound healing while preventing HSs in infected wounds.

A paintable and adhesive hydrogel cardiac patch with sustained release of ANGPTL4 for infarcted heart repair

The infarcted heart undergoes irreversible pathological remodeling after reperfusion involving left ventricle dilation and excessive inflammatory reactions in the infarcted heart,frequently leading to fatal functional damage.Extensive attempts have been made to attenuate pathological remodeling in infarcted hearts using cardiac patches and anti-inflammatory drug delivery.In this study,we developed a paintable and adhesive hydrogel patch using dextran-aldehyde(dex-ald)and gelatin,incorporating the anti-inflammatory protein,ANGPTL4,into the hydrogel for sustained release directly to the infarcted heart to alleviate inflammation.We optimized the material composition,including polymer concentration and molecular weight,to achieve a paintable,adhesive hydrogel using 10%gelatin and 5%dex-ald,which displayed in-situ gel formation within 135 s,cardiac tissue-like modulus(40.5 kPa),suitable tissue adhesiveness(4.3 kPa),and excellent mechanical stability.ANGPTL4 was continuously released from the gelatin/dex-ald hydrogel without substantial burst release.The gelatin/dex-ald hydrogel could be conveniently painted onto the beating heart and degraded in vivo.Moreover,in vivo studies using animal models of acute myocardial infarction revealed that our hydrogel cardiac patch containing ANGPTL4 significantly improved heart tissue repair,evaluated by echocardiography and histological evaluation.The heart tissues treated with ANGPTL4-loaded hydrogel patches exhibited increased vascularization,reduced inflammatory macrophages,and structural maturation of cardiac cells.Our novel hydrogel system,which allows for facile paintability,appropriate tissue adhesiveness,and sustained release of anti-inflammatory drugs,will serve as an effective platform for the repair of various tissues,including heart,muscle,and cartilage.

Ultrasound-triggered biomimetic ultrashort peptide nanofiber hydrogels promote bone regeneration by modulating macrophage and the osteogenic immune microenvironment

The immune microenvironment plays a vital role in bone defect repair.To create an immune microenvironment that promotes osteogenesis,researchers are exploring ways to enhance the differentiation of M2-type macrophages.Functional peptides have been discovered to effectively improve this process,but they are limited by low efficiency and rapid degradation in vivo.To overcome these issues,peptide with both M2 regulatory and self-assembly modules was designed as a building block to construct an ultrasound-responsive nanofiber hydrogel.These nanofibers can be released from hydrogel in a time-dependent manner upon ultrasound stimulation,activating mitochondrial glycolytic metabolism and the tricarboxylic acid cycle,inhibiting reactive oxygen species production and enhancing M2 macrophage polarization.The hydrogel exhibits advanced therapeutic potential for bone regeneration by triggering M2 macrophages to secrete BMP-2 and IGF-I,accelerating the differentiation of bone marrow mesenchymal stem cells(BMSCs)into osteoblasts.Thus,modularly designed biomimetic ultrashort peptide nanofiber hydrogels provide a novel strategy to rebuild osteogenic immune microenvironments for bone repair.

Full-thickness osteochondral defect repair using a biodegradable bilayered scaffold of porous zinc and chondroitin sulfate hydrogel

The regeneration of osteochondral tissue necessitates the re-establishment of a gradient owing to the unique characteristics and healing potential of the chondral and osseous phases.As the self-healing capacity of hyaline cartilage is limited,timely mechanical support during neo-cartilage formation is crucial to achieving optimal repair efficacy.In this study,we devised a biodegradable bilayered scaffold,comprising chondroitin sulfate(CS)hydrogel to regenerate chondral tissue and a porous pure zinc(Zn)scaffold for regeneration of the underlying bone as mechanical support for the cartilage layer.The photocured CS hydrogel possessed a compressive strength of 82 kPa,while the porous pure Zn scaffold exhibited a yield strength of 11 MPa and a stiffness of 0.8 GPa.Such mechanical properties are similar to values reported for cancellous bone.In vitro biological experiments demonstrated that the bilayered scaffold displayed favorable cytocompatibility and promoted chondrogenic and osteogenic differentiation of bone marrow stem cells.Upon implantation,the scaffold facilitated the simultaneous regeneration of bone and cartilage tissue in a porcine model,resulting in(i)a smoother cartilage surface,(ii)more hyaline-like cartilage,and(iii)a superior integration into the adjacent host tissue.Our bilayered scaffold exhibits significant potential for clinical application in osteochondral regeneration.