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Infection‐induced bone defects present significant challenges in clinical bone regeneration, frequently leading to poor bone induction, recurring infections, and complications such as pain and chronic inflammation. This study introduces a novel Ti/Lignin‐Ag@PLL composite coating with a "sandwich" structure, designed to integrate pro‐adhesion, photothermal‐photodynamic antibacterial, and osteogenic properties. The Ti/Lignin‐Ag@PLL composite coating is fabricated using self‐assembly technology, in which Ag+ is reduced to silver nanoparticles (Ag‐NPs) by lignin, followed by Polylysine (PLL) grafting. Photothermal conversion efficiency is evaluated under near‐infrared (NIR) laser irradiation, while antibacterial activity is tested against E. coli and S. aureus. Biocompatibility is also assessed using vascular endothelial cells (VECs) and osteoblasts (OBs). The results indicate that the Ti/Lignin‐Ag@PLL coating demonstrates a 31% photothermal conversion efficiency and nearly 100% antibacterial efficacy against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) under NIR irradiation for 10 min. Without irradiation, the antibacterial rates are 85% and 94%, respectively, after 24 h. Additionally, the coating significantly promotes cell adhesion, proliferation, and osteogenesis, as evidenced by the upregulation of Runx2 and Collagen I. This study uniquely contributes to the development of a multifunctional composite coating that effectively combines robust antibacterial properties with enhanced osteogenic potential, offering a promising solution for bone tissue repair and infection prevention. [ABSTRACT FROM AUTHOR]

Efferocytosis, by phagocytosing and processing apoptotic cells in injured skin, directly influences the immune microenvironment. However, the comprehensive widespread inflammation and disrupted efferocytosis in injured skin cannot be effectively halted. Herein, "Grid Efferocytosis" strategy within injury site is proposed, which segments the inflammation regulatory into grid microdomains, and further rectifies intra‐grid immune microenvironment to accelerate tissue repair. GelMA/PLA/Laponite gridded fiber membranes (GPL) are custom‐designed via near‐field electrostatic printing, and then coated with HAMA‐PBA/EGCG hydrogel by photo‐crosslinking and dynamic borate bonding to form a composite fiber membrane (GPL‐E). Gridded modulation via GPL‐E confines the entire chaotic inflammatory microenvironment into controllable microinflammatory niches. Leveraging the hydrogel coating and boronic ester bond dissociation induced by microenvironmental glucose and reactive oxygen species, GPL‐E achieves dynamic anti‐glucose and anti‐oxidation within microdomains, reconstructing macrophage efferocytosis. Notably, the "grid efferocytosis" recruits repair cells into the grid by magnesium ion release triggered by Laponite exposure on fibers, and enhances endothelial cell vascularization by ≈2.5‐fold. In a mouse diabetic ischemic flap model, implantation of grid GPL‐E maintains flap‐to‐base fusion, attenuates inflammatory infiltration & spread, and improves blood perfusion for flap survival. This study demonstrates that "Grid Efferocytosis" rectifies the immune microenvironment, fostering tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Traditional high‐dose antibiotic treatments of intracellular methicillin‐resistant staphylococcus aureus (MRSA) are highly inefficient and associated with a high rate of infection relapse. As an effective antibacterial technology, sonodynamic therapy (SDT) may be able to break the dilemma. However, indiscriminate reactive oxygen species (ROS) release leads to potential side effects. This study incorporates Staphylococcal Protein A antibody‐modified Cu2+/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS‐SPA) into hydrogel microspheres (HAMA@Cu(II)NS‐SPA) to achieve precise eradication of intracellular bacteria. This eradication is under bioorthogonal activation mediated by bacillithiol (BSH) (internally) and ultrasound (US) (externally). To specify, the US responsiveness of Cu(II)NS‐SPA is restored when it is reduced to Cu(I)NS‐SPA by the BSH secreted characteristically by intracellular MRSA, thus forming a bioorthogonal activation with the external US, which confines ROS production within the infected MΦ. Under external US activation at 2 W cm−2, over 95% of intracellular MRSA can be cleared. In vivo, a single injection of HAMA@Cu(II)NS‐SPA achieves up to two weeks of antibacterial sonodynamic therapy, reducing pro‐inflammatory factor expression by 90%, and peri‐implant bone trabeculae numbers exceed the control group by five times. In summary, these micro/nano hydrogel microspheres mediated by internal and external bioorthogonal activation can precisely eliminate intracellular MRSA, effectively treating multi‐drug resistant intracellular bacterial infections. [ABSTRACT FROM AUTHOR]

The presence of bacterial persisters is a key factor contributing to chronic infection. However, no effective treatment methods are currently available. Thus, a platform is developed, called reactive oxygen species (ROS) bomb, based on microenvironment‐adaptive hydrogel microspheres, to oxidize the cell membranes of persisters in chronic periprosthetic joint infection (PJI). Fenton reagent hydroxy iron oxide (FeOOH) and a glucose oxidase (GOx)/calcium phosphate (CaP) acid‐responsive shell are sequentially induced on the surface of mesoporous polydopamine (PDA) nanoparticles by the PDA‐mediated ion precipitation and interfacial adhesion, followed by the coloaded with glucose into microfluidic hyaluronic acid hydrogel microspheres. Hydroxyl radicals are explosively generated through GOx‐mediated glucose oxidase, H2O2 production, and its Fenton‐like reactions with FeOOH, which also benefit from the weakly acidic microenvironment around persisters, result in the destruction of bacterial cell membrane, and subsequent overflow of cellular contents such as dsDNA, proteins, and K+. The bactericidal rates of methicillin‐resistant Staphylococcus aureus and Staphylococcus epidermidis persisters are up to 99.14% and 98.96%, and the bacterial loads in lesion location are significantly decreased after ROS bombs treated, effectively alleviated the inflammation and bone resorption damage. This work provides a new strategy toward persisters clearance and shows great application potential in other chronic infection‐related diseases. [ABSTRACT FROM AUTHOR]

Reactive astrogliosis is the main cause of secondary injury to the central nerves. Biomaterials can effectively suppress astrocyte activation, but the mechanism remains unclear. Herein, Differentially Expressed Genes (DEGs) are identified through whole transcriptome sequencing in a mouse model of spinal cord injury, revealing the VIM gene as a pivotal regulator in the reactive astrocytes. Moreover, DEGs are predominantly concentrated in the extracellular matrix (ECM). Based on these, 3D injectable electrospun short fibers are constructed to inhibit reactive astrogliosis. Histological staining and functional analysis indicated that fibers with unique 3D network spatial structures can effectively constrain the reactive astrocytes. RNA sequencing and single‐cell sequencing results reveal that short fibers downregulate the expression of the VIM gene in astrocytes by modulating the "ECM receptor interaction" pathway, inhibiting the transcription of downstream Vimentin protein, and thereby effectively suppressing reactive astrogliosis. Additionally, fibers block the binding of Vimentin protein with inflammation‐related proteins, downregulate the NF‐κB signaling pathway, inhibit neuron apoptosis, and consequently promote the recovery of spinal cord neural function. Through mechanism elucidation‐material design‐feedback regulation, this study provides a detailed analysis of the mechanism chain by which short fibers constrain the abnormal spatial expansion of astrocytes and promote spinal cord neural function. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a common degenerative disease characterized by continuous detachment of lubrication factors from damaged cartilage matrix. This study proposes a paradigm that combines natural polyanionic polysaccharides (hyaluronic acid, HA) with dopamine (DA) to design a synovial lubrication factors‐recruiting biomimetic polyphenolized lubrication system. The biomimetic lubricants can use DA's polarity and hydrophilic groups as specific binding sites of type II collagen's polarity and hydrophilic groups to stably bind cartilage surface, and further utilize molecular specific interaction to recruit detached, joint endogenous or chondrocytes expressed synovial lubrication factors, continuously forming supramolecular lubrication complex onto cartilage matrix to induce joint lubrication. Simultaneously, the biolubricants can also utilize catechol groups to eliminate anionic free radicals and resist reactive oxygen species invasion in the early stages of joint lubrication failure. The prepared biolubricants exhibit low coefficient of friction (µ < 0.08), which is attributed to fluid and hydration lubrication provided by HA and DA side chains through fluid dynamic effect and interfacial hydration adsorption. Cell and animal experiments also demonstrate polyphenolic biolubricants have good biocompatibility and promote cartilage regeneration. Therefore, the developed synovial lubricants‐recruiting biomimetic polyphenolized biolubricants have potential for treating osteoarthritis, and also provide a theoretical basis for other biological tissues with lubrication problems. [ABSTRACT FROM AUTHOR]

Antibacterial photodynamic therapy (aPDT) and antibacterial sonodynamic therapy (aSDT) utilize sensitizers (photosensitizers/sonosensitizers) to produce reactive oxygen species (ROS) for antibacterial treatment under the stimulation of light/ultrasound, which have the characteristics of broad‐spectrum antibacterial properties, low drug‐resistance, and effective targeting of infected tissues. Nanomaterials in aPDT/aSDT are primarily used as nano‐sensitizers or nano‐carriers of sensitizers. They enhance the stability and permeability of sensitizers, improve targeting of sensitizers, strengthen photodynamic/sonodynamic properties of sensitizers (modification of sensitizers absorption efficiency and light/ultrasonic response stress by modulation of nanoparticle shape, size, and structure). Also, they improve modifiability of sensitizers (controlling the release rate and time of the sensitizer as needed to optimize the therapeutic effect), enhance programmability and multifunctionality of sensitizers (flexible application of nanotechnology for designing sensitizers with multiple functions, such as drug delivery, targeted therapy, and therapeutic monitoring), and expand possibilities for combination therapies (the nano‐carriers can be loaded with other therapeutic agents, enabling combination therapies). Nanomaterials are expected to further promote the development of aPDT/aSDT and achieve improved antibacterial effects. This review summarizes the progress in nanomaterials in aPDT/aSDT in recent years and based on the current development strategies to provide a theoretical reference for the application of nanomaterials in aPDT/aSDT. [ABSTRACT FROM AUTHOR]

Bionic lubricant materials are a class of materials inspired by natural organisms and offer excellent lubrication properties and biocompatibility. In the field of sports medicine, their application opens up new possibilities for the prevention and treatment of sports‐related diseases. The authors will introduce the existing theoretical models of friction in the locomotor system, the characteristics and advantages of biomimetic lubrication materials and discuss in depth their applications in the field of sports medicine. The development of bionic lubrication materials opens up unprecedented opportunities for sports medicine to provide more effective and long‐lasting treatment options for patients. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative disease caused by a variety of factors with joint pain as the main symptom, including fibrosis, chapping, ulcers, and loss of cartilage. Traditional treatment can only delay the progression of OA, and classical delivery system have many side effects. In recent years, microspheres have shown great application prospects in the field of OA treatment. Microspheres can support cells, reproduce the natural tissue microenvironment in vitro and in vivo, and are an efficient delivery system for the release of drugs or biological agents, which can promote cell proliferation, migration, and differentiation. Thus, they have been widely used in cartilage repair and regeneration. In this review, preparation processes, basic materials, and functional characteristics of various microspheres commonly used in OA treatment are systematically reviewed. Then it is introduced surface modification strategies that can improve the biological properties of microspheres and discussed a series of applications of microsphere functionalized scaffolds in OA treatment. Finally, based on bibliometrics research, the research development, future potential, and possible research hotspots of microspheres in the field of OA therapy is systematically and dynamically evaluated. The comprehensive and systematic review will bring new understanding to the field of microsphere treatment of OA. [ABSTRACT FROM AUTHOR]

Stable regulation of protein fate is a prerequisite for successful bone tissue repair. As a ubiquitin‐specific protease (USP), USP26 can stabilize the protein fate of β‐catenin to promote the osteogenic activity of mesenchymal cells (BMSCs) and significantly increased bone regeneration in bone defects in aged mice. However, direct transfection of Usp26 in vivo is inefficient. Therefore, improving the efficient expression of USP26 in target cells is the key to promoting bone tissue repair. Herein, 3D printing combined with microfluidic technology is applied to construct a functional microunit (protein fate regulating functional microunit, denoted as PFFM), which includes GelMA microspheres loaded with BMSCs overexpressing Usp26 and seeded into PCL 3D printing scaffolds. The PFFM provides a microenvironment for BMSCs, significantly promotes adhesion, and ensures cell activity and Usp26 supplementation that stabilizes β‐catenin protein significantly facilitates BMSCs to express osteogenic phenotypes. In vivo experiments have shown that PFFM effectively accelerates intervertebral bone fusion. Therefore, PFFM can provide new ideas and alternatives for using USP26 for intervertebral fusion and other hard‐to‐repair bone defect diseases and is expected to provide clinical translational potential in future treatments. [ABSTRACT FROM AUTHOR]

Due to the deficiency of mechanical supporting after discectomy and weak proliferative capacity of annulus fibrosus (AF) cells, the AF defect repair remains a clinical challenge. Herein, a myofibroblasts derived extracellular vesicles (M‐EVs) functional "brick‐cement" bio‐integrated system (M‐EVs@PGBgel) is developed to repair AF defect. The modified Poly(glycerol‐sebacate) (PGBS), "bio‐brick" layer, exhibited excellent support features on account of its elastomeric mechanical properties. The loaded M‐EVs in the "bio‐cement" layer activated ITGA6/PI3K/AKT pathway, regulated M2 macrophage polarization, thus synergistically promoting AF cell proliferation and migration. The "bio‐cement" layer integrated PGBS and remnant tissue at the defect through the Schiff base reaction and aided M‐EVs' sustained release. This study demonstrated that M‐EVs@PGBgel significantly improved the disc's biological and mechanical properties in the AF defect microenvironments and promoted AF regeneration in vivo. The M‐EVs@PGBgel shows promise as an effective strategy to simultaneously address the mechanical imbalance and biological disruptions resulting from AF defect. [ABSTRACT FROM AUTHOR]

The microvascular network plays an important role in providing nutrients to the injured tissue and exchanging various metabolites. However, how to achieve efficient penetration of the injured tissue is an important bottleneck restricting the reconstruction of microvascular network. Herein, the hydrogel precursor solution can efficiently penetrate the damaged tissue area, and ultrasound triggers the release of thrombin from liposomes in the solution to hydrolyze fibrinogen, forming a fibrin solid hydrogel network in situ with calcium ions and transglutaminase as catalysts, effectively solving the penetration impedance bottleneck of damaged tissues and ultimately significantly promoting the formation of microvascular networks within tissues. First, the fibrinogen complex solution is effectively permeated into the injured tissue. Second, ultrasound triggered the release of calcium ions and thrombin, activates transglutaminase, and hydrolyzes fibrinogen. Third, fibrin monomers are catalyzed to form fibrin hydrogels in situ in the damaged tissue area. In vitro studies have shown that the fibrinogen complex solution effectively penetrated the artificial bone tissue within 15 s after ultrasonic triggering, and formed a hydrogel after continuous triggering for 30 s. Overall, this innovative strategy effectively solved the problem of penetration resistance of ultrasound‐triggered hydrogels in the injured tissues, and finally activates in situ microvascular networks regeneration. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) seriously impede diabetic wound healing. The disruption or scavenging of NETs using deoxyribonuclease (DNase) or cationic nanoparticles has been limited by liberating trapped bacteria, short half‐life, or potential cytotoxicity. In this study, a positive correlation between the NETs level in diabetic wound exudation and the severity of wound inflammation in diabetic patients is established. Novel NETs scavenging bio‐based hydrogel microspheres 'micro‐cage', termed mPDA‐PEI@GelMA, is engineered by integrating methylacrylyl gelatin (GelMA) hydrogel microspheres with cationic polyethyleneimine (PEI)‐functionalized mesoporous polydopamine (mPDA). This unique 'micro‐cage' construct is designed to non‐contact scavenge of NETs between nanoparticles and the diabetic wound surface, minimizing biological toxicity and ensuring high biosafety. NETs are introduced into 'micro‐cage' along with wound exudation, and cationic mPDA‐PEI immobilizes them inside the 'micro‐cage' through a strong binding affinity to the cfDNA web structure. The findings demonstrate that mPDA‐PEI@GelMA effectively mitigates pro‐inflammatory responses associated with diabetic wounds by scavenging NETs both in vivo and in vitro. This work introduces a novel nanoparticle non‐contact NETs scavenging strategy to enhance diabetic wound healing processes, with potential benefits in clinical applications. [ABSTRACT FROM AUTHOR]

The incidence of large bone and articular cartilage defects caused by traumatic injury is increasing worldwide; the tissue regeneration process for these injuries is lengthy due to limited self‐healing ability. Endogenous bioelectrical phenomenon has been well recognized to play an important role in bone and cartilage homeostasis and regeneration. Studies have reported that electrical stimulation (ES) can effectively regulate various biological processes and holds promise as an external intervention to enhance the synthesis of the extracellular matrix, thereby accelerating the process of bone and cartilage regeneration. Hence, electroactive biomaterials have been considered a biomimetic approach to ensure functional recovery by integrating various physiological signals, including electrical, biochemical, and mechanical signals. This review will discuss the role of endogenous bioelectricity in bone and cartilage tissue, as well as the effects of ES on cellular behaviors. Then, recent advances in electroactive materials and their applications in bone and cartilage tissue regeneration are systematically overviewed, with a focus on their advantages and disadvantages as tissue repair materials and performances in the modulation of cell fate. Finally, the significance of mimicking the electrophysiological microenvironment of target tissue is emphasized and future development challenges of electroactive biomaterials for bone and cartilage repair strategies are proposed. [ABSTRACT FROM AUTHOR]

Significance of endogenous mineralization in bone reconstruction is paramount, as it facilitates the accumulation of calcium ions for bone tissue deposition. However, conventional 3D‐printed scaffolds lack the capacity for calcium ion enrichment and mineralization, coupled with their low bone inductive activity. Inspired from the development of natural plant seeds, a biomimetic 3D printing scaffold is developed by implanting photosensitive black phosphorus "bone seeds" (BS), guiding a sequential process mirroring rooting (osteoblast recruitment), sprouting (fibrous callus mineralization), flowering (osseous callus formation), and fruiting (callus plasticity). BS were trapped onto porous 3D polycaprolactone (PCL) scaffolds with aminated surfaces via electrostatic interactions between phosphates and amino groups, creating the PCL‐BS scaffold that can actively capture calcium ions for accelerating the endogenous regeneration of critical bone defects. In vitro and in vivo experiments show that the PCL‐BS scaffold has good biocompatibility and strong osteogenic ability for rapid new bone regeneration under near‐infrared (NIR) stimulation. In addition, whole transcriptome sequencing analysis is performed to reveal the transcriptomic mechanism of BS involved in signal transduction and network regulation during bone regeneration. This NIR light‐regulated biomimetic BS inspired by seed planting, introduces a pioneering concept in the design of 3D printing bone repair scaffolds. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IDD) is widely recognized as the primary culprit of chronic low back pain. Restoring deteriorated intervertebral disc (IVD) and alleviating IDD‐induced low back pain are remaining enormous challenges. There is a genetic susceptibility to IDD, and gene therapy has some therapeutic potential. However, traditional gene therapy still has certain drawbacks, including host immunity, temporary release, and suppression of gene medication function. Although regenerative materials can effectively improve the local microenvironment, they cannot treat IDD from the root. Gene‐functionalized regenerative material (GRM) is constructed based on physical embedding or forming chemical bonds by introducing particular genes, such as pDNA, siRNA, mRNA, and miRNA, into the regenerated materials. The findings demonstrate that GRM not only enhances the safety and controllability of gene therapy, but also effectively repairs IDD by overcoming the constraint that simple regenerative materials cannot reverse the disease's progression from the root. This article provided a brief overview of the physiological and pathological features of the IVD, genetic susceptibility to IDD, available treatment options, and their limitations. Then, the significance of GRM‐based treatment of IDD is proposed, and the future challenges and development in this field are finally prospected. [ABSTRACT FROM AUTHOR]

The dynamic balance between hypoxia and oxidative stress constitutes the oxygen‐related microenvironment in injured tissues. Due to variability, oxygen homeostasis is usually not a therapeutic target for injured tissues. It is found that when administered intravenously, mesenchymal stem cells (MSCs) and in vitro induced apoptotic vesicles (ApoVs) exhibit similar apoptotic markers in the wound microenvironment where hypoxia and oxidative stress co‐existed, but MSCs exhibited better effects in promoting angiogenesis and wound healing. The derivation pathway of ApoVs by inducing hypoxia or oxidative stress in MSCs to simulate oxygen homeostasis in injured tissues is improved. Two types of oxygen‐related environmental stressed ApoVs are identified that directly target endothelial cells (ECs) for the accurate regulation of vascularization. Compared to normoxic and hypoxic ones, oxidatively stressed ApoVs (Oxi‐ApoVs) showed the strongest tube formation capacity. Different oxygen‐stressed ApoVs deliver similar miRNAs, which leads to the broad upregulation of EC phosphokinase activity. Finally, local delivery of Oxi‐ApoVs‐loaded hydrogel microspheres promotes wound healing. Oxi‐ApoV‐loaded microspheres achieve controlled ApoV release, targeting ECs by reducing the consumption of inflammatory cells and adapting to the proliferative phase of wound healing. Thus, the biogenerated apoptotic vesicles responding to oxygen‐related environmental stress can target ECs to promote vascularization. [ABSTRACT FROM AUTHOR]

The prevalence of infertility caused by endometrial defects is steadily increasing, posing a significant challenge to women's reproductive health. In this study, injectable "homing‐like" bioactive decellularized extracellular matrix short‐fibers (DEFs) of porcine skin origin are innovatively designed for endometrial and fertility restoration. The DEFs can effectively bind to endometrial cells through noncovalent dipole interactions and release bioactive growth factors in situ. In vitro, the DEFs effectively attracted endometrial cells through the "homing‐like" effect, enabling cell adhesion, spreading, and proliferation on their surface. Furthermore, the DEFs effectively facilitated the proliferation and angiogenesis of human primary endometrial stromal cells (HESCs) and human umbilical vein endothelial cells (HUVECs), and inhibited fibrosis of pretreated HESCs. In vivo, the DEFs significantly accelerated endometrial restoration, angiogenesis, and receptivity. Notably, the deposition of endometrial collagen decreased from 41.19 ± 2.16% to 14.15 ± 1.70% with DEFs treatment. Most importantly, in endometrium‐injured rats, the use of DEFs increased the live birth rate from 30% to an impressive 90%, and the number and development of live births close to normal rats. The injectable "homing‐like" bioactive DEFs system can achieve efficient live births and intrauterine injection of DEFs provides a new promising clinical strategy for endometrial factor infertility. [ABSTRACT FROM AUTHOR]

0D biomaterials (0DBMs) can serve as carriers to enhance and extend the regulatory effects of biological cues they transport on cell fate via bacterial/mammalian cell internalization. However, accurately delivering and amplifying biosignals through 0DBMs remains challenging to cope with ecological niche destabilization induced by factors such as trauma or infection. Herein, the "zero‐dimensional amplification" approach is employed to develop a surface carboxylate carbon dot (CQD‐COOH) conjugated with a neutrophil constitutive peptide (LL‐37), resulting in the formation of a 0D peptide quantum dot (LQD). Hydrogel‐released LQDs, when internalized by bacteria, cause the bacteria to programmatically rupture and die, whereas LQDs internalized by mesenchymal stem cells (MSCs) activate the cellular CXCL12/CXCR4 signaling axis, which directs the stem cells to homing and anchor to the surface of the hydrogel coating. Notably, this strategy of "zero‐dimensional amplification" enables the antimicrobial performance of LL‐37 to be boosted approximately 1.3‐fold, significantly extending the transmission efficiency of biosignals. Meanwhile, 0D lipid nanoparticles (lipo‐NPs) with targeting function incorporated into the hydrogel could deliver the bio‐small molecule MK‐4 to MCSs and induce their endocytosis, further enhancing osseointegration. Thus, the hydrogel coating (HGLL) under this strategy can significantly remodel the ecological niche of the implant–bone interface in infected environment. [ABSTRACT FROM AUTHOR]

Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging‐related diseases, such as osteoarthritis (OA). In this study, cartilage lesion‐localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde‐ and methacrylic anhydride (MA)‐modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro‐apoptotic liposomes (liposomes encapsulating ABT263, A‐Lipo) and PDGF‐BB, namely A‐Lipo/PAHM, are prepared by microfluidic and photo‐cross‐linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde‐functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A‐Lipo induced apoptosis of senescent chondrocytes (Sn‐chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging‐related diseases. [ABSTRACT FROM AUTHOR]

The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of "seeding and harvest", are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast‐to‐DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two‐pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds. [ABSTRACT FROM AUTHOR]

Destruction of cartilage due to the abnormal remodeling of subchondral bone (SB) leads to osteoarthritis (OA), and restoring chondro‐bone metabolic homeostasis is the key to the treatment of OA. However, traditional intra‐articular injections for the treatment of OA cannot directly break through the cartilage barrier to reach SB. In this study, the hydrothermal method is used to synthesize ultra‐small size (≈5 nm) selenium‐doped carbon quantum dots (Se‐CQDs, SC), which conjugated with triphenylphosphine (TPP) to create TPP‐Se‐CQDs (SCT). Further, SCT is dynamically complexed with hyaluronic acid modified with aldehyde and methacrylic anhydride (AHAMA) to construct highly permeable micro/nano hydrogel microspheres (SCT@AHAMA) for restoring chondro‐bone metabolic homeostasis. In vitro experiments confirmed that the selenium atoms scavenged reactive oxygen species (ROS) from the mitochondria of mononuclear macrophages, inhibited osteoclast differentiation and function, and suppressed early chondrocyte apoptosis to maintain a balance between cartilage matrix synthesis and catabolism. In vivo experiments further demonstrated that the delivery system inhibited osteoclastogenesis and H‐vessel invasion, thereby regulating the initiation and process of abnormal bone remodeling and inhibiting cartilage degeneration in SB. In conclusion, the micro/nano hydrogel microspheres based on ultra‐small quantum dots facilitate the efficient penetration of articular SB and regulate chondro‐bone metabolism for OA treatment. [ABSTRACT FROM AUTHOR]

Disturbance of spatiotemporal oxygen balance is the main cause of delayed healing or nonhealing of large bone defects. The accurate administration of oxygen to regulate disruptions in the spatiotemporal oxygen equilibrium during 9 h of hypoxia is imperative for bone tissue regeneration. Herein, oxygen‐loaded nanobubbles prepared by double emulsification are successfully embedded in GelMA/HepMA microsphere macromolecular meshwork by microfluidic techniques, and a spatiotemporalized hydrogel microsphere is constructed by noncovalently binding bone morphogenetic protein 2 (BMP‐2). The spatiotemporalized hydrogel microspheres precisely "remote control" oxygen release by ultrasound in vitro 9 h after bone injury to regulate spatiotemporal oxygen homeostasis disorder, maintain a high level of vascular endothelial growth factor (VEGF) expression, and accelerate bone repair. The spatiotemporalized hydrogel microspheres possess good oxygen‐carrying capacity and ultrasonic responsiveness, and the oxygen concentration increases to 1.63, 1.95, 2.11, and 2.29 times under the ultrasound action at different intensities of 1, 2, 3, and 4 W, respectively, providing the conditions for the precise regulation of spatiotemporal oxygen balance disorder by ultrasound. In the in vitro hypoxia model and in vivo rat femoral defect model, the spatiotemporal hydrogel microspheres show good vascularization and osteogenesis capabilities, which provide a new strategy for the clinical treatment of large bone defects. [ABSTRACT FROM AUTHOR]

The high density structure of cartilage matrix negative charge seriously hinders the penetration and enrichment of drugs/genes into cartilage tissue. In this study, hexachlorocyclotriphosphonitrile is used as the core to prepare self‐polymerized phosphorus dendrimers with inflammatory reaction through substitution and condensation reaction. The vector can achieve efficient penetration of the damaged articular cartilage (slightly acidic condition) and effective anchoring of cartilage matrix (normal physiological condition) through the size effect under inflammatory response. Meanwhile, as a gene "delivery library," G1‐NC5.HCl@siRNA is gradually released with microspheres degrading; the long‐term silencing of specific genes is realized. Further, G1‐NC5.HCl@siRNA is loaded into the hydrogel microspheres by ionic bond coordination and microfluidic techniques to improve the residency effect of G1‐NC5.HCl@siRNA in the joint cavity. The results of cartilage in vitro and in vivo experiments show that the gene complex has a better penetration effect at pH = 6.6, and the cartilage penetration effect decreases at pH = 7.6, which can effectively anchor in the cartilage matrix site for continuous drug delivery. Further, the composite hydrogel microspheres significantly improve the degeneration of osteoarthritis (OA) cartilage and promote cartilage regeneration. Therefore, the self‐polymerized hydrogel microsphere delivery system with inflammatory response is a promising penetrant/anchoring carrier system for OA treatment. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis (PMO) is often accompanied by neuroendocrine changes in the hypothalamus, which closely associates with the microbial diversity, community composition, and intestinal metabolites of gut microbiota (GM). With the emerging role of GM in bone metabolism, a potential neuroendocrine signal neuropeptide Y (NPY) mediated brain‐gut‐bone axis has come to light. Herein, it is reported that exogenous overexpression of NPY reduced bone formation, damaged bone microstructure, and up‐regulated the expressions of pyroptosis‐related proteins in subchondral cancellous bone in ovariectomized (OVX) rats, but Y1 receptor antagonist (Y1Ra) reversed these changes. In addition, it is found that exogenous overexpression of NPY aggravated colonic inflammation, impaired intestinal barrier integrity, enhanced intestinal permeability, and increased serum lipopolysaccharide (LPS) in OVX rats, and Y1Ra also reversed these changes. Most importantly, NPY and Y1Ra modulated the microbial diversity and changed the community composition of GM in OVX rats, and thereby affecting the metabolites of GM (e.g., LPS) entering the blood circulation. Moreover, fecal microbiota transplantation further testified the effect of NPY‐mediated GM changes on bone. In vitro, LPS induced pyroptosis, reduced viability, and inhibited differentiation of osteoblasts. The study demonstrated the existence of NPY‐mediated brain‐gut‐bone axis and it might be a novel emerging target to treat PMO. [ABSTRACT FROM AUTHOR]

Geometry and angles play crucial roles in cellular processes; however, its mechanisms of regulation remain unclear. In this study, a series of three dimensional (3D)‐printed microfibers with different geometries is constructed using a near‐field electrostatic printing technique to investigate the regulatory mechanisms of geometry on stem cell function and bone regeneration. The scaffolds precisely mimicked cell dimensions with high porosity and interoperability. Compared with other spatial topography angles, microfibers with a 90° topology can significantly promote the expression of osteogenic gene proteins in bone marrow‐derived mesenchymal stem cells (BMSCs). The effects of different spatial structures on the expression profiles of BMSCs differentiation genes are correlated and validated using microRNA sequencing. Enrichment analysis shows that the 90° microfibers promoted osteogenesis in BMSCs by significantly upregulating miR‐222‐5p/cbfb/Runx2 expression. The ability of the geometric architecture to promote bone regeneration, as assessed using the cranial defect model, demonstrates that the 90° fiber scaffolds significantly promote new bone regeneration and neovascular neural network formation. This study is the first to elucidate the relationship between angular geometry and cellular gene expression, contributing significantly to the understanding of how geometric architecture can promote stem cell differentiation, proliferation, and function for structural bone regeneration. [ABSTRACT FROM AUTHOR]

Apoptosis is the natural programmed cell death process, which is responsible for abnormal cell clearance. However, many cancer cells develop various mechanisms to escape apoptosis through interrupting apoptosome assembly, which is a key step to initiate apoptosis. This promotes tumorigenesis and drug resistance, and thus, poses a great challenge in cancer treatment. Herein, a biomimetic lipid nanocarrier mimicking mitochondrial Cytochrome C (Cyt C) binding is developed. Cardiolipin, the major phospholipid of mitochondrial inner membrane, is introduced as the main component in biomimetic liposomal formulation. With the help of cardiolipin, Cyt C is sufficiently loaded in liposome based on electrostatic and hydrophobic interaction with cardiolipin. Lonidamine (LND) is added in hydrophobic phase of liposome to modulate the metabolic activity within cancer cells and sensitize the cells to Cyt C‐induced apoptosis. The results suggest that LND reduces ATP level and creates favorable environment for Cyt C induced apoptosome assembly, exhibiting higher apoptosis level and anti‐tumor efficacy in vitro and in vivo. The conjugation of a tumor‐homing peptide, LinTT1, on the nanovesicle, increases the efficacy due to enhanced tumor accumulation. Overall, this biomimetic lipid nanocarrier proves to be an efficient delivery system with great potential of pro‐apoptosis cancer therapy. [ABSTRACT FROM AUTHOR]

Objective: Macrolide antibiotics are often used to prevent infection and inflammation after functional endoscopic sinus surgery for the treatment of chronic rhinosinusitis (CRS). The purpose of this study was to investigate the anti‐inflammatory and antibacterial effects of the clarithromycin‐loaded poly(‐lactide) (CLA‐PLLA) membrane and its mechanism. Study Design: Randomized controlled trial. Setting: Animal Experiment Center. Methods: We compared the difference between poly(l‐lactide) (PLLA) and CLA‐PLLA membranes by observing the morphology of fibrous scaffolds, measuring water contact angle, tensile strength, and drug release capacity, and evaluating the antimicrobial activity of CLA‐PLLA. Twenty‐four rabbits were divided into a PLLA group and a CLA‐PLLA group after establishing CRS models. Another 5 normal rabbits comprised the control group. After 3 months, we placed the PLLA membrane in the nasal cavity of the PLLA group and the CLA‐PLLA membrane in the CLA‐PLLA group. Then, 14 days later, we evaluated the histological and ultrastructural changes in the sinus mucosa, protein, and messenger RNA (mRNA) levels of interleukin (IL)‐4, IL‐8, tumor necrosis factor‐α, transforming growth factor‐β1, α‐smooth muscle actin, and type I collagen. Results: The CLA‐PLLA membrane showed no significant difference in physical performance to the PLLA membrane, which continuously released 95% of the clarithromycin (CLA) for 2 months. The CLA‐PLLA membrane had significant bacteriostatic properties that can improve the morphology of mucosal tissues, and inhibit protein and mRNA expression of inflammatory cytokines. In addition, CLA‐PLLA also inhibited the expression of fibrosis‐associated marker molecules. Conclusion: The CLA‐PLLA membrane released CLA slowly and continuously, providing antibacterial, anti‐inflammatory, and antifibrotic effects in a rabbit model of postoperative CRS. [ABSTRACT FROM AUTHOR]

Intraperitoneal sporadic tumor is a common and complicated syndrome in cancers, causing a high rate of death, and people find that intraperitoneal chemotherapy (IPC) can treat intraperitoneal sporadic tumors better than intravenous chemotherapy and surgery. However, the effectiveness and side effects of IPC are controversial, and the operation process of IPC is complicated. Herein, the injectable paclitaxel‐loaded (PTX‐loaded) electrospun short fibers are constructed through a series process of electrospinning, homogenizing, crosslinking, and subsequent polydopamine coating and folate acid (FA) modification. The evenly dispersed short fibers exhibited effective tumor cell killing and good injectable ability, which is convenient to use and greatly improved the complex operation procedure. Mussel‐like protein poly‐dopamine coating and FA modification endowed short fibers with the ability of targeted adhesion to tumors, and therefore the short fibers further acted as a kind of micro membrane that could release drugs to tumors at close range, maintaining local high drug concentration and prevent paclitaxel killing normal tissues. Thus, the target‐adhesive injectable electrospun short fibers are expected to be the potential candidate for cancer treatment, especially the intraperitoneal sporadic tumors, which are hard to treat by surgery or intravenous chemotherapy. [ABSTRACT FROM AUTHOR]

Lentiviral‐vector‐based therapies, widely used for treating various diseases, face limitations because of release burst, rapid clearance, and immune activation. Herein, a lentiviral vector delivery platform is proposed utilizing a virus‐engineered microsol electrospun scaffold. Identifying a remarkable upregulation of polypyrimidine tract binding protein1 (PTB) in spinal cord injury (SCI) rats, a scaffold is constructed comprising a hyaluronic acid (HA) core encapsulating brain‐derived neurotrophic factor (BDNF) and a polydopamine (PDA)‐modified linear poly‐l‐lactic acid (PLLA) shell, with shPTB lentiviral vectors (LV‐shPTB) grafted via PDA. In vitro, the LV‐shPTB achieves an infection efficiency of 70%, and the oriented scaffolds significantly reduce the expression of inflammatory factors, induce the reprogramming of fibroblasts into neurons, and sustain the release of BDNF for over 2 weeks. In vivo, the scaffolds provide physical support and neural guidance, as well as released BDNF and LV‐shPTB. LV‐shPTB delivery leads to the reprogramming of fibroblasts into neurons, and the sustained BDNF delivery maintains the neurons' proliferation and growth, which further promotes the recovery of neurological function in SCI rats. These results demonstrate the potential application of virus‐engineered delivery platforms in SCI treatment and other medical fields. [ABSTRACT FROM AUTHOR]

Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which trigger a prolonged excessive inflammatory reaction and lead to failure of bone regeneration. In this study, seamless adhesive biomimetic periosteum patches (HABP/Sr‐PLA) were prepared to fill microcracks in defective bone via interfacial self‐assembly induced by Sr ions mediated metal‐ligand interactions among pamidronate disodium‐modified hyaluronic acid (HAPD), black phosphorus (BP), and hydrophilic polylactic acid (PLA). In vitro, HABP/Sr‐PLA exhibited excellent self‐healing properties, seamlessly filled bone microcracks, and significantly enhanced osteogenesis and angiogenesis. Furthermore, in a rat cranial defect model, HABP/Sr‐PLA was demonstrated to significantly promote the formation of blood vessels and new bone under mild 808 nm photothermal stimulation (42.8 °C), and the highest protein expression of CD31 and OPN was five times higher than that of the control group and other groups. Therefore, the proposed seamless microcrack‐filled bionic periosteum patch is a promising clinical strategy for promoting bone repair. [ABSTRACT FROM AUTHOR]

Non‐invasive management of intestinal microvascular injury with hemorrhage under constant biochemical‐mechanical encroachment of luminal contents is a major clinical challenge. Herein, an oral hydrogel microsphere is designed, encapsulating the platelet membrane fragment self‐assembled nanohydrogel fabricated by double‐crosslinking of methacrylated hyaluronic acid and Rebamipide‐loaded dendrimer (Rng@PMS), for self‐localization of hemorrhagic focus and intensive management of intestinal microvascular injury via suppression of inflammation‐mediated tissue injury and reintegration of the damaged mucosal barrier. The results indicate that Rng@PMS effectively adheres to exposed collagen on injured microvasculature and attaches to over 90% of activated macrophages within 10 min, endowing Rng@PMS with a significantly prolonged enteral dwell time (over 24 hours). Importantly, Rng@PMS generated from alginate is designed for oral colon‐targeted delivery to avoid the erosion of gastrointestinal contaminants. In vivo study reveals oral administration of microspheres in murine hematochezia model upregulates the intestinal barrier proteins zonula occludens‐1, Occludin, and muc2, and inhibits infiltration of neutrophils, dendritic cells, and macrophages in hemorrhagic foci, thereby reducing the hematochezia score from 4 to 0.8, and the pathology score from 5.3 to 0.5. Oral microspheres for in situ management of intestinal microvascular injury may be applicable more broadly to noninvasively treat diseases with symptoms of mucosal hemorrhage. [ABSTRACT FROM AUTHOR]