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The worldwide prevalence of musculoskeletal disorders is expected to rise due to an accelerating aging population and increasing associated factors. Despite the high rate of disability induction, clinical options for the treatment of musculoskeletal disorders remain limited. Hydrogel microspheres (HMSs), which are colloidal particles with crosslinked polymer networks at the nanometer scale, are characterized by excellent biocompatibility, easy‐to‐tune structures (e.g., stiffness, porosity, and composition), and high encapsulation efficiency of therapeutic agents (e.g., drugs and cells). At present, multiple techniques are utilized for the fabrication of HMSs and encapsulation of therapeutic agents. The HMSs can be produced and used in different states to match specific utilizations. These desirable properties, along with their injectability, bestow HMSs with mutifunctionalities that can be utilized for a variety of biomedical applications (e.g., delivery of biologics, tissue regeneration, and bio‐lubrication), and thus enable them to be promising tools for tackling a variety of clinical diseases. Herein, the focus is the fabrication and application of therapeutic HMSs for i) bone disorders, ii) cartilage and osteochondral disorders, iii) intervertebral disc (IVD) disorders, and iv) neurovascular disorders, with the aim of overviewing the recent progress to summarize key contributions and findings and highlight the limitations and opportunities in this field. [ABSTRACT FROM AUTHOR]

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced with different degrees of methacryloyl substitution; however, the synthesis of this polymer has not been tuned towards producing selectively modified materials for single-component pH-responsive hydrogels. In this work, we have explored two different synthetic routes targeting different gelatin functional groups (amine, hydroxyl, and/or carboxyl) to produce two GelMA analogs: gelatin A methacryloyl glycerylester (polymer A) and gelatin B methacrylamide (polymer B). Polymers A and B were used to fabricate pH-responsive hydrogel microspheres in a flow-focusing microfluidic device. At neutral pH, polymer A and B microspheres displayed an average diameter of ~40 µm. At pH 6, microspheres from polymer A showed a swelling ratio of 159.1 ± 11.5%, while at pH 10, a 288.6 ± 11.6% swelling ratio was recorded for polymer B particles. [ABSTRACT FROM AUTHOR]

The malignant cycle of synovitis considerably impacts the progression of osteoarthritis (OA). Therefore, the precise localization of synovitis, targeted disruption of the inflammatory cycle, and real‐time monitoring of its dynamics are crucial for the effective diagnosis and management of OA. Here, porous HAMA/GelMA microspheres are synthesized using microfluidic technology. Interleukin‐10 (IL‐10) nanobubbles, prepared via double emulsification, are grafted with folic acid (FA) via an amide reaction and subsequently impregnated and adsorbed onto the microspheres, thereby constructing an ultrasonic contrast microsphere system. This system facilitates not only ultrasonic imaging for accurate localization of synovitis but also the targeted and controlled delivery of IL‐10 under ultrasound conditions. In vitro, under ultrasound intensities of 0, 0.5, and 1.5 W, the system effectively releases IL‐10 at the rates of 19.95%, 30.95%, and 40.67%, respectively. In vivo, the biodegradability of the system facilitates real‐time tracking and monitoring of synovitis for at least 14 days. In summary, ultrasonic contrast microspheres enable precise localization and real‐time monitoring of synovitis. Under ultrasound conditions, these microspheres enable targeted and controlled drug delivery, effectively disrupting vicious inflammatory cycles. This strategy pioneers new pathways for the management and precise treatment of OA. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION This study aimed to improve the stability and utilization of sulforaphene (SFE) and to enhance the intestinal stability and pH‐sensitive release of SFE in the gastrointestinal tract. To achieve this objective, calcium chloride (CaCl2) was used as a crosslinking agent to fabricate novel SFE‐loaded gellan gum (GG)‐ε‐polylysine (ε‐PL) pH‐sensitive hydrogel microspheres by using the ionic crosslinking technique.The molecular docking results of GG, ε‐PL, and SFE were good and occurred in the natural state. The loading efficiency (LE) of all samples was above 70%. According to the structural characterization results, GG and ε‐PL successfully embedded SFE in a three‐dimensional network structure through electrostatic interaction. The swelling characteristics and in vitro release results revealed that the microspheres were pH‐sensitive, and SFE was mainly retained inside the hydrogel microsphere in the stomach, and subsequently released in the intestine. The result of cytotoxicity assay showed that the hydrogel microspheres were non‐toxic and had an inhibitory effect on human colon cancer Caco‐2 cells.Thus, the hydrogel microspheres could improve SFE stability and utilization and achieve the intestinal targeted delivery of SFE. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Abstract By integrating magnetic resonance-visible components with scaffold materials, hydrogel microspheres (HMs) become visible under magnetic resonance imaging(MRI), allowing for non-invasive, continuous, and dynamic monitoring of the distribution, degradation, and relationship of the HMs with local tissues. However, when these visualization components are physically blended into the HMs, it reduces their relaxation rate and specificity under MRI, weakening the efficacy of real-time dynamic monitoring. To achieve MRI-guided in vivo monitoring of HMs with tissue repair functionality, we utilized airflow control and photo-crosslinking methods to prepare alginate-gelatin-based dual-network hydrogel microspheres (G-AlgMA HMs) using gadolinium ions (Gd (III)), a paramagnetic MRI contrast agent, as the crosslinker. When the network of G-AlgMA HMs degrades, the cleavage of covalent bonds causes the release of Gd (III), continuously altering the arrangement and movement characteristics of surrounding water molecules. This change in local transverse and longitudinal relaxation times results in variations in MRI signal values, thus enabling MRI-guided in vivo monitoring of the HMs. Additionally, in vivo data show that the degradation and release of polypeptide (K2 (SL)6 K2 (KK)) from G-AlgMA HMs promote local vascular regeneration and soft tissue repair. Overall, G-AlgMA HMs enable non-invasive, dynamic in vivo monitoring of biomaterial degradation and tissue regeneration through MRI, which is significant for understanding material degradation mechanisms, evaluating biocompatibility, and optimizing material design.

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]

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]

Osteoarthritis (OA) is a degenerative disease potentially exacerbated due to inflammation, cartilage degeneration, and increased friction. Both mesenchymal stem cells (MSCs) and pro-inflammatory macrophages play important roles in OA. A promising approach to treating OA is to modify multi-functional hydrogel microspheres to target the OA microenvironment and structure. Arginyl-glycyl-aspartic acid (RGD) is a peptide widely used in bioengineering owing to its cell adhesion properties, which can recruit BMSCs and macrophages. We developed TLC-R, a microsphere loaded with TGF-β1-containing liposomes. The recruitment effect of TLC-R on macrophages and BMSCs was verified by in vitro experiments, along with its function of promoting chondrogenic differentiation of BMSCs. And we evaluated the effect of TLC-R in balancing OA metabolism in vitro and in vivo. When TLC-R was co-cultured with BMSCs and lipopolysaccharide (LPS)-treated macrophages, it showed the ability to recruit both cells in substantial numbers. As the microspheres degraded, TGF-β1 and chondroitin sulfate (ChS) were released to promote chondrogenic differentiation of the recruited BMSCs, modulate chondrocyte metabolism and inhibit inflammation induced by the macrophages. Furthermore, in vivo analysis showed that TLC-R restored the narrowed space, reduced osteophyte volume, and improved cartilage metabolic homeostasis in OA rats. Altogether, TLC-R provides a comprehensive and novel solution for OA treatment by dual-modulating inflammatory and chondrocyte metabolism.

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.

Abstract 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 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.

The rational design of multifunctional biomaterials with hierarchical porous structure and on-demand biological activity is of great consequence for bone tissue engineering (BTE) in the contemporary world. The advanced combination of trace element cerium ions (Ce3+) with bone repair materials makes the composite material capable of promoting angiogenesis and enhancing osteoblast activity. Herein, a living and phosphorylated injectable porous hydrogel microsphere (P-GelMA-Ce@BMSCs) is constructed by microfluidic technology and coordination reaction with metal ion ligands while loaded with exogenous BMSCs. Exogenous stem cells can adhere to and proliferate on hydrogel microspheres, thus promoting cell-extracellular matrix (ECM) and cell-cell interactions. The active ingredient Ce3+ promotes the proliferation, osteogenic differentiation of rat BMSCs, and angiogenesis of endotheliocytes by promoting mineral deposition, osteogenic gene expression, and VEGF secretion. The enhancement of osteogenesis and improvement of angiogenesis of the P-GelMA-Ce scaffold is mainly associated with the activation of the Wnt/β-catenin pathway. This study could provide novel and meaningful insights for treating bone defects with biofunctional materials on the basis of metal ions.

Abstract Background Cell transplantation has been demonstrated as a promising approach in tissue regeneration. However, the reactive oxygen species (ROS) accumulation and inflammation condition establish a harsh microenvironment in degenerated tissue, which makes the transplanted cells difficult to survive. Methods In this study, we constructed a keep-charging hydrogel microsphere system to enable cells actively proliferate and function in the degenerated intervertebral disc. Specifically, we combined Mg2+ to histidine-functionalized hyaluronic acid (HA-His-Mg2+) through coordination reaction, which was further intercrossed with GelMA to construct a double-network hydrogel microsphere (GelMA/HA-His-Mg2+, GHHM) with microfluidic methods. In vitro, the GHHM loaded with nucleus pulposus cells (GHHM@NPCs) was further tested for its ability to promote NPCs proliferation and anti-inflammatory properties. In vivo, the ability of GHHM@NPCs to promote regeneration of NP tissue and rescue intervertebral disc degeneration (IVDD) was evaluated by the rat intervertebral disc acupuncture model. Results The GHHM significantly enhanced NPCs adhesion and proliferation, providing an ideal platform for the NPCs to grow on. The loaded NPCs were kept active in the degenerative intervertebral disc microenvironment as charged by the Mg2+ in GHHM microspheres to effectively support the loaded NPCs to reply against the ROS-induced inflammation and senescence. Moreover, we observed that GHHM@NPCs effectively alleviated nucleus pulposus degeneration and promoted its regeneration in the rat IVDD model. Conclusion In conclusion, we constructed a keep charging system with a double-network hydrogel microsphere as a framework and Mg2+ as a cell activity enhancer, which effectively maintains NPCs active to fight against the harsh microenvironment in the degenerative intervertebral disc. The GHHM@NPCs system provides a promising approach for IVDD management. Graphical Abstract

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced with different degrees of methacryloyl substitution; however, the synthesis of this polymer has not been tuned towards producing selectively modified materials for single-component pH-responsive hydrogels. In this work, we have explored two different synthetic routes targeting different gelatin functional groups (amine, hydroxyl, and/or carboxyl) to produce two GelMA analogs: gelatin A methacryloyl glycerylester (polymer A) and gelatin B methacrylamide (polymer B). Polymers A and B were used to fabricate pH-responsive hydrogel microspheres in a flow-focusing microfluidic device. At neutral pH, polymer A and B microspheres displayed an average diameter of ~40 µm. At pH 6, microspheres from polymer A showed a swelling ratio of 159.1 ± 11.5%, while at pH 10, a 288.6 ± 11.6% swelling ratio was recorded for polymer B particles.

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]

Background: Cell transplantation has been demonstrated as a promising approach in tissue regeneration. However, the reactive oxygen species (ROS) accumulation and inflammation condition establish a harsh microenvironment in degenerated tissue, which makes the transplanted cells difficult to survive. Methods: In this study, we constructed a keep-charging hydrogel microsphere system to enable cells actively proliferate and function in the degenerated intervertebral disc. Specifically, we combined Mg2+ to histidine-functionalized hyaluronic acid (HA-His-Mg2+) through coordination reaction, which was further intercrossed with GelMA to construct a double-network hydrogel microsphere (GelMA/HA-His-Mg2+, GHHM) with microfluidic methods. In vitro, the GHHM loaded with nucleus pulposus cells (GHHM@NPCs) was further tested for its ability to promote NPCs proliferation and anti-inflammatory properties. In vivo, the ability of GHHM@NPCs to promote regeneration of NP tissue and rescue intervertebral disc degeneration (IVDD) was evaluated by the rat intervertebral disc acupuncture model. Results: The GHHM significantly enhanced NPCs adhesion and proliferation, providing an ideal platform for the NPCs to grow on. The loaded NPCs were kept active in the degenerative intervertebral disc microenvironment as charged by the Mg2+ in GHHM microspheres to effectively support the loaded NPCs to reply against the ROS-induced inflammation and senescence. Moreover, we observed that GHHM@NPCs effectively alleviated nucleus pulposus degeneration and promoted its regeneration in the rat IVDD model. Conclusion: In conclusion, we constructed a keep charging system with a double-network hydrogel microsphere as a framework and Mg2+ as a cell activity enhancer, which effectively maintains NPCs active to fight against the harsh microenvironment in the degenerative intervertebral disc. The GHHM@NPCs system provides a promising approach for IVDD management. [ABSTRACT FROM AUTHOR]

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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]

Natural and biodegradable polymers with pH-responsive properties, such as alginate and chitosan, are widely exploited for drug delivery applications, most notably in the form of biocompatible microspheres. In addition, thermo-responsive poly(N-isopropyl-acrylamide) (PNIPAM) is often added to biomedical delivery systems due to its lower critical solution temperature close to human physiological conditions. In this work, multi-responsive microspheres (MRMs) consisting of a hydrogel matrix made of alginate, chitosan, and PNIPAM were successfully prepared by extrusion dripping and proposed as delivery system for Ozoile (Stable Ozonides) derived from biological olive oil. Ozoile acts as a biological inducer, regulating the main metabolic pathways and stimulating the endogenous defence system. The MRMs containing Ozoile were prepared from alginate/NIPAM emulsions integrating the lipophilic bioactive principle. The MRMs were further optimised with a chitosan coating to improve their stability and control the degradation behaviour of the hydrogel matrix, with subsequent release of Ozoile. Results in terms of chemical composition from Fourier transform infrared (FTIR) spectroscopy, thermo-responsive properties from differential scanning calorimetry (DSC) analysis, swelling and degradation behaviour were used to establish the potential use of the MRMs for the therapeutic release of Ozoile at specific inflammatory sites. [ABSTRACT FROM AUTHOR]

To efficiently remove U(VI) from aqueous solutions, porous polyvinyl alcohol/carboxylated carbon nanotubes/sodium alginate (PPCS) hydrogel microspheres were prepared using the physical cross-linking method. The successful formation of highly porous PPCS hydrogel microspheres was confirmed by SEM and BET. Moreover, PPCS hydrogel microspheres were recovered from aqueous solutions more easily than carbon nanotubes. The main mechanism of PPCS for U(VI) removal may be the chelation of hydroxyl and carboxyl groups. PPCS may be a promising and recyclable adsorbent for uranium extraction. [ABSTRACT FROM AUTHOR]

The key to regenerative medicine is in situ regeneration of lesion cells, so as to achieve lesion repair and regeneration. However, the complex environment of the joint cavity where cartilage is located leads to poor efficacy of traditional therapies to promote cartilage repair and regeneration. Development of hydrogel microspheres offers an attractive solution for regenerative medicine aimed at cartilage repair to address these limitations. Hydrogel microspheres have the potential of injectable and multi-functional transformation, which can effectively regulate the pathophysiological changes of cells and extracellular matrix at the site of cartilage injury. This review summarizes the application of various functional modified hydrogel microspheres in cartilage repair and regeneration. The common techniques and biomaterials used to prepare hydrogel microspheres are first briefly introduced. In particular, the microfluidic technology is highlighted in detail. Besides, the construction strategies of hydrogel microspheres with different functions and their mechanisms to promote cartilage repair and regeneration are further presented. Finally, the problems and challenges of hydrogel microspheres for cartilage repair are summarized.

Postmenopausal osteoporosis is one of the most prevalent skeletal disorders in women and is featured by the imbalance between intraosseous vascularization and bone metabolism. In this study, a pH‐responsive shell–core structured micro/nano‐hydrogel microspheres loaded with polyhedral oligomeric silsesquioxane (POSS) using gas microfluidics and ionic cross‐linking technology are developed. This micro/nano‐hydrogel microsphere system (PDAP@Alg/Cs) can achieve oral delivery, intragastric protection, intestinal slow/controlled release, active targeting to bone tissue, and thus negatively affecting intraosseous angiogenesis and osteoclastogenesis. According to biodistribution data, PDAP@Alg/Cs can successfully enhance drug intestinal absorption and bioavailability through intestine adhesion and bone targeting after oral administration. In vitro and in vivo experiments reveal that PDAP@Alg/Cs promoted type H vessel formation and inhibited bone resorption, effectively mitigating bone loss by activating HIF‐1α/VEGF signaling pathway and promoting heme oxygenase‐1 (HO‐1) expression. In conclusion, this novel oral micro/nano‐hydrogel microsphere system can simultaneously accelerate intraosseous vascularization and decrease bone resorption, offering a brand‐new approach to prevent postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

The localization of lesion cells and targeted regulation of organelle function can promote the lesion repair. However, conventional regulation is difficult to reach deep lesions and target mitochondria. In this study, dynamic spiral Mosaic technology is ued to construct heat transfer microneedles with spiral Mosaic micro/nano hydrogel microspheres (ST‐needle), using molecular chain motion in response to heat stimulation to regulate the adhesion of non‐oriented triblock polymer, as a dual delivery system for heat energy and biological factors. The ST‐needle system use its physical property to accurately reach the deep lesions and transfer heat to the lesion cells. Heat activates the dynamic spiral Mosaic mechanism of the ST‐needle system, removing the Mosaic state of hydrogel microspheres and realizing the arrival of heat and hydrogel microspheres into lesion together. Through the rapid inhibition of mitochondrial apoptosis by heat, and long‐term induce mitophagy by hydrogel microspheres releasing biological factors, finally complete the synergistic targeted regulation of mitochondrial function. In vitro/vivo experiments show that ST‐needle system can inhibit chondrocyte apoptosis more effectively (64.41% lower than conventional regulation). Based on dynamic spiral Mosaic technique and the synergistic regulation of heat and biological factors, the ST‐needle system is a promising method for lesion repair. [ABSTRACT FROM AUTHOR]

The sufficient imitation of tissue structures and components represents an effective and promising approach for tissue engineering and regenerative medicine applications. Dental pulp disease is one of the most common oral diseases, although functional pulp regeneration remains challenging. Herein, we propose a strategy that employs hydrogel microspheres incorporated with decellularized dental pulp matrix-derived bioactive factors to simulate a pulp-specific three-dimensional (3D) microenvironment. The dental pulp microenvironment-specific microspheres constructed by this regenerative strategy exhibited favorable plasticity, biocompatibility, and biological performances. Human dental pulp stem cells (hDPSCs) cultured on the constructed microspheres exhibited enhanced pulp-formation ability in vitro. Furthermore, the hDPSCs-microcarriers achieved the regeneration of pulp-like tissue and new dentin in a semi-orthotopic model in vivo. Mechanistically, the decellularized pulp matrix-derived bioactive factors mediated the multi-directional differentiation of hDPSCs to regenerate the pulp tissue by eliciting the secretion of crucial bioactive cues. Our findings demonstrated that a 3D dental pulp-specific microenvironment facilitated by hydrogel microspheres and dental pulp-specific bioactive factors regenerated the pulp-dentin complex and could be served as a promising treatment option for dental pulp disease. Injectable bioscaffolds are increasingly used for regenerative endodontic treatment. Despite their success related to their ability to load stem cells, bioactive factors, and injectability, conventional bulk bioscaffolds have drawbacks such as ischemic necrosis in the central region. Various studies have shown that ischemic necrosis in the central region can be corrected by injectable hydrogel microspheres. Unfortunately, pristine microspheres or microspheres without dental pulp-specific bioactive factor would oftentimes fail to regulate stem cells fates in dental pulp multi-directional differentiation. Our present study reported the biofabrication of dental pulp-derived decellularized matrix functionalized gelatin microspheres, which contained dental pulp-specific bioactive factors and have the potential application in endodontic regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

As a substitute for feed antibiotics, potassium diformate (KDF) can effectively inhibit bacterial overgrowth in the gastrointestinal tract. To avoid the sudden release of KDF in the stomach, this article proposes a new controlled drug delivery system for controlled drug release. In this system, P-type zeolite molecular sieve (Zeolite P) and drug KDF are combined and embedded into the hydrogel microspheres of sodium alginate (ALG) and sodium carboxymethyl cellulose (CMC). In addition, ALG/CMC/Zeolite P composite hydrogel microspheres were prepared with Ca2+ as the crosslinking agent. The structure, composition, morphology, and thermal stability of the hydrogel microspheres were systematically characterized. The effect of the composition ratio of ALG and CMC on the swelling properties of the hydrogel microspheres was also investigated. The results revealed that ALG and CMC form a hydrogen bond and chelate with Ca2+ to form a double crosslinked network structure. Thus, Zeolite P can be effectively encapsulated in the hydrogel microspheres to form a dense three-dimensional network structure. Particularly, Zeolite P helps in improving the thermal stability of microspheres, balance the swelling properties, and control the release of KDF. The drug release results and release kinetics reveal that the ALG/CMC/Zeolite P composite hydrogel has higher drug release in an environment with pH 7.4. The release kinetics follow the Ritger–Peppas model and the first-order kinetic model, which indicates that the composite hydrogel has good specific pH sensitivity. In vitro antibacterial experiments revealed that the composite hydrogel microspheres have broad-spectrum antibacterial activity, and certain inhibitory effects on Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. [ABSTRACT FROM AUTHOR]

Bone tissue repair is influenced by the synergistic interaction between acute immune microenvironment and osteogenesis. In this study will be independently by film dispersion method and static loading shell polymers and resveratrol liposome preparation CS - Res @ Lipo (CRL) and microfluidic technology preparation of HAMA@HepMA hydrogel microspheres (MS) by condensation reaction of chemical grafting, and then the non-covalent binding site of the MS microsphere was used to skillfully bind BMP-2, construct procedural release of hydrogel microspheres (CRL @ BMP - 2 @ MS). CRL@BMP-2@MS inhibit the acute immune peak by rapidly releasing Res, in addition, the sustained liberation of BMP-2 synchronizes osteoimmunity and osteogenesis, thereby accelerating bone repair. The results showed that Res was released with an increased cumulative rate of 72.4 ± 3.6% in the first 24 h, TNF-α and IL-1β levels were significantly decreased by 4.27 times and 3.65 times as compared to the control group, respectively. Furthermore, continuous release of approximately 40.26 ± 6.8% of BMP-2 occurred within the first 72 h, CRL@BMP-2@MS microspheres significantly increased osteogenic activity compared with the control group by 2.98 and 2.82 times, respectively. In conclusion, the programmed CRL@BMP-2@MS constructed in this study can realize the programmed synergistic linkage of immunity and osteogenesis, dynamically regulate bone repair, and the treatment of clinical bone repair will be based on a new strategy for diagnosis and treatment.

Abstract Postmenopausal osteoporosis is one of the most prevalent skeletal disorders in women and is featured by the imbalance between intraosseous vascularization and bone metabolism. In this study, a pH‐responsive shell–core structured micro/nano‐hydrogel microspheres loaded with polyhedral oligomeric silsesquioxane (POSS) using gas microfluidics and ionic cross‐linking technology are developed. This micro/nano‐hydrogel microsphere system (PDAP@Alg/Cs) can achieve oral delivery, intragastric protection, intestinal slow/controlled release, active targeting to bone tissue, and thus negatively affecting intraosseous angiogenesis and osteoclastogenesis. According to biodistribution data, PDAP@Alg/Cs can successfully enhance drug intestinal absorption and bioavailability through intestine adhesion and bone targeting after oral administration. In vitro and in vivo experiments reveal that PDAP@Alg/Cs promoted type H vessel formation and inhibited bone resorption, effectively mitigating bone loss by activating HIF‐1α/VEGF signaling pathway and promoting heme oxygenase‐1 (HO‐1) expression. In conclusion, this novel oral micro/nano‐hydrogel microsphere system can simultaneously accelerate intraosseous vascularization and decrease bone resorption, offering a brand‐new approach to prevent postmenopausal osteoporosis.

Hollow mesoporous silica nanoparticles have been widely applied as a carrier material in the molecular imprinting process because of their excellent properties, with high specific surface area and well-defined active centers. However, these kinds of materials face the inevitable problem that they have low mass transfer efficiency and cannot be conveniently recycled. In order to solve this problem, this work has developed a composite hydrogel microsphere (MMHSG) encapsulated with hollow mesoporous imprinted nanoparticles for the selective extraction of 2'-deoxyadenosine (dA). Subsequently, the hollow mesoporous imprinted polymers using dA as template molecule and synthesized 5-(2-carbomethoxyvinyl)-2′-deoxyuridine (AcrU) as functional monomer were encapsulated in hydrogel. MMHSG displayed good performance in specifically recognizing and quickly separating dA, whereas no imprinting effect was observed among 2′-deoxyguanosine (dG), deoxycytidine (dC), or 5′-monophosphate disodium salt (AMP). Moreover, the adsorption of dA by MMHSG followed chemisorption and could reach adsorption equilibrium within 60 min; the saturation adsorption capacity was 20.22 μmol·g−1. The introduction of AcrU could improve selectivity through base complementary pairing to greatly increase the imprinting factor to 3.79. Therefore, this was a successful attempt to combine a hydrogel with hollow mesoporous silica nanoparticles and molecularly imprinted material. [ABSTRACT FROM AUTHOR]

Octenyl succinic anhydride (OSA) starch is an important edible additive in the food field, and its synthesis method has attracted much attention. Lipase as a biocatalyst can improve the synthesis efficiency of OSA starch, and significantly inhibit the occurrence of side reactions. However, free lipase has not been widely applied in the synthesis of OSA starch due to the difficulty of separation from starch and poor reusability. In this work, a promising strategy for the synthesis of OSA starch catalyzed by lipase immobilized on polydopamine magnetic hydrogel microspheres (PMHM) is reported. The prepared lipase-polydopamine magnetic hydrogel microspheres (L-PMHM) can be uniformly dispersed in starch slurry, which is conducive to the full contact between lipase and starch. L-PMHM (Km =2.6276 μmol/mL) exhibits better affinity to the substrate than free lipase (Km = 3.4301 μmol/mL). Compared with the OSA starch catalyzed by free lipase (DS = 0.0176), the degree of substitution of OSA starch catalyzed by L-PMHM is up to 0.0277 in a short reaction time. In cyclic catalysis, L-PHMM can remain about 48 % of their original activity after 20 reuses and can be quickly separated from the product. These results suggest that L-PMHM has great potential as a biocatalyst for the efficient synthesis of OSA starch. • A novel strategy for the synthesis of OSA starch catalyzed by lipase immobilized on hydrogel microspheres is proposed. • The hydrogel microspheres are uniformly dispersed in the starch slurry to make the immobilized lipase fully contact with the starch. • The immobilized lipase exhibits favorable adhesion, environmental stability, catalytic activity and reutilization. [ABSTRACT FROM AUTHOR]

Since it is difficult for human eyes to distinguish between two identical colors with only <15% variation in brightness, mono-color fluorescent hydrogel microspheres have some limitations in the detection of lactate. Herein, we prepared novel dual-color fluorescent hydrogel microspheres, which can achieve hue transformation. Microspheres were prepared by introducing a fluorescent nanoparticle as the reference signal while CdTe QDs were used as the response signal. We used smartphones with image processing software to collect and analyze data. In this way, the signal of lactate was converted to RGB (red, green, and blue) values, which can be quantitatively read. Within 10 to 1500 μM, the R/G values of the microspheres had a linear relationship with the logarithm of the lactate concentration. Moreover, color cards for lactate detection were prepared, from which the color change and concentration of lactate could be easily read by the naked eye. It is worth mentioning that this method was successfully applied to screen patients with hyperlactatemia. [ABSTRACT FROM AUTHOR]

Calcium alginate (Ca-alginate) hydrogel microspheres, distinguished by their unique viscoelastic attributes, have found valuable utility in encapsulating bioactive components and facilitating targeted release applications. However, the rapid profiling of the viscoelasticity of these hydrogel microspheres has posed a significant challenge. In this study, we have developed a continuous-flow methodology for swift viscoelastic profiling of a substantial population of hydrogel microspheres, employing embedded electrode pairs and validated with 0.5–2.0% w / v Ca-alginate hydrogel microspheres. Our approach involves the measurement of microsphere size and travel trajectories through the observation of electric signal variations across the embedded electrode pairs. These signals arise from the displacements of the leading and trailing edges of the microspheres. By applying a quasi-linear viscoelastic (QLV) model to interpret the electric signals, we can effectively deduce the viscoelastic properties of the microspheres. Notably, this innovative technique enables fast viscoelasticity screening with a concise constriction channel featuring a minimal number of electrode pairs. The measurement is independent of the applied flow rate. The outcome of our work has led to significantly improved measurement throughput of up to 2650 counts/min for Ca-alginate hydrogel microspheres with 0.5% w / v. Furthermore, this approach can distinguish hydrogel microspheres of varying qualities and chemical compositions based on their viscoelastic properties. This breakthrough holds significant promise for real-time sorting and separation of microspheres, which is particularly useful for developing innovative food structures and texturizers, along with possibilities across a wide spectrum of engineered foods, such as plant-based, printable or bioinspired hydrogels. [Display omitted] • Determining viscoelasticity of hydrogel microspheres through electric measurements. • Measurement throughput is several folds higher than previous approaches. • Flow-rate independent viscoelasticity measurement is implemented. • Differentiating concentration of alginate-based microspheres that are indistinguishable by previous approaches. [ABSTRACT FROM AUTHOR]

The regeneration of skin appendages including hair follicles (HF), sweat glands (SwG), and sebaceous glands (SeG) is the prerequisite for functional skin repair. However, it is far from being done that how to induce in situ multiple skin appendage regeneration (MSAR) during wound healing. LGR6+ epidermal stem cells (EpSC) have been reported to generate all skin cell lineages. Given the advantages of biomaterials for tissue repair and their influence on cellular behavior that may regulate cell reprogramming, we developed a cell-reprogrammed three lineage-driven biomimetic device (TLBD) by using liposome nanoparticle drug delivery system, photo-responsive hyaluronic acid shell, positively charged polyamide and epidermal cell recruitment factor modification, microfluidic and photo-crosslinking techniques. The LGR6+ EpSC-activating chemical cocktail was the active center of TLBD, and polyamide for a positive charge that made TLBD match the wound electric fields. In vitro and in vivo studies demonstrated that TLBD can efficiently recruit endogenous epidermal cells and activate the LGR6+ EpSC property, prompting their response to wound microenvironment to differentiate into HF, SwG, and SeG lineages, thus facilitating re-epithelialization, wound healing and in situ MSAR. As a novel biomaterial used for in situ skin reprogramming, TLBD may have the great potential for functionally recapitulating damaged skin. [Display omitted] • Skin appendages are of great importance to skin function and homeostasis. • The cell-reprogrammed TLBD that can drive three skin lineage regeneration is developed. • TLBD foster in situ recruitment and activation of LGR6+ EpSC. • EGF and charged polyamide modifications were utilized within TLBD. • TLBD present a promise method for in situ skin reprogramming and functional wound healing. [ABSTRACT FROM AUTHOR]

The occurrence of osteoarthritis (OA) is highly associated with the reduced lubrication property of the joint, where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism. In this study, bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel, we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment. Particularly, the lubricating microspheres (GelMA@DMA-MPC) were fabricated by dip coating a self-adhesive polymer (DMA-MPC, synthesized by free radical copolymerization) on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres (GelMA, prepared via microfluidic technology), and encapsulated with an anti-inflammatory drug of diclofenac sodium (DS) to achieve the dual-functional performance. The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres. In addition, the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model, and the biological tests including qRT-PCR, immunofluorescence staining assay, X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA. In summary, the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release, therefore representing a facile and promising technique for the treatment of OA.

The repair of large bone defects in clinic is a challenge and urgently needs to be solved. Tissue engineering is a promising therapeutic strategy for bone defect repair. In this study, hydrogel microspheres (HMs) were fabricated to act as carriers for bone marrow mesenchymal stem cells (BMSCs) to adhere and proliferate. The HMs were produced by a microfluidic system based on light-induced gelatin of gelatin methacrylate (GelMA). The HMs were demonstrated to be biocompatible and non-cytotoxic to stem cells. More importantly, the HMs promoted the osteogenic differentiation of stem cells. In vivo, the ability of bone regeneration was studied by way of implanting a BMSC/HM system in the cranial defect of rats for 8 weeks. The results confirmed that the BMSC/HM system can induce superior bone regeneration compared with both the HMs alone group and the untreated control group. This study provides a simple and effective research idea for bone defect repair, and the subsequent optimization study of HMs will provide a carrier material with application prospects for tissue engineering in the future. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) metabolism balance is essential for maintaining tissue structure and function. However, the complex crosstalk between the ECM, resident cellular, and tissue microenvironment makes long‐term maintenance of ECM metabolism balance in an abnormal microenvironment difficult to achieve. Herein, an injectable circRNA silencing‐hydrogel microsphere (psh‐circSTC2‐lipo@MS) is constructed by grafting circSTC2 silencing genes‐loaded 1,2‐dioleoyl‐3‐trimethylammonium‐propane/cholesterol/1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOTAP/Chol/DOPE) cationic liposomes on methacrylated hyaluronic acid (HAMA) microspheres via amide bonds, which could silence pathological genes in nucleus pulposus (NP) cells to regulate ECM metabolism balance in the nutrient‐restricted microenvironment, thereby inhibiting intervertebral disc (IVD) degeneration. HAMA microspheres prepared by microfluidics displayed good degradability, swellability, and injectability. And lipoplexes can be efficiently loaded and released for 27 d through chemical grafting. Cocultured under nutrient‐restricted conditions for 72 h, psh‐circSTC2‐lipo@MS significantly promotes the synthesis of ECM‐related proteins and inhibits the secretion of ECM catabolism‐related proteases in NP cells. In the rat IVD nutrient‐restricted model, local injection of psh‐circSTC2‐lipo@MS promotes ECM synthesis and restored NP tissue after 8 weeks. In summary, this study confirms that psh‐circSTC2‐lipo@MS as a safe and controllable targeted gene delivery system has great potential in regulating the ECM metabolism balance under an abnormal microenvironment. [ABSTRACT FROM AUTHOR]

Point-of-care testing (POCT) of chloramphenicol (CAP) in fresh milk from private ranches is essential to ensure food safety. It's still a great challenge to meet simultaneously rapid and accurate during POCT of CAP. Here, we present a POCT device integrating hydrogel microsphere immunoassay and smartphone Fourier analysis for fast and sensitive detection of CAP. Based on the excellent biocompatibility and outstanding mechanical properties of hydrogel microspheres (100 μm), the antibody activity can be maintained and the mechanical deformation of the hydrogel cross-linking lattice is induced by squeezing to accelerate the antigen-antibody reaction of CAP and anti-CAP antibodies. The signal-to-noise ratio of the detection result is optimized adaptively by a designed microsphere Fourier analysis algorithm for precise CAP concentration detection. The results show that the method decreases incubation time from 60 min to 25 min and meets detection limit requirements of industrial production (0.05 ng/mL, with a dynamic range of 0.05–8 ng/mL). This method not only achieves rapid and accurate on-site detection of CAP in milk but also applies to other low concentrations of harmful substances detection in food field. • Mechanical deformation accelerate the uptake of the analyte into the microgel spheres. • Fourier analysis enhances fluorescence detection for highly sensitive CAP detection. • Test data is saved by smartphone and expected to link with FDA to ensure milk quality. [ABSTRACT FROM AUTHOR]

• GelMA and fucoidan hydrogel microspheres were developed to resemble native NP matrix. • GelMA@FD microspheres supported NP cell proliferation and promoted ECM synthesis. • GelMA@FD improved mitochondrial energy metabolism by regulating redox homeostasis. • Injection of cell-laden GelMA@FD microspheres reconstructed NP tissues in rat lumbar IVDs. Nucleus pulposus (NP) discectomy is a clinical procedure for the treatment of late-stage intervertebral disc (IVD) degeneration; however, it is associated with the potential for serious complications. The reconstruction of the NP tissue presents challenges due to its avascular structure and prolonged compression within the IVD. In this study, we have developed a novel biomimetic hydrogel microsphere composed of gelatin methacryloyl (GelMA) and fucoidan, a polysaccharide derived from marine brown seaweed, to mimic the extracellular matrix (ECM) of the native NP. The GelMA and fucoidan (GelMA@FD) hydrogel microspheres demonstrate favorable cytocompatibility and significantly enhance the synthesis of matrix components in nucleus pulposus cells (NPCs), including aggrecan and type II collagen. Transcriptome sequencing analysis demonstrates a correlation between the augmentation of matrix synthesis and the enrichment of genes and pathways related to mitochondrial function. Subsequent molecular investigations provide evidence that NPCs cultured on GelMA@FD exhibit enhanced mitochondrial functions, including elevated adenosine triphosphate production and respiratory chain factor expression, alongside a reduction in mitochondrial reactive oxygen species. When implantated into rat lumbar IVDs that have undergone discectomy, the incorporation of NPCs within GelMA@FD hydrogel microspheres facilitates the regeneration of the NP and reinstates its structural and biomechanical properties. This is substantiated by the observed augmentation in IVD disc height and water content within the NP compartment. Collectively, these results demonstrate the potential of employing cell-laden GelMA@FD hydrogel microspheres as a promising strategy for NP regeneration in degenerated IVDs. [ABSTRACT FROM AUTHOR]

The dense structure and the high‐density negative charge of the cartilage matrix impede drug penetration into the cartilage. Effectively breaking through these barriers and transporting target drugs to the cartilage is currently difficult. Herein, an adhesive hydrogel microsphere characterized by its positively charged nanosized secondary structure that allows it to penetrate deep into the cartilage through charge guidance is introduced as an efficient drug delivery system for cartilage adhesion, cartilage matrix penetration, and chondrocytes targeting and solves the problem of drug‐penetration impedance due to cartilage. The dopamine‐modified structure on the surface of the microspheres can attach the microspheres onto the cartilage surface, while the charge‐guided secondary structure can carry drugs to penetrate the cartilage matrix, release drugs under reactive oxygen species stimulation, act on chondrocytes. The experiments show that the injectable microspheres successfully deliver antioxidants to chondrocytes in osteoarthritis environments. The apoptosis rate of chondrocytes under oxidative stress decreases from 38.36 ± 5.48% to 12.86 ± 4.27%, which is significantly better than that in the direct drug treatment group (28.43 ± 5.87%). The micro/nano‐hydrogel microsphere effectively penetrates the cartilage matrix and releases the drug in ROS response, realizing the improvement of drug utilization and efficacy and thereby demonstrating the efficient delivery of cartilage drugs. [ABSTRACT FROM AUTHOR]

Damaged skin cannot prevent harmful bacteria from invading tissues, causing infected wounds and even serious tissue damage. Traditional treatments can not only kill pathogenic bacteria, but also suppress the growth of beneficial bacteria, thus destroying the balance of the damaged skin microbial ecosystem. Here, a living bacterial hydrogel scaffold is reported that accelerates infected wound healing through beneficial bacteria secreting antibacterial substances. Lactobacillus reuteri, a common probiotic, is encapsulated in hydrogel microspheres by emulsion polymerization and further immobilized in a hydrogel network by covalent cross‐linking of methacrylate‐modified hyaluronic acid. Owing to light‐initiated crosslinking, the hydrogel dressing can be generated in situ at the wound site. This hydrogel scaffold not only protects bacteria from immune system attack, but also prevents bacteria from escaping into the local environment, thus avoiding potential threats. Both in vitro and in vivo experiments show that it has excellent ability against harmful bacteria and anti‐inflammatory capabilities, promoting infected wound closure and new tissue regeneration. This work may open up new avenues for the application of living bacteria in the clinical management of infected wounds. [ABSTRACT FROM AUTHOR]

Abstract Damaged skin cannot prevent harmful bacteria from invading tissues, causing infected wounds and even serious tissue damage. Traditional treatments can not only kill pathogenic bacteria, but also suppress the growth of beneficial bacteria, thus destroying the balance of the damaged skin microbial ecosystem. Here, a living bacterial hydrogel scaffold is reported that accelerates infected wound healing through beneficial bacteria secreting antibacterial substances. Lactobacillus reuteri, a common probiotic, is encapsulated in hydrogel microspheres by emulsion polymerization and further immobilized in a hydrogel network by covalent cross‐linking of methacrylate‐modified hyaluronic acid. Owing to light‐initiated crosslinking, the hydrogel dressing can be generated in situ at the wound site. This hydrogel scaffold not only protects bacteria from immune system attack, but also prevents bacteria from escaping into the local environment, thus avoiding potential threats. Both in vitro and in vivo experiments show that it has excellent ability against harmful bacteria and anti‐inflammatory capabilities, promoting infected wound closure and new tissue regeneration. This work may open up new avenues for the application of living bacteria in the clinical management of infected wounds.

Abstract Hydrogel microspheres are a novel functional material, arousing much attention in various fields. Microfluidics, a technology that controls and manipulates fluids at the micron scale, has emerged as a promising method for fabricating hydrogel microspheres due to its ability to generate uniform microspheres with controlled geometry. With the development of microfluidic devices, more complicated hydrogel microspheres with multiple structures can be constructed. This review presents an overview of advances in microfluidics for designing and engineering hydrogel microspheres. It starts with an introduction to the features of hydrogel microspheres and microfluidic techniques, followed by a discussion of material selection for fabricating microfluidic devices. Then the progress of microfluidic devices for single‐component and composite hydrogel microspheres is described, and the method for optimizing microfluidic devices is also given. Finally, this review discusses the key research directions and applications of microfluidics for hydrogel microsphere in the future.

Hollow mesoporous silica nanoparticles have been widely applied as a carrier material in the molecular imprinting process because of their excellent properties, with high specific surface area and well-defined active centers. However, these kinds of materials face the inevitable problem that they have low mass transfer efficiency and cannot be conveniently recycled. In order to solve this problem, this work has developed a composite hydrogel microsphere (MMHSG) encapsulated with hollow mesoporous imprinted nanoparticles for the selective extraction of 2’-deoxyadenosine (dA). Subsequently, the hollow mesoporous imprinted polymers using dA as template molecule and synthesized 5-(2-carbomethoxyvinyl)-2′-deoxyuridine (AcrU) as functional monomer were encapsulated in hydrogel. MMHSG displayed good performance in specifically recognizing and quickly separating dA, whereas no imprinting effect was observed among 2′-deoxyguanosine (dG), deoxycytidine (dC), or 5′-monophosphate disodium salt (AMP). Moreover, the adsorption of dA by MMHSG followed chemisorption and could reach adsorption equilibrium within 60 min; the saturation adsorption capacity was 20.22 μmol·g−1. The introduction of AcrU could improve selectivity through base complementary pairing to greatly increase the imprinting factor to 3.79. Therefore, this was a successful attempt to combine a hydrogel with hollow mesoporous silica nanoparticles and molecularly imprinted material.

Microfluidic hydrogel microspheres have been broadly studied across a wide range of industries and applications, and their use in the medical field, including control cells and drug delivery, is increasing. The usual design of these materials is intended to enable the efficient and smart encapsulation of cells and/or drugs in microspheres in which the functionalities and features are effectively controlled, lending itself some unique properties. These characteristics promote exchanges and cooperation in multiple disciplines and boost the development of precision medicine, new manufacturing technologies, and applied materials. This review begins with a discussion of microfluidic hydrogel microspheres and then introduces the preparation equipment, main principles, and related characteristics of the microspheres. Furthermore, the medical applications of microfluidic hydrogel microspheres for delivering cells and drugs are emphasized. Finally, this review discusses perspectives and future directions for accelerating the development and application of microfluidic hydrogel microspheres for controlled delivery. [ABSTRACT FROM AUTHOR]

Since it is difficult for human eyes to distinguish between two identical colors with only

Hydrogel microspheres stand out in drug delivery due to their small particle size, biocompatibility and good internal stability. In this paper, pH-sensitive hydrogels are prepared by microfluidic technology for targeted drug delivery in the small intestine. A coaxial dual-channel microfluidic chip is constructed. By analyzing the effects of flow rates and three fracture stages (Rayleigh-Plateau instability crushing stage, pressure difference crushing stage and shear force crushing stage) on the size of hydrogel microspheres, the optimal control stage of the microsphere size is determined (shear force crushing stage). Based on this, the accurate control model of the hydrogel microsphere size is proposed. In addition, based on the coaxial dual channel microfluidic chip, a monolayer hydrogel microcapsule loaded with Indometacin is prepared. The core-shell hydrogel microcapsules loaded with Indometacin are prepared by an improved coaxial three channel microfluidic chip. The swelling rates of both microcapsules in simulated intestinal fluid are significantly higher than those in simulated gastric fluid. The results of in vitro simulated release experiments show that the two hydrogel microcapsules basically do not release in simulated gastric juice. In simulated intestinal fluid, single-layer hydrogel microcapsules show rapid release, while core-shell hydrogel microcapsules showed slow release. In conclusion, the alginate-based hydrogel microcapsules have good stability and pH sensitivity, and are suitable for targeted drug delivery in the small intestine. [ABSTRACT FROM AUTHOR]

The repair of large bone defects in clinic is a challenge and urgently needs to be solved. Tissue engineering is a promising therapeutic strategy for bone defect repair. In this study, hydrogel microspheres (HMs) were fabricated to act as carriers for bone marrow mesenchymal stem cells (BMSCs) to adhere and proliferate. The HMs were produced by a microfluidic system based on light-induced gelatin of gelatin methacrylate (GelMA). The HMs were demonstrated to be biocompatible and non-cytotoxic to stem cells. More importantly, the HMs promoted the osteogenic differentiation of stem cells. In vivo, the ability of bone regeneration was studied by way of implanting a BMSC/HM system in the cranial defect of rats for 8 weeks. The results confirmed that the BMSC/HM system can induce superior bone regeneration compared with both the HMs alone group and the untreated control group. This study provides a simple and effective research idea for bone defect repair, and the subsequent optimization study of HMs will provide a carrier material with application prospects for tissue engineering in the future.

Poly (acrylic acid-co-acrylamide) hydrogel microspheres were prepared via Pickering emulsion polymerization with hydrophobic silica as emulsifiers. The functional groups and the morphology of the hydrogel microspheres were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy, respectively. The effect of the dosage of hydrophobic silica on Pickering emulsion polymerization was investigated, and the hydrogel microspheres with different particle sizes were used to remove copper ions in water. The results showed that the diameter (D) of the hydrogel microspheres was inversely proportional to the dosage (S) of the hydrophobic silica used. The size of the hydrogel microspheres mainly affected the adsorption equilibrium time, and the maximum adsorption capacity could reach 85 mg/g at pH = 5. The results of desorption experiment demonstrated that copper ions were adsorbed by hydrogel microspheres mainly through chemical interaction. Pickering emulsion polymerization was an efficient and environmentally friendly approach for the fabrication of granular hydrogels. [ABSTRACT FROM AUTHOR]

Considering the complicated and irregular anatomical structure of root canal systems, injectable microspheres have received considerable attention as cell carriers in endodontic regeneration. Herein, we developed injectable hybrid RGD-alginate/laponite (RGD-Alg/Lap) hydrogel microspheres, co-encapsulating human dental pulp stem cells (hDPSCs) and vascular endothelial growth factor (VEGF). These microspheres were prepared by the electrostatic microdroplet method with an average size of 350~450 μm. By adjusting the content of laponite, the rheological properties and the degradation rate of the microspheres in vitro could be conditioned. The release of VEGF from the RGD-Alg/0.5%Lap microspheres was in a sustained manner for 28 days while the bioactivity of VEGF was preserved. In addition, the encapsulated hDPSCs were evenly distributed in microspheres with a cell viabilit y exceeding 85%. The deposition of abundant extracellular matrix such as fibronectin (FN) and collagen type I (Col-I) was shown in microspheres after 7 days. The laponite in the system significantly up-regulated the expression of odontogenic-related genes of hDPSCs at day 7. Furthermore, after subcutaneous implantation with tooth slices in a nude mouse model for 1 month, the hDPSCs-laden RGD-Alg/0.5%Lap+VEGF microspheres significantly promoted the regeneration of pulp-like tissues as well as the formation of new micro-vessels. These results demonstrated the great potential of laponite-enhanced hydrogel microspheres in vascularized dental pulp regeneration. Injectable cell-laden microspheres have recently gained great attention in endodontic regeneration. Here we first developed hybrid alginate/laponite hydrogel microspheres (size about 350~450 μm) by electrostatic microdroplet method, which exhibited tunability in mechanical property and sustained release ability. The incorporation of laponite and the sustained release of VEGF supported not only dental pulp stem cells differentiation in vitro but neotissue regeneration in vivo. These features combined with the simplicity in preparation, made the microspheres ideally suited to simultaneous cells and growth factors delivery in dental pulp regeneration and even other tissue regeneration application. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The three‐dimensional structure of nanocomposite microgels was precisely determined by cryo‐electron micrography. Several nanocomposite microgels that differ with respect to their nanocomposite structure, which were obtained from seeded emulsion polymerization in the presence of microgels, were used as model nanocomposite materials for cryo‐electron micrography. The obtained three‐dimensional segmentation images of these nanocomposite microgels provide important insights into the interactions between the hydrophobic monomers and the microgels, that is, hydrophobic styrene monomers recognize molecular‐scale differences in polarity within the microgels during the emulsion polymerization. This result led to the formation of unprecedented multi‐layered nanocomposite microgels, which promise substantial potential in colloidal applications. [ABSTRACT FROM AUTHOR]