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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 Cu 2+ /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., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Excessive cell-free DNA (cfDNA) can induce chronic inflammation by activating intracellular nucleic acid sensors. Intervention in cfDNA-mediated "pro-inflammatory signaling transduction" could be a potential alleviating strategy for chronic inflammation, such as in diabetic wounds. However, effectively and specifically downgrading cfDNA concentration in the pathological microenvironment remains a challenge. Therefore, this work prepares free-standing polydopamine nanosheets through DNA-guided assembly and loaded them into microfluidic hydrogel microspheres. The π─π stacking/hydrogen bonding interactions between polydopamine nanosheets and the π-rich bases of cfDNA, along with the cage-like spatial confinement created by the hydrogel polymer network, achieved cfDNA capture and storage, respectively. Catechol in polydopamine nanosheets can also assist in reducing reactive oxygen species (ROS) levels. Efficient cfDNA binding independent of serum proteins, specific interdiction of abnormal activation of cfDNA-associated toll-like receptor 9, as well as down-regulation of inflammatory cytokines and ROS levels are shown in this system. The chronic inflammation alleviating and the pro-healing effects on the mice model with diabetic wounds are also investigated. This work presents a new strategy for capturing and storing cfDNA to intervene in cell signaling transduction. It also offers new insights into the regulatory mechanisms between inflammatory mediators and biomaterials in inflammation-related diseases., (© 2024 Wiley‐VCH GmbH.)

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., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

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 (K 2 (SL) 6 K 2 (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., (© 2024. The Author(s).)

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., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

An effective treatment for the irregular partial-thickness cartilage defect in the early stages of osteoarthritis (OA) is lacking. Cartilage tissue engineering is effective for treating full-thickness cartilage defects with limited area. In this study, we designed an injectable multifunctional poly(lactic-co-glycolic acid) (PLGA) microsphere to repair partial-thickness cartilage defects. The microsphere was grafted with an E7 peptide after loading the microsphere with kartogenin (KGN) and modifying the outer layer through dopamine self-polymerization. The microsphere could adhere to the cartilage defect, recruit synovial mesenchymal stem cells (SMSCs) in situ, and stimulate their differentiation into chondrocytes after injection into the articular cavity. Through in vivo and in vitro experiments, we demonstrated the ability of multifunctional microspheres to adhere to cartilage matrix, recruit SMSCs, and promote their differentiation into cartilage. Following treatment, the cartilage surface of the model group with partial-thickness cartilage defect showed smooth recovery, and the glycosaminoglycan content remained normal; the untreated control group showed significant progression of OA. The microsphere, a framework for cartilage tissue engineering, promoted the expression of SMSCs involved in cartilage repair while adapting to cell migration and growth. Thus, for treating partial-thickness cartilage defects in OA, this innovative carrier system based on stem cell therapy can potentially improve therapeutic outcomes. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells (MSCs) therapy is effective in the repair of cartilage injury. However, because of the particularity of partial-thickness cartilage injury, it is difficult to recruit enough seed cells in situ, and there is a lack of suitable scaffolds for cell migration and growth. Here, we developed polydopamine surface-modified PLGA microspheres (PMS) containing KGN and E7 peptides. The adhesion ability of the microspheres is facilitated by the polydopamine layer wrapped in them; thus, the microspheres can adhere to the injured cartilage and recruit MSCs, thereby promoting their differentiation into chondrocytes and accomplishing cartilage repair. The multifunctional microspheres can be used as a safe and potential method to treat partial-thickness cartilage defects in OA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

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]

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 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]

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]

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]

Artemisinin and its derivatives (artemisinins) are first‐line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid‐acting medicines with an extremely short half‐life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long‐acting gene/artemisinin co‐delivery nano‐microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co‐delivery nano‐lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug‐embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin‐embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex (MTAsi@MG) is further prepared by immobilization of TNF‐α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano‐microplex for intra‐articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long‐term treatment is first realized. Undoubtedly, this intra‐articular injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co‐delivery systems for RA therapy. [ABSTRACT FROM AUTHOR]

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]

The mitochondrial respiratory chain (MRC) plays an essential role in regulating cellular energy metabolism and oxidative stress. Repairing damaged MRC function can efficiently provide cells with energy to fight inflammation. Herein, with the inspiration by a rechargeable battery, microfluidics was used to prepare hyaluronic acid hydrogel microspheres as shells and con-covalently connected the inner core-SS-31 peptide and Wyrgrl peptide co-modified long-circulating liposomes loaded with resveratrol (REV) to the nanonetwork of microspheres to construct a "Mito-Battery" that could promote cell energy production and fight inflammation by targeted regulation of MRC functions. Modification of peptide could increase its cellular uptake and enhance the mitochondrial-targeting of "Mito-Battery." Meanwhile, REV loaded in the liposomes can activate SIRT3 protein and synergistically enhance the MRC electron transfer efficiency with SS-31. "Mito-Battery" effectively delayed the progression of the disease in a rat bone and joint model. Thus, "Mito-Battery" has great potential in the treatment of degenerative diseases related to MRC dysfunction. [Display omitted] • Enhance the MRC electron transfer efficiency to therapy osteoarthritis via injectable Micro-nano hydrogel microsphere. • The SS-31 and Wyrgrl peptide co-modified liposomes had high-efficiency targeting ability to chondrocytes mitochondria. • The liposomes were anchored to the nano-network of microspheres through the charge dipolar effect. • The micro-nano hydrogel microspheres promote the sustained release of resveratrol and maintain SS-31 peptide activity. [ABSTRACT FROM AUTHOR]

Direct injection is a minimally invasive method of stem cell transplantation for numerous injuries and diseases. However, despite its promising potential, its clinical translation is difficult due to the low cell retention and engraftment after injection. With high versatility, high-resolution control and injectability, microfabrication of stem-cell laden biomedical hydrogels holds great potential as minimally invasive technology. Herein, a strategy of microfluidics-assisted technology entrapping bone marrow-derived mesenchymal stem cells (BMSCs) and growth factors in photocrosslinkable gelatin (GelMA) microspheres to ultimately generate injectable osteogenic tissue constructs is presented. Additionally, it is demonstrated that the GelMA microspheres can sustain stem cell viability, support cell spreading inside the microspheres and migration from the interior to the surface as well as enhance cell proliferation. This finding shows that encapsulated cells have the potential to directly and actively participate in the regeneration process. Furthermore, it is found that BMSCs encapsulated in GelMA microspheres show enhanced osteogenesis in vitro and in vivo, associated with a significant increase in mineralization. In short, the proposed strategy can be utilized to facilitate bone regeneration with minimum invasiveness, and can potentially be applied along with other matrices for extended applications. [ABSTRACT FROM AUTHOR]

Pomegranate‐structured composite microspheres composed of core mesoporous silica nanoparticles capped by a poly(l‐lactide) shell are prepared via one‐step electrospraying, which releases encapsulated model anti‐inflammatory drugs for up to 70 d and inhibits proliferation against macrophages over the long release period. [ABSTRACT FROM AUTHOR]

Electrospraying is a one-step technique for fabricating polymeric microspheres/nanospheres, and the surface characterization of polymeric microspheres fabricated under high voltage is different from an emulsion method. In this study, biodegradable poly( l-lactide) (PLLA) microspheres were successfully fabricated by electrospraying, and electrospraying parameters were used to investigate the size and ζ potential of the electrosprayed PLLA microspheres. The results demonstrate that electrospraying was a one-step method for fabricating monodispersed PLLA microspheres with a size of 1.92 ± 0.35 μm and that the enrichment of methyl groups on the surface of the microspheres contributed to the strong hydrophobicity of electrosprayed PLLA microspheres. Of all the electrospraying parameters investigated, the size and ζ potential of the PLLA microspheres increased with increasing solution concentration and flow rate and decreased with increasing injection voltage and collecting distance. The results provide a theoretical basis for preparing electrosprayed polymeric microspheres as drug carriers. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013 [ABSTRACT FROM AUTHOR]

Keywords: biomaterials; cell delivery; drug delivery; hydrogel microspheres; microfluidics EN biomaterials cell delivery drug delivery hydrogel microspheres microfluidics 1 1 1 08/06/21 20210802 NES 210802 In article number 2103339, Ming Cai, Wenguo Cui, and co-workers review the latest developments in the controlled delivery of microfluidic hydrogel microspheres, and the medical applications of microfluidic hydrogel microspheres to deliver cells and drugs are emphasized. Biomaterials, cell delivery, drug delivery, hydrogel microspheres, microfluidics Microfluidic Hydrogel Microspheres: Injectable Microfluidic Hydrogel Microspheres for Cell and Drug Delivery (Adv. Funct. [Extracted from the article]

Injectable Porous Microspheres: Metabolism Balance Regulation via Antagonist-Functionalized Injectable Microsphere for Nucleus Pulposus Regeneration (Adv. Funct. Keywords: antagonists; injectables; microenvironment; porous microsphere; regeneration EN antagonists injectables microenvironment porous microsphere regeneration 1 1 1 12/24/20 20201222 NES 201222 Inspired by the inflammation of the intervertebral disc degene ration microenvironment, in article number 2006333, Bruno Sarmento, Wenguo Cui, Liang Chen, and co-workers design antagonist-functionalized injectable porous microspheres with functions of modulating inflammation responses and regulating extracellular matrix metabolism balance to satisfy the specific demand on early-stage restoration of the intervertebral disc microenvironment and its regeneration. Antagonists, injectables, microenvironment, porous microsphere, regeneration. [Extracted from the article]

A bone regeneration strategy with minimum invasiveness is developed on page 2809 by W. Cui, D. Weitz, and co‐workers, using microfluidics‐fabricated photocrosslinkable gelatin microspheres encapsulating bone marrow‐derived mesenchymal stem cells and growth factors. The cell‐laden microspheres are found to enhance and accelerate osteogenesis in vitro and in vivo, associated with a significant increase in mineralization. [ABSTRACT FROM AUTHOR]

Organic/inorganic composites have advantages in promoting bone repair; however, early changes in the local immune response after material implantation and the mechanisms that affect the late osteogenesis have not been revealed systematically. Herein, we prepared injectable composite poly (l -lactic acid)/nano hydroxyapatite (PLLA/nHA) porous microspheres (MS@SL@nHA) using a microfluidic technology to explore the changes in the osteo-immune microenvironment and potential mechanisms using immunology and bioinformatics. Immunological analysis revealed that macrophages (Mφ) phagocytosed the nHA released from the composite microspheres, increased the proportion of M2 Mφ, regulated the early inflammatory response, exerted strong paracrine effects, and improved the osteo-immune microenvironment. Bioinformatics analysis showed that the signal transduction and adhesion ability were enhanced after Mφ activation, the inflammatory signaling pathways were inhibited, regulating the polarization direction, and the expression of cell growth factors was up-regulated to promote late osteogenesis. In vivo studies demonstrated that the composite microspheres effectively regulated Mφ polarization, and the paracrine secreted growth factors created a microsphere-centered osteogenesis pattern at the defect site. In conclusion, we successfully prepared injectable composite PLLA/nHA porous microspheres and systematically explored the osteogenesis-related mechanisms using immunological and bioinformatics analysis to provide theoretical evidence for bone repair materials that contribute to bone differentiation. Organic/inorganic composites have significant advantages in promoting bone repair. In this study, we prepared injectable PLLA/nHA composite microspheres and deeply explored their osteogenic mechanisms, which provided a certain supplement to the theoretical system of osteogenic differentiation of bone repair materials. [Display omitted] [ABSTRACT FROM AUTHOR]

Inspired by the native osteoimmune microenvironment, an injectable porous microsphere featured hierarchical micro/nano-structure was presented for ECM-mimicking 3D structural support and paracrine-transformed osteoimmuno-reprogramming via collaboration with multiple endogenous cells, such as macrophages, HUVECs and BMSCs. [Display omitted] • Proposing of an injectable porous microsphere with hierarchical micro/nano-structure. • Well integration between micro pore structure and nanofibers with dual-bonds. • Integrin-mediated M2Mφ polarizing and paracrine-transformed osteoimmune reprogramming. • Outstanding biological effects with M2Mφ derived VEGF, PDGF-BB, TGF-β1 and BMP-2. • High performance in treating the refractory bone defect. The 'clean-to-repair' rhythm in the dynamic pathological osteoimmune microenvironment is essential to bone healing but often disturbed by the intense inflammation. Inspired by the native osteoimmune microenvironment, we presented an injectable porous microsphere featured hierarchical micro/nano-structure via an ingenious integration of microfluidic microspheres and self-assembly collagen nanofibers, which could mimic the extracellular matrix and activate the integrin-mediated macrophage (Mφ) polarization, so as to realize a paracrine-transformed microenvironment reprogramming. The integrated hierarchical structure endowed with multiscale fibrous topology and optimized chemical cues well balanced the contradiction between large pores and reduced motifs. In vitro , owing to the modulation of integrin-mediated M2Mφ polarization and its paracrine secretion of endogenous cytokines, such as VEGF, PDGF-BB, TGF-β1, and BMP-2, the microsphere not only supported the tissue repair cell growth, but also promoted angiogenesis and mineralization by 2 and 3 folds, respectively. The capabilities of the osteoimmuno-reprogramming microsphere in progressive vascular sprouting maturation and in situ osteoinduction and osseointegration were further verified in a rat femoral condylar defect model. Hence, the so-produced hierarchical structured microsphere could manipulate the osteoimmune microenvironment by M2Mφ polarization and reconstruct the bone defects. [ABSTRACT FROM AUTHOR]

Nanofat (NF) is a fine emulsion that has been used to treat a variety of diseases given its abundance of bioactive components. However, the biological functions of NF have been limited due to its inability to localize during implantation. In this study, NF was immobilized in microfluidic-generated aldehyde-modified polylactic glycolic acid (PLGA) porous microspheres (PMs) via Schiff base condensation and non-covalent binding in a three-dimensional (3D) porous network (PMs@NF). The PMs effectively enhanced the cartilage-targeted retention efficiency of NF, which also resulted in remarkable lubrication performance, with the friction coefficient being reduced by ∼80%, which was maintained over time. Meanwhile, the 3D penetrating structure of the microspheres stimulated cytokine secretion by the NF-derived stem cells, upregulating the expression of anabolism-related genes and downregulating catabolism, and the expression of inflammation-related and pain-related genes. Injecting PMs@NF into the knee joint cavity of a rat model with destabilization of the medial meniscus (DMM) reduced osteophyte formation and protected the cartilage from degeneration, thereby inhibiting the progression of osteoarthritis and improving animal behavior. In summary, this study developed a multifunctional platform with NF immobilization and super-lubrication, which showed great potential for the minimally invasive treatment of osteoarthritis. [ABSTRACT FROM AUTHOR]

[Display omitted] • An integrated bio-signal peptide system is created by solid-phase synthesis. • Biological signal integrated microspheres are constructed via click reaction. • Osteogenic and angiogenic bio-signals are delivers to promote bone regeneration. Biological signal peptides can regulate a variety of biological functions and have been extensively studied. However, it is still a challenge on how to effectively deliver integrated biological signal peptides and apply them to bone tissue repair. Herein, based on microfluidic technology, an integrated biological signal peptide system (SVVYGLR-BFP) was first constructed by coupling osteogenic and angiogenic signal peptides via solid-phase synthesis method, and then crosslinked into a biological signal integrated microspheres composed of methacrylate gelatin (GelMA) by clicking reaction of sulfhydryl and double bonds (GelMA-S-B), which realized effective delivery of integrated biological signal peptides to promote bone repair. The results of the pharmacokinetics study showed that GelMA-S-B could achieve an efficient sustained release in the bone defect area, and continuously deliver integrated biological signals. Compared with the control group, GelMA-S-B can effectively deliver osteogenesis and angiogenesis biosignal peptides to activate the ALP and PI3K signaling pathways, thereby significantly promoting the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the vascularization of human umbilical vein endothelial cells (HUVECs). In vivo experiments have shown that GelMA-S-B can remarkably facilitate bone tissue regeneration at bone defects by inducing osteogenic differentiation and neovascularization. In summary, a tissue engineering system for local delivery of integrated biological signal peptides is designed to ensure long-term peptide release, minimal invasiveness, and easy preparation, and ultimately realize effective treatment of bone defect regeneration. [ABSTRACT FROM AUTHOR]

• Proposing a new microfluidic technology for the preparation of cell loaded porous microspheres. • Ensuring stable yield and uniform size distribution of the generated microspheres. • Realizing controllability of the cross-linking strength. • Achieving high-capacity loading of the cells into the microspheres. Injection of cell-laden hydrogel microspheres is a minimally invasive method for tissue regeneration. However, microspheres are usually limited by structural heterogeneity, uneven size, low cell loading capacity, and poor cell survival rate. We devised a microfluidics synchronous cross-linked technology to obtain injectable homogenous porous microspheres of desired particle (50–400 μm) and pore (0–50 μm) size by adjusting the flow rate and concentration of gelatin methacrylamide (GelMA). The synchronous cross-linking controlled the strength of cross-linking and prevented fusion and uneven cross-linking. The freeze-dried microspheres of particle size 300 μm and pore size 50 μm rapidly adsorbed murine bone marrow-derived stem cells (BMSCs) and maintained their viability and osteogenic potential in vitro. In addition, the cell-loaded porous microspheres promoted tissue regeneration when injected locally into a murine bone defect model. Our results show that hydrogel microspheres generated by the microfluidics synchronous cross-linked technology are stable and biocompatible, and have strong regenerative potential when loaded with stem cells. [ABSTRACT FROM AUTHOR]