Methacrylated Hyaluronic Acid Research Articles

Dual-crosslinking gelatin-hyaluronic acid methacrylate based biomimetic PDAC desmoplastic niche enhances tumor-associated macrophages recruitment and M2-like polarization

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by deposition of desmoplastic matrix (including collagen and hyaluronic acid). And the interactions between tumor-associated macrophages (TAMs) and tumor cells play a crucial role in progression of PDAC. Hence, the appropriate model of tumor cell-macrophage interaction within the unique PDAC TME is of significantly important. To this end, a 3D tumor niche based on dual-crosslinking gelatin methacrylate and hyaluronic acid methacrylate hydrogels was constructed to simulate the desmoplastic tumor matrix with matching compressive modulus and composition. The bionic 3D tumor niche creates an immunosuppressive microenvironment characterized by the downregulation of M1 markers and upregulation of M2 markers in TAMs. Mechanistically, RNA-seq analysis revealed that the PI3K-AKT signaling pathway might modulate the phenotypic balance and recruitment of macrophages through regulating SELE and VCAM-1. Furthermore, GO and GSEA revealed the biological process of leukocyte migration and the activation of cytokine-associated signaling were involved. Finally, the 3D tumor-macrophage niches with three different ratios were fabricated which displayed increased M2-like polarization and stemness. The utilization of the 3D tumor niche has the potential to provide a more accurate investigation of the interplay between PDAC tumor cells and macrophages within an in vivo setting.

MMP13-responsive hydrogel microspheres for osteoarthritis treatment by precise delivery of celecoxib

Osteoarthritis (OA) is characterized by cartilage degradation, inflammatory responses, and osteophyte formation. Matrix metalloproteinase 13 (MMP13) is a hallmark of OA development, and increased MMP13 expression is closely associated with extracellular matrix degradation. MMP13 expression varies significantly at different stages of OA progression. While cyclooxygenase 2 (COX-2) inhibitors are commonly used to treat OA, their long-term systemic administration increases the risks of adverse effects. Therefore, with the aim of achieving localized and responsive delivery of the COX-2 inhibitor celecoxib, the current study investigated an innovative MMP13-responsive micro-nano hydrogel microsphere system. Celecoxib-loaded cationic liposomes are non-covalently attached within the microsphere, enabling controlled drug release for OA treatment. In an OA environment with elevated MMP13 expression, the system is degraded via the action of MMP13 substrate peptide (MMP13sp), facilitating accelerated release of drug-loaded liposomes to improve the inflammatory microenvironment and treat OA rapidly. Compared to a phosphate-buffered saline solution with hyaluronidase (HAase), the prepared hyaluronic acid methacrylate microspheres HAMA/MMP13sp/Lipo@celecoxib exhibited rapid degradation in a solution containing a physiological concentration of MMP13/HAase, demonstrating specific enzyme responsiveness for precise anti-inflammatory drug release. The MMP13-responsive hydrogel microsphere system achieves intelligent and controllable drug release in OA, effectively decelerating disease progression and promoting articular cartilage repair.

Biomimetically ordered ultralong hydroxyapatite nanowires-based hierarchical hydrogel scaffold with osteoimmunomodulatory and osteogenesis abilities for augmenting bone regeneration

Artificial construction of tissue engineering implants with bone-mimicking structure and osteogenic function is of great significance for bone regeneration, but it remains a formidable challenge. Herein, inspired by natural bone, a biomimetically hierarchical hydrogel scaffold with highly ordered arrangement and multi-layered concentric circular structure is constructed by a convenient free-injection method for osteoimmunomodulation and bone defect regeneration. Ultralong hydroxyapatite nanowires act as skeleton unit to assemble into the hierarchically ordered nanowire bundles and further hybridization with hyaluronic acid methacrylate and loading with layered double hydroxide nanosheets to form the stable biomimetic scaffold. The biomimetic scaffold exhibits anisotropic structure, high water content and porosity, mechanical robustness, and sustained release of bioactive ions. In particular, the excellent biocompatibility together with ordered topography and biochemical cue can guide recruitment and directional migration of stem cells, and effectively promote osteogenic differentiation and vascularization in vitro. Moreover, the biomimetic scaffold induces M2 phenotype polarization of macrophages, thus creating a favorable osteoimmune environment. The in vivo study proves that the biomimetic scaffold can attenuate inflammation, promote vascularized ossification, and further accelerate new bone formation. This study provides an innovative strategy to construct multifunctional anisotropic biomaterials for bone tissue engineering.

Photo-responsive polydopamine nanoenzyme microneedles with oxidative stress regulation ability for atopic dermatitis treatment

As a common chronic inflammatory skin disease, atopic dermatitis (AD) troubles many people, while its effective therapy is a challenge. Here, we present novel polydopamine (PDA) nanoenzyme integrated near-infrared ray (NIR)-responsive microneedles (MNs) with antioxidant capacity for AD treatment. Such MNs are composed of a hyaluronic acid (HA) backing layer and hyaluronic acid methacrylate (HAMA) tips that are loaded with PDA nanoenzyme. Owing to the photo-thermal conversion capability of PDA nanoenzyme, the MNs can enhance local microcirculatory blood flow, inhibit bacterial growth, and consequently alleviate inflammation and facilitate lesion repair. Besides, the antioxidant properties of PDA nanoparticles could markedly reduce the ROS production in HaCaT cells under conditions of elevated oxidative stress. Based on these features, we have demonstrated that the MNs could effectively realize remission in AD mouse models. Thus, we believe that the proposed NIR-responsive PDA nanoenzyme MNs could serve as a promising therapeutic approach for the treatment and management of clinic AD.

Dual-Modified Hyaluronic Acid for Tunable Double Cross-Linked Hydrogel Adhesives.

Conventional techniques for the closure of wounds, such as sutures and staples, have significant drawbacks that can negatively impact wound healing. Tissue adhesives have emerged as promising alternatives, but poor adhesion, low mechanical properties, and toxicity have hindered their widespread clinical adoption. In this work, a dual modified, aldehyde and methacrylate hyaluronic acid (HA) biopolymer (HA-MA-CHO) has been synthesized through a simplified route for use as a double cross-linked network (DCN) hydrogel (HA-MA-CHO-DCN) adhesive for the effective closure and sealing of wounds. HA-MA-CHO-DCN cross-links in two stages: initial cross-linking of the aldehyde functionality (CHO) of HA-MA-CHO using a disulfide-containing cross-linker, 3,3'-dithiobis (propionic hydrazide) (DTPH), leading to the formation of a self-healing injectable gel, followed by further cross-linking via ultraviolet (UV) initiated polymerization of the methacrylate (MA) functionality. This hydrogel adhesive shows a stable swelling behavior and remarkable versatility as the storage modulus (G') has shown to be highly tunable (103-105 Pa) for application to many different wound environments. The new HA-MA-CHO-DCN hydrogel showed excellent adhesive properties by surpassing the burst pressure and lap-shear strength for the widely used bovine serum albumin-glutaraldehyde (BSAG) glue while maintaining excellent cell viability.

Highly Active Frozen Nanovesicles Microneedles for Senile Wound Healing via Antibacteria, Immunotherapy, and Skin Regeneration.

Senile wound healing risks a variety of health complications and makes both economic and psychological burdens on patients greatly. Poor activity of aged dermal fibroblasts (A-FBs) and local disordered immunoreaction in the deep dermis contribute to delayed wound healing. Therefore, the locally complex microenvironment in deep requires additional processing. Herein, a novel double-layer hyaluronic acid methacrylate (HAMA)/polyvinyl alcohol (PVA) microneedle patch (MNP) coated by young fibroblast-derived exosomes (Y-EXOs) (Y-EXOs@HAMA/PVA MNP) is presented for deep drug delivery, aged wound healing and immunoregulation. A spraying and freeze-drying method is applied for keeping the bioactivity of the nanovesicles. An ideal loading of Y-EXOs and enhanced strength for penetration have realized after circulation for times. The Y-EXOs@HAMA/PVA MNP shows an excellent influence on delayed wound healing of aged skin with active A-FBs, more deposition of collagen and less production of IL-17A compared with application of aged fibroblast-derived exosomes (A-EXOs). Moreover, the content microRNAs in Y-EXOs and A-EXOs are sequenced for further study. This study initiatively demonstrates that Y-EXOs have effective function on both anti-aging and anti-inflammation and Y-EXOs@HAMA/PVA MNP is expected as a novel strategy for deep drug delivery for promoting hard wound healing in aged skin in future clinical application.

Efficient Loading and Sustained Delivery of Methotrexate Using a Tip-Swellable Microneedle Array Patch for Psoriasis Treatment.

Methotrexate (MTX), a primary treatment for moderate to severe psoriasis, is limited in clinical use due to suboptimal results and severe side effects from subcutaneous (SC) injection and oral administration. Microneedles offer a promising alternative for direct MTX delivery to targeted skin lesions, but issues such as drug wastage, dosage inaccuracy, and limited drug residence time in the lesions remain. This study introduces a tip-swellable microneedle array patch (TSMAP) using photo-cross-linked methacrylated hyaluronic acid (MeHA) and biocompatible resin for effective MTX loading and sustained delivery. A two-cast micromolding with vacuum drying is employed to concentrate cross-linked MeHA in about 30% of the needle's height at the tip, thereby ensuring that only the TSMAP tip swells. Efficient MTX loading into TSMAP tips is achieved through a 30 s drug solution immersion and 10 min drying, potentially minimizing drug waste from incomplete skin insertion due to skin elasticity. The MTX-loaded TSMAP effectively penetrates both porcine and psoriasis-like mouse skin with its tips detaching from the resin substrate and embedding deeply into the skin tissue, thereby functioning as a drug release reservoir. TSMAP significantly prolongs drug retention in skin compared with SC injection and dissolvable microneedles. The in vivo study demonstrates that TSMAP-mediated MTX delivery substantially enhances therapeutic outcomes in alleviating psoriasis symptoms and downregulating psoriasis-associated cytokines, outperforming oral administration, SC injection, and dissolvable microneedles. Thus, TSMAP could offer an efficient and user-friendly alternative for drug administration in the treatment of various skin diseases.

Self-Adhesive, Strong Antifouling, and Mechanically Reinforced Methacrylate Hyaluronic Acid Cross-Linked Carboxybetaine Zwitterionic Hydrogels.

Hyaluronic acid and zwitterionic hydrogels are soft materials with poor mechanical properties. The unique structures and physiological properties make them attractive candidates for ideal hydrogel dressings, but the crux of lacking satisfying mechanical strengths and adhesive properties is still pendent. In this study, the physical cross-linking of dipole-dipole interactions of zwitterionic pairs was utilized to enhance the mechanical properties of hydrogels. The hydrogels have been prepared by copolymerizing methacrylate hyaluronic (HAGMA) with carboxybetaine methacrylamide (CBMAA) (the mass ratio of [HAGMA]/[CBMAA] is 2:5, 1:5, 1:10, or 1:20), obtaining HA-CB2.5, HA-CB5.0, HA-CB10.0, or HA-CB20.0 hydrogel. Therein, the HA-CB20.0 hydrogel with a high CBMAA content can generate a strong dipole-dipole interaction to form internal physical cross-links, exhibit stretchability and low elastic modulus, and withstand 99% compressive deformation and cyclic compression under strain at 90%. Moreover, the HA-CB20.0 hydrogel is adhesive to diverse substrates, including skin, glass, stainless steel, and plastic. The synergistic effect of HAGMA and CBMAA shows strong anti-biofouling, high water absorption, biodegradability under hyaluronidase, and biocompatibility.

A sequential physical and chemical dual crosslinked multifunctional hydrogel with enhanced mechanical and osteogenic effects for vascularized bone tissue regeneration

Hydrogels have been recognized for their versatile in regenerative medicine; however, their inadequate mechanical and osteogenic properties have limited their applicability in bone tissue engineering (BTE). Hence, we present a novel approach to address this issue by developing sulfated methacrylate hyaluronic acid hydrogels (SMeHA@CM) doped with alendronate (ALN), calcium ions (Ca2+), and magnesium ions (Mg2+). This hydrogel system incorporates sequential physical and chemical crosslinking to facilitate the treatment of bone defects. Physical crosslinks form between the SO32−, ALN, and Ca2+/Mg2+ ions, resulting in nanocluster crosslinking and complete filling of irregular bone defects. Subsequently, the methacrylate groups within the polymer chain undergo polymerization under ultraviolet light irradiation, forming the second stage of chemical crosslinking in the SMeHA@CM hydrogel. These chemical crosslinks contribute strong chemical bonds, enhancing biomechanical strength, and stable support for bone regeneration. The SMeHA@CM hydrogel exhibits remarkable osteogenic capacity, primarily attributed to the cooperative action of SO32− and Mg2+ ions, which promote the recruitment of bone marrow stem cells and angiogenesis. Furthermore, the sustained release of SO32−-ALN-Ca2+/Mg2+ nanoclusters from the hydrogel system offers additional benefits for bone regeneration. Moreover, both in-vitro and in-vivo assessments confirm the significant potential of the newly developed SMeHA@CM hydrogel for applications in BTE.

Stem cell-derived small extracellular vesicles embedded into methacrylated hyaluronic acid wound dressings accelerate wound repair in a pressure model of diabetic ulcer

Over the past years, the development of innovative smart wound dressings is revolutionizing wound care management and research. Specifically, in the treatment of diabetic foot wounds, three-dimensional (3D) bioprinted patches may enable personalized medicine therapies. In the present work, a methacrylated hyaluronic acid (MeHA) bioink is employed to manufacture 3D printed patches to deliver small extracellular vesicles (sEVs) obtained from human mesenchymal stem cells (MSC-sEVs). The production of sEVs is maximized culturing MSCs in bioreactor. A series of in vitro analyses are carried out to demonstrate the influence of MSC-sEVs on functions of dermal fibroblasts and endothelial cells, which are the primary functional cells in skin repair process. Results demonstrate that both cell populations are able to internalize MSC-sEVs and that the exposure to sEVs stimulates proliferation and migration. In vivo experiments in a well-established diabetic mouse model of pressure ulcer confirm the regenerative properties of MSC-sEVs. The MeHA patch enhances the effectiveness of sEVs by enabling controlled release of MSC-sEVs over 7 days, which improve wound epithelialization, angiogenesis and innervation. The overall findings highlight that MSC-sEVs loading in 3D printed biomaterials represents a powerful technique, which can improve the translational potential of parental stem cell in terms of regulatory and economic impact.

Biomimetic Structure Hydrogel Loaded with Long-Term Storage Platelet-Rich Plasma in Diabetic Wound Repair.

Exploring the preparation of multifunctional hydrogels from a bionic perspective is an appealing strategy. Here, a multifunctional hydrogel dressing inspired by the characteristics of porous extracellular matrix produced during Acomys wound healing is prepared. These dressings are printed by digital light processing printing of hydrogels composed of gelatin methacrylate, hyaluronic acid methacrylate, and pretreated platelet-rich plasma (PRP) to shape out triply periodic minimal surface structures, which are freeze-dried for long-term storage. These dressings mimic the porous extracellular matrix of Acomys, while the freeze-drying technique effectively extends the storage duration of PRP viability. Through in vivo and in vitro experiments, the biomimetic dressings developed in this study modulate cell behavior and facilitate wound healing. Consequently, this research offers a novel approach for the advancement of regenerative wound dressings.

Bicomponent hydrogel laden with TGF-β3-nucleus pulposus stem cells for disc degeneration repair

Degenerative intervertebral disc (IVD) disease, which cannot be completely treated with open or minimally invasive surgery, is primarily caused by nucleus pulposus (NP) degeneration. Meanwhile, NP regeneration requires the intricate coordination of stem cells, growth factors, and biomaterials. The current study sought to develop a regenerative approach for IVD degeneration. To this end, we used a lentiviral vector to introduce the transforming growth factor-β3 (TGF-β3) gene into NP mesenchymal stem cells (NPMSCs) to construct genetically modified seed cells. In addition, bicomponent gelatin methacrylate/hyaluronic acid methacrylate (GH) hydrogels were synthesized based on gelatin methacrylate (GelMA) and hyaluronic acid methacrylate (HAMA) precursors as carriers for TGF-β3-NPMSCs delivery. In vitro differentiation of the loaded stem cells into NP-like structures was improved by the hydrogels' superior mechanical and cytocompatibility features. Moreover, the stem cell-loaded GH hydrogel was delivered to NP tissue via a minimally invasive approach to construct an injectable “transgenic cell-hydrogel” in situ microenvironment, which attenuated IVD degeneration, preserved the integrity of the NP tissue, and sped up extracellular matrix synthesis in a rat model. Collectively, the results of this study demonstrate the potential of this novel therapeutic strategy as an effective regenerative approach for IVD degeneration.

Photocurable and Temperature-Sensitive Bioadhesive Hydrogels for Sutureless Sealing of Full-Thickness Corneal Wounds.

Penetrating corneal wounds can cause severe vision impairment and require prompt intervention to restore globe integrity and minimize the risk of infection. Tissue adhesives have emerged as a promising alternative to suturing for mitigating postoperative complications. However, conventional water-soluble adhesives suffer formidable challenges in sealing penetrating corneal wounds due to dilution or loss in a moist environment. Inspired by the robust adhesion of mussels in aquatic conditions, an injectable photocurable bioadhesive hydrogel (referred to as F20HD5) composed of polyether F127 diacrylate and dopamine-modified hyaluronic acid methacrylate is developed for sutureless closure of corneal full-thickness wounds. F20HD5 exhibits high transparency, wound-sealing ability, proper viscosity, biodegradability, and excellent biocompatibility. It allows in situ cross-linking via visible light, thereby providing sufficient mechanical strength and adhesiveness. In vivo, the adhesive hydrogel effectively closed penetrating linear corneal incisions and corneal injuries with minimal tissue loss in rabbits. During the 56-day follow-up, the hydrogel facilitates the repair of the injured corneas, resulting in more symmetrical curvatures and less scarring in distinction to the untreated control. Thus, bioinspired hydrogel holds promise as an effective adhesive for sealing full-thickness corneal wounds.

3D Bioprinting and Characterization of Bioinks with Different Concentrations of Hyaluronic Acid Methacrylate (AHMA)

The 3D Bioprinting technique for tissue engineering has been constantly developed and generating different results due to the range of applicability of the technique. It is necessary to study and analyze matrices to use this technology, as an example of hydrogels, which are viable for use in conjunction with cells to create the bioink used in bioprinting, verifying their physicochemical properties, cellular reviews, and properties mechanics for the desired application. Based on this, this work aims to analyze these properties, focusing on the hyaluronic acid (HA) matrix in different concentrations during the manufacture of bioink for 3D bioprinting for future application in tissue engineering.

An injectable and 3D printable pro-chondrogenic hyaluronic acid and collagen type II composite hydrogel for the repair of articular cartilage defects

Current treatments for repairing articular cartilage defects are limited. However, pro-chondrogenic hydrogels formulated using articular cartilage matrix components (such as hyaluronic acid (HA) and collagen type II (Col II)), offer a potential solution if they could be injected into the defect via minimally invasive arthroscopic procedures, or used as bioinks to 3D print patient-specific customised regenerative scaffolds—potentially combined with cells. However, HA and Col II are difficult to incorporate into injectable/3D printable hydrogels due to poor physicochemical properties. This study aimed to overcome this by developing an articular cartilage matrix-inspired pro-chondrogenic hydrogel with improved physicochemical properties for both injectable and 3D printing (3DP) applications. To achieve this, HA was methacrylated to improve mechanical properties and mixed in a 1:1 ratio with Col I, a Col I/Col II blend or Col II. Col I possesses superior mechanical properties to Col II and so was hypothesised to enhance hydrogel mechanical properties. Rheological analysis showed that the pre-gels had viscoelastic and shear thinning properties. Subsequent physicochemical analysis of the crosslinked hydrogels showed that Col II inclusion resulted in a more swollen and softer polymer network, without affecting degradation time. While all hydrogels exhibited exemplary injectability, only the Col I-containing hydrogels had sufficient mechanical stability for 3DP applications. To facilitate 3DP of multi-layered scaffolds using methacrylated HA (MeHA)-Col I and MeHA-Col I/Col II, additional mechanical support in the form of a gelatin slurry support bath freeform reversible embedding of suspended hydrogels was utilised. Biological analysis revealed that Col II inclusion enhanced hydrogel-embedded MSC chondrogenesis, thus MeHA-Col II was selected as the optimal injectable hydrogel, and MeHA-Col I/Col II as the preferred bioink. In summary, this study demonstrates how tailoring biomaterial composition and physicochemical properties enables development of pro-chondrogenic hydrogels with potential for minimally invasive delivery to injured articular joints or 3DP of customised regenerative implants for cartilage repair.

Customization of an Ultrafast Thiol-Norbornene Photo-Cross-Linkable Hyaluronic Acid-Gelatin Bioink for Extrusion-Based 3D Bioprinting.

Light-based three-dimensional (3D) bioprinting has been widely studied in tissue engineering. Despite the fact that free-radical chain polymerization-based bioinks like hyaluronic acid methacrylate (HAMA) and gelatin methacryloyl (GelMA) have been extensively explored in 3D bioprinting, the thiol-ene hydrogel system has attracted increasing attention for its ability in building hydrogel scaffolds in an oxygen-tolerant and cell-friendly way. Herein, we report a superfast curing thiol-ene bioink composed of norbornene-modified hyaluronic acid (NorHA) and thiolated gelatin (GelSH) for 3D bioprinting. A new facile approach was first introduced in the synthesis of NorHA, which circumvented the cumbersome steps involved in previous works. Additionally, after mixing NorHA with macro-cross-linker GelSH, the customized NorHA/GelSH bioinks exhibited fascinating superiorities over the gold standard GelMA bioinks, such as an ultrafast curing rate (1-5 s), much lowered photoinitiator concentration (0.03% w/v), and flexible physical performances. Moreover, the NorHA/GelSH hydrogel greatly avoided excess ROS generation, which is important for the survival of the encapsulated cells. Last, compared with the GelMA scaffold, the 3D-printed NorHA/GelSH scaffold not only exhibited excellent cell viability but also guaranteed cell proliferation, revealing its superior bioactivity. In conclusion, the NorHA/GelSH system is a promising candidate for 3D bioprinting and tissue engineering applications.

Type I collagen concentration affects neurite outgrowth of adult rat DRG explants by altering mechanical properties of hydrogels

Type I collagen is a predominant fibrous protein that makes up the extracellular matrix. Collagen enhances cell attachment and is commonly used in three-dimensional culture systems, to mimic the native extracellular environment, for primary sensory neurons such as dorsal root ganglia (DRG). However, the effects of collagen concentration on adult rat DRG neurite growth have not been assessed in a physiologically relevant, three-dimensional culture. This study focuses on the effects of type I collagen used in a methacrylated hyaluronic acid (MAHA)-laminin-collagen gel (triple gel) on primary adult rat DRG explants in vitro. DRGs were cultured in triple gels, and the neurite lengths and number of support cells were quantified. Increased collagen concentration significantly reduced neurite length but did not affect support cell counts. Mechanical properties, fiber diameter, diffusivity, and mesh size of the triple gels with varying collagen concentration were characterized to further understand the effects of type I collagen on hydrogel property that may affect adult rat DRG explants. Gel stiffness significantly increased as collagen concentration increased and is correlated to DRG neurite length. Collagen concentration also significantly impacted fiber diameter but there was no correlation with DRG neurite length. Increasing collagen concentration had no significant effect on mesh size and diffusivity of the hydrogel. These data suggest that increasing type I collagen minimizes adult rat DRG explant growth in vitro while raising gel stiffness. This knowledge can help develop more robust 3D culture platforms to study sensory neuron growth and design biomaterials for nerve regeneration applications.

Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments

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

Zn2+ incorporated composite polysaccharide microspheres for sustained growth factor release and wound healing.

The development of new wound dressings has always been an issue of great clinical importance and research promise. In this study, we designed a novel double cross-linked polysaccharide hydrogel microspheres based on alginate (ALG) and hyaluronic acid methacrylate (HAMA) from gas-assisted microfluidics for wound healing. The microspheres from gas-assisted microfluidics showed an uniform size and good microsphere morphology. Moreover, this composite polysaccharide hydrogel microspheres were constructed by harnessing the fact that zinc ions (Zn2+) can cross-link with ALG as well as histidine-tagged vascular endothelial growth (His-VEGF) to achieve long-term His-VEGF release, thus promoting angiogenesis and wound healing. Meanwhile, Zn2+, as an important trace element, can exert antibacterial and anti-inflammatory effects, reshaping the trauma microenvironment. In addition, photo cross-linked HAMA was introduced into the microspheres to further improve its mechanical properties and drug release ability. In summary, this novel Zn2+ composite polysaccharide hydrogel microspheres loaded with His-VEGF based on a dual cross-linked strategy exhibited synergistic antimicrobial and angiogenic effects in promoting wound healing.

Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3-Energized and Microenvironment-Modulated Hydrogel Microspheres to Impede Osteoarthritis.

Full-range therapeutic regimens for osteoarthritis (OA) should consider organs (joints)-tissues (cartilage)-cells (chondrocytes)-organelles cascade, of which the subcellular mitochondria dominate eukaryotic cells' fate, and thus causally influence OA progression. However, the dynamic regulation of mitochondrial rise and demise in impaired chondrocytes and the exact role of mitochondrial metronome sirtuins 3 (SIRT3) is not clarified. Herein, chondrocytes are treated with SIRT3 natural agonist dihydromyricetin (DMY) or chemical antagonist 3-TYP, respectively, to demonstrate the positive action of SIRT3 on preserving cartilage extracellular matrix (ECM). Molecular mechanical investigations disclose that SIRT3-induced chondroprotection depended on the repression of mitochondrial apoptosis (mtApoptosis) and the activation of mitophagy. Inspired by the high-level matrix proteinases and reactive oxygen species (ROS) in the OA environment, by anchoring gelatin methacrylate (GelMA) and benzenediboronic acid (PBA) to hyaluronic acid methacrylate (HAMA) with microfluidic technology, a dual-responsive hydrogel microsphere laden with DMY is tactfully fabricated and named as DMY@HAMA-GelMA-PBA (DMY@HGP). In vivo injection of DMY@HGP ameliorated cartilage abrasion and subchondral bone sclerosis, as well as promoted motor function recovery in post-traumatic OA (PTOA) model via recouping endogenous mtApoptosis and mitophagy balance. Overall, this study unveils a novel mitochondrial dynamic-oriented strategy, holding great promise for the precision treatment of OA.