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Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications., (© 2023 The Authors. Small published by Wiley‐VCH GmbH.)

Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Burn injuries are difficult to manage due to the defect of large skin tissues, leading to major disability or even death. Human fibroblast growth factor 2 (hFGF2) is known to promote burn wound healing. However, direct administration of hFGF2 to the wound area would affect the bioactivity. To provide a supportive environment for hFGF2 and control its release in a steady fashion, in this research, we developed novel thermosensitive poloxam hydrogels delivered with hFGF2-linked Camelina lipid droplets (CLD-hFGF2 hydrogels). Cryopreserved scanning electron microscopy (SEM) results indicated that the incorporation of CLD-hFGF2 does not significantly affect the inner structure of hydrogels. The rheological properties showed that CLD-hFGF2 hydrogels gelated in response to temperature, thus optimizing the delivery method. In vitro, CLD-hFGF2 could be released from hydrogels for 3 days after drug delivery (the release rate was 72%), and the release solution could still promote the proliferation and migration of NIH3T3 cells. In vivo, compared with hydrogels alone or with direct CLD-hFGF2 administration, CLD-hFGF2 hydrogels had the most obvious effect on deep second-degree burn wound healing. This work indicates that CLD-hFGF2 hydrogels have potential application value in burn wound healing.

Directed differentiation of bone marrow mesenchymal stem cells (BMSCs) toward chondrogenesis plays a predominant role in cartilage repair. However, the uncontrolled inflammatory response to implants is found to impair the stability of scaffolds and the cartilage regeneration outcome. Herein, we fabricated an injectable hydrogel crosslinked by strontium-doped bioglass (SrBG) to modulate both human BMSC (hBMSC) differentiation and the inflammatory response. The results revealed that the introduction of Sr ions could simultaneously enhance the proliferation of hBMSCs, upregulate cartilage-specific gene expression, and improve the secretion of glycosaminoglycan. Moreover, after cultured with SA/SrBG extracts in vitro, a majority of macrophages were polarized toward the M2 phenotype and subsequently facilitated the chondrogenic differentiation of hBMSCs. Furthermore, after the composite hydrogel was injected into a cartilage defect model, neonatal cartilage-like tissues with a smooth surface and tight integration with original tissues could be found. This study suggests that the synergistic strategy based on an enhanced differentiation ability and a regulated inflammatory response is promising and may lead the way to new anti-inflammatory biomaterials.

Abnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG). Most current cellular HTM model systems do not sufficiently replicate the complex native three dimensional (3D) cell-ECM interface, limiting their use for investigating POAG pathology. Tissue-engineered hydrogels are ideally positioned to overcome shortcomings of current models. Here, we report a novel biomimetic HTM hydrogel and test its utility as a POAG disease model. HTM hydrogels were engineered by mixing normal donor-derived HTM cells with collagen type I, elastin-like polypeptide and hyaluronic acid, each containing photoactive functional groups, followed by UV crosslinking. Glaucomatous conditions were induced with dexamethasone (DEX), and effects of the Rho-associated kinase (ROCK) inhibitor Y27632 on cytoskeletal organization and tissue-level function, contingent on HTM cell-ECM interactions, were assessed. DEX exposure increased HTM hydrogel contractility, f-actin and alpha smooth muscle actin abundance and rearrangement, ECM remodeling, and fibronectin deposition - all contributing to HTM hydrogel condensation and stiffening consistent with glaucomatous HTM tissue behavior. Y27632 treatment produced precisely the opposite effects and attenuated the DEX-induced pathologic changes, resulting in HTM hydrogel relaxation and softening. For model validation, confirmed glaucomatous HTM (GTM) cells were encapsulated; GTM hydrogels showed increased contractility, fibronectin deposition, and stiffening vs. normal HTM hydrogels despite reduced GTM cell proliferation. We have developed a biomimetic HTM hydrogel model for detailed investigation of 3D cell-ECM interactions under normal and simulated glaucomatous conditions. Its bidirectional responsiveness to pharmacological challenge and rescue suggests promising potential to serve as screening platform for new POAG treatments with focus on HTM biomechanics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recently, hydrogel wound dressings were popular in wound healing because of their advantages over traditional gauze dressings. The alginate/carboxymethyl chitosan (SA/CMCS) hydrogel wound dressing has been widely studied because of its biocompatibility and antibacterial ability. However, the poor mechanical stability and lack of bioactivity limit their applications. Bioglass (BG) has been well acknowledged as a bioactive material, and SA/BG hydrogels have been reported to be able to promote wound healing. Calcium ions released from BG can further cross-link SA, which may enhance the mechanical stability of the SA/CMCS hydrogels. Therefore, in this study, BG was incorporated into SA/CMCS hydrogel in order to obtain a bioactive alginate/CMCS/BG (SA/CMCS/BG) hydrogel wound dressing with improved mechanical stability. Results showed that the Young's modulus of SA/CMCS/BG hydrogel was three times higher than that of SA/CMCS hydrogel. In addition to better antibacterial and coagulation properties, SA/CMCS/BG hydrogels possess stronger bioactivity than SA/CMCS hydrogels as they could accelerate skin wound closure by regulating the host inflammation responses, stimulating angiogenesis, and enhancing collagen deposition in wound sites, which suggests that SA/CMCS/BG hydrogels are good candidates for clinic wound dressings.

Inflammatory response is a critical stage in typical wound healing. Although studies have reported that some bioactive materials can modulate the polarization of macrophages to benefit tissue regeneration, the roles of the inflammatory responses, especially the crucial roles of macrophages, in tissue regeneration stimulated by biomaterials remains unclear. Bioactive glass (BG) and hydrogel containing BG have been reported to be able to promote both hard and soft tissue regeneration. However, the critical roles of macrophages in tissue regeneration enhanced by BG have not been fully elucidated. In this study, the effects of BG/sodium alginate (SA) hydrogel (BG/SA hydrogel) on the behaviors of macrophages as well as on the interactions between macrophages and repairing cells were investigated. In addition, macrophage-depleted mice were used to investigate the necessity of macrophages in the regeneration of full-thickness skin wounds treated with BG/SA hydrogel. Our results indicated that BG/SA hydrogel could polarize macrophages towards M2 phenotype in vitro and in vivo and upregulate the expression of anti-inflammatory genes. In addition, the M2 polarized macrophages could further recruit fibroblasts and endothelial cells as well as enhance the extracellular matrix (ECM) synthesis of fibroblasts and vascularization of endothelial cells in vitro and in vivo. Depletion of macrophages in the wound sites impeded the recruitment of repairing cells and reduced the formation of blood vessels and ECM, slowing down skin regeneration. These results provide an insight into the biomaterial-immune system interactions and demonstrate that modulation of macrophages by BG/SA hydrogel in the inflammatory response is crucial in skin regeneration enhanced by the hydrogel., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A series of agar/κ-carrageenan mixed hydrogels with different mass ratios were prepared, and their physicochemical properties, gelling behavior and drug release performance were determined and analyzed. The results showed that the gel strength, the gelling temperature and the gel melting temperature decreased with the increase of κ-carrageenan, while the apparent viscosities increased. Optical rotation and differential scanning calorimetry (DSC) indicated that there did exist intermolecular interactions between agar and κ-carrageenan, and the detailed gelling mechanism of the mixed hydrogels was proposed, which was different from that of the previous research. Besides, agar/κ-carrageenan mixed hydrogels were used as carriers for the delivery of metformin hydrochloride (MET). The results showed that the drug loading efficiency and the sustained release capacity of agar hydrogels could be enhanced by the addition of κ-carrageenan, and the release profile was mainly dominated by the electrostatic interaction between the MET and the polysaccharides. These results indicated that κ-carrageenan had the potential to improve the physicochemical properties and drug release performance of agar hydrogel., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Wound healing is a dynamic and complex process that contains several sequential phases. However, most of the current drug delivery systems were designed to treat only one certain phase of wound repair, ignoring the fact that every stage plays critical roles in the wound healing process and those critical stages coordinately work to ensure optimal tissue regeneration. Therefore, a delivery system that can precisely meet the requirements of each wound healing stage is desired to enhance tissue regeneration. In this study, an injectable sodium alginate/bioglass (SA/BG) composite hydrogel was used to carry SA microparticles containing a conditioned medium (CM) of cells (SA CM ). Inside the SA CM microparticles, poly(lactic- co -glycolic acid) (PLGA) microspheres containing pirfenidone (PFD) were encapsulated (PLGA PFD ). This multilayer injectable hydrogel system (SA/BG-SA CM -PLGA PFD ) was designed to sequentially deliver bioactive molecules for meeting the bioactivity requirement and timeline of each wound healing stage. First, SA/BG hydrogels could rapidly release BG ionic products in the first 1-3 days to regulate the inflammatory response of the host and initiate the subsequent tissue regeneration. Then, SA CM hydrogel microparticles could release CM of RAW 264.7 cells stimulated with BG ionic products in 2-7 days to facilitate the formation of the vascularized granulation tissue. Finally, PLGA PFD microspheres released PFD in 8-20 days to prevent the fibrosis and scar formation in the regenerated skin. Thus, this SA/BG-SA CM -PLGA PFD delivery system could restrain host inflammation, accelerate wound healing, and inhibit the fibrosis formation in a diabetic mouse skin damage model, enhancing skin regeneration. As the bioactive components in each layer of the system can be adjusted according to the requirements of different tissue regeneration, this three-layered injectable biomaterial system has a wide application potential in the regenerative medicine field.

The research on multiple hydrogen bonds (H-bonds) hydrogels have gradually aroused wide interest. In this paper, a multiple H-bonds-reinforced poly(acrylamide-co-2-vinyl-4,6-diamino-2-vinyl-1,3,5-triazine)/tannic acid (P(Am-co-VDT)/TA) hydrogels are prepared. The results suggest that the prepared hydrogel has two types of H-bonds crosslinking regions: A "soft" region of H-bonds between the diaminotriazine (DAT) moieties on the polymer chains and the TA pyrogallol/catechol groups, and a "hard" region of H-bonds forming by DAT moieties with itself. The hard crosslinking region exhibits significantly higher activation energy than the soft region. Such soft and hard dual physically crosslinked networks dramatically enhance the mechanical properties of P(Am-co-VDT)/TA hydrogels in a synergistic manner (tensile strength is 2.34 MPa, elongation at break is 410%). Due to the multiple hydrogen bonds, the hydrogel has good pH sensitivity and rapid response to shape memory within a few minutes. In addition, the hydrogels have the capacity of physical adsorption of the anti-inflammatory drug diclofenac sodium and other molecules with a specific spatially arranged chemical composition. These hydrogels with high mechanical strength, excellent shape memory behavior, and capacity of adsorption of anti-inflammatory drug could be attractive candidates for applications in the fields of biomedicine, tissue engineering, and medical materials., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A versatile ionic crosslink lithography (ICL) approach is reported to achieve geometry transitions of strong polyvinyl alcohol/sodium alginate (PVA/SA) hydrogels in a controllable and programmable manner. Specifically, localized PVA/SA and PVA/SA/Fe 3+ hydrogel domains of significantly different swellabilities (i.e., in-plane gradient) are created by patterning and selective ionic crosslinking of one single type of PVA/SA hydrogel. A simple two-step sequential pre- and free-swelling, or each alone, directs the patterned, inhomogeneous hydrogel to transform in various programmable and quasi-quantitative ways through local bulging and/or global buckling. All types of shape changing are reversible and repeatable due to the reversible nature of ionic coordination in the hydrogel networks. The flexibility and versatility of 3D printing is also demonstrated in creating through-thickness gradient in PVA and PVA/SA hydrogel assemblies with similar morphing capability. The ICL approach developed in this work may help shed some light on developing strong and shape morphing hydrogels as soft sensors and actuators and for potentially biomimetic transformations. The ICL approach may also be transferable to fabrication of many other types of hydrogel materials for similar applications., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The unique capabilities of ultrafast lasers to introduce user-defined microscale modifications within 3D cell-laden hydrogels have been used to investigate fundamental cellular phenomenon such as adhesion, alignment, migration and organization. In this work, we report a new material modification phenomenon coined as 'densification' and its influence on the behavior of encapsulated cells. Femtosecond laser writing technique was used to write densified lines of width 1-5 μm within the bulk of gelatin methacrylate (GelMA) constructs. We found that densified micro-lines within cell-laden GelMA constructs resulted in preferential and localized alignment of encapsulated human endothelial cells. Degree of cellular alignment was characterized as a function of cell-culture time and the spacing between the densified line patterns. This phenomenon was found to be true for several cell lines, including mouse fibroblasts and osteocytes, and mesenchymal stem cells derived from human induced pluripotent cells. This first report of physical densification using fs lasers can be potentially extended for investigating cell behavior within other photosensitive hydrogels.

Diabetic wound is hard to heal mainly because of the difficulty in vascularization in the wound area. Accumulating results have shown that desferrioxamine (DFO) can promote secretion of hypoxia inducible factor-1 (HIF-1α), thereby upregulating the expression of angiogenic growth factors and facilitating revascularization. Our preliminary study has demonstrated that Si ions in bioglass (BG) can upregulate vascular endothelial growth factor (VEGF) expression, thus promoting revascularization. It is hypothesized that the combined use of BG and DFO may have a synergistic effect in promoting VEGF expression and revascularization. To prove this, we first determined DFO concentration range that had no apparent cytotoxicity on human umbilical vein endothelial cells (HUVECs). Then, the optimal concentration of DFO promoting tube formation of HUVECs was determined by cell migration and tube formation assays. In addition, we demonstrated that combination use of BG and DFO improved the migration and tube formation of HUVECs as compared with the use of either BG or DFO alone as BG and DFO could synergistically upregulate VEGF expression. Furthermore, a sodium alginate hydrogel containing both BG and DFO was developed, and this hydrogel better facilitated diabetic skin wound healing than the use of either BG or DFO alone as BG and DFO in the hydrogels worked synergistically in promoting HIF-1α and VEGF expression and subsequently vascularization in the wound sites. Therefore, in this study, the synergistic effect in promoting revascularization between BG and DFO was first demonstrated and an injectable hydrogel simultaneously containing BG and DFO was developed for enhancing repair of diabetic chronic skin defects by taking advantages of the synergistic effects of BG and DFO in promoting revascularization. The study opens up a new prospect for the development of skin repair-promoting biomaterials.

Unlabelled: Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4-1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo, the combination of PL and human MSCs improved local tissue perfusion after 8days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration., Statement of Significance: Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel's desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs' angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia., (Published by Elsevier Ltd.)

In this study, an injectable calcium silicate (CS)/sodium alginate (SA) hybrid hydrogel was prepared using a novel material composition design. CS was incorporated into an alginate solution and internal in situ gelling was induced by the calcium ions directly released from CS with the addition of d-gluconic acid δ-lactone (GDL). The gelling time could be controlled, from about 30s to 10 min, by varying the amounts of CS and GDL added. The mechanical properties of the hydrogels with different amounts of CS and GDL were systematically analyzed. The compressive strength of 5% CS/SA hydrogels was higher than that of 10% CS/SA for the same amount of GDL. The swelling behaviors of 5% CS/SA hydrogels with different contents of GDL were therefore investigated. The swelling ratios of the hydrogels decreased with increasing GDL, and 5% CS/SA hydrogel with 1% GDL swelled by only less than 5%. Scanning electron microscopy (SEM) observation of the scaffolds showed an optimal interconnected porous structure, with the pore size ranging between 50 and 200 μm. Fourier transform infrared spectroscopy and SEM showed that the CS/SA composite hydrogel induced the formation of hydroxyapatite on the surface of the materials in simulated body fluid. In addition, rat bone mesenchymal stem cells (rtBMSCs) cultured in the presence of hydrogels and their ionic extracts were able to maintain the viability and proliferation. Furthermore, the CS/SA composite hydrogel and its ionic extracts stimulated rtBMSCs to produce alkaline phosphatase, and its ionic extracts could also promote angiogenesis of human umbilical vein endothelial cells. Overall, all these results indicate that the CS/SA composite hydrogel efficiently supported the adhesion, proliferation and differentiation of osteogenic and angiogenic cells. Together with its porous three-dimensional structure and injectable properties, CS/SA composite hydrogel possesses great potential for bone regeneration and tissue engineering applications., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Abnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG). Most current cellular HTM model systems do not sufficiently replicate the complex native three dimensional (3D) cell-ECM interface, limiting their use for investigating POAG pathology. Tissue-engineered hydrogels are ideally positioned to overcome shortcomings of current models. Here, we report a novel biomimetic HTM hydrogel and test its utility as a POAG disease model. HTM hydrogels were engineered by mixing normal donor-derived HTM cells with collagen type I, elastin-like polypeptide and hyaluronic acid, each containing photoactive functional groups, followed by UV crosslinking. Glaucomatous conditions were induced with dexamethasone (DEX), and effects of the Rho-associated kinase (ROCK) inhibitor Y27632 on cytoskeletal organization and tissue-level function, contingent on HTM cell-ECM interactions, were assessed. DEX exposure increased HTM hydrogel contractility, f-actin and alpha smooth muscle actin abundance and rearrangement, ECM remodeling, and fibronectin deposition - all contributing to HTM hydrogel condensation and stiffening consistent with glaucomatous HTM tissue behavior. Y27632 treatment produced precisely the opposite effects and attenuated the DEX-induced pathologic changes, resulting in HTM hydrogel relaxation and softening. For model validation, confirmed glaucomatous HTM (GTM) cells were encapsulated; GTM hydrogels showed increased contractility, fibronectin deposition, and stiffening vs. normal HTM hydrogels despite reduced GTM cell proliferation. We have developed a biomimetic HTM hydrogel model for detailed investigation of 3D cell-ECM interactions under normal and simulated glaucomatous conditions. Its bidirectional responsiveness to pharmacological challenge and rescue suggests promising potential to serve as screening platform for new POAG treatments with focus on HTM biomechanics.

Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro‐inflammatory response of lipopolysaccharide (LPS)‐stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate‐based core–shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric‐simulated environment while dissolved in an intestinal‐simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment. [ABSTRACT FROM AUTHOR]

Hydrogels are widely utilized for articular cartilage regeneration. However, traditional hydrogels with nano‐sized pores lead to poor cell and tissue infiltration. Furthermore, hydrogels that can stimulate each phase of cartilage regeneration to enhance cartilage repair are highly demanded. Herein, a macro‐porous hydrogel is fabricated by crosslinking mixed sodium alginate (SA) and hyaluronic acid (HA) solution into SA/HA micro‐fibers (µ‐fibers) first and subsequently crosslinking the µ‐fibers into hydrogel blocks. Besides, exosomes derived from NR8383 cells activated by lipopolysaccharides (LPS) and stimulated with bioglass (BG) ion extracts (LPS/BG‐exo) are incorporated into the hydrogel as they exhibit a strong ability to regulate inflammation homeostasis and recruit bone marrow mesenchymal stem cells (BMMSCs). Meanwhile, poly (lactic‐co‐glycolic acid) (PLGA) microspheres containing kartogenin (KGN) (PLGAKGN) are encapsulated within the hydrogel for inducing the chondrogenic differentiation of recruited BMMSCs when KGN is released after the LPS/BG‐exo. Thus, the obtained macro‐porous SA/HAexo‐PLGAKGN hydrogel can not only significantly improve the infiltration of tissues into the hydrogel but also sequentially deliver LPS/BG‐exo and KGN to enhance the cartilage regeneration in a rat cartilage defect model. Prospectively speaking, the SA/HAexo‐PLGAKGN hydrogel is a potential candidate for other tissue regeneration as the bioactive substances can be adjusted according to different purposes. [ABSTRACT FROM AUTHOR]

The pathogenesis of steroid‐induced osteonecrosis of the femoral head (SONFH) involves a glucocorticoid‐induced imbalance of osteogenic and adipogenic differentiation, and apoptosis of bone marrow mesenchymal stem cells (BMSCs). An increasing number of genes, especially noncoding RNAs, have been implicated in the function of BMSCs. Our previous studies have confirmed the key role of LINC00473 and miR‐23a‐3p on the osteogenic, adipogenic differentiation, and apoptosis of BMSCs. However, the underlying mechanism of this process is still unclear. Based on bioinformatics analysis, here we investigated the effects of LINC00473 on the LRP5/Wnt/β‐catenin signaling pathway in the osteogenesis and adipogenesis of BMSCs, as well as the PEBP1/Akt/Bad/Bcl‐2 signaling pathway in dexamethasone‐ (Dex‐) induced apoptosis of BMSCs. Our data showed that LINC00473 could promote osteogenesis and suppress the adipogenesis of BMSCs through the activation of the miR‐23a‐3p/LRP5/Wnt/β‐catenin signaling pathway axis, while rescuing BMSCs from Dex‐induced apoptosis by activating the miR‐23a‐3p/PEBP1/Akt/Bad/Bcl‐2 signaling pathway axis. Notably, we observed that LINC00473 interacted with miR‐23a‐3p in an Argonaute 2 (AGO2)‐dependent manner based on dual‐luciferase reporter assay, AGO2‐related RNA immunoprecipitation, and RNA antisense purification assay. Furthermore, injectable thermosensitive polylactic‐co‐glycolic acid (PLGA) hydrogel loaded with rat‐derived BMSCs (rBMSCs) modified by LINC00473 were used for the treatment of SONFH in a rat model. Our results demonstrated that PLGA hydrogels provided a suitable environment for harboring rBMSCs. Besides, transplantation of PLGA hydrogels loaded with rBMSCs modified by LINC00473 could significantly promote the bone repair and reconstruction of the necrotic area at the femoral head in our SONFH rat model. Surprisingly, compared with the transplantation of BMSCs alone, the transplanted rBMSCs encapsulated within the PLGA hydrogel could migrate from the medullary cavity to the femoral head. In summary, LINC00473 promoted osteogenesis, inhibited adipogenesis, and antagonized Dex‐induced apoptosis of BMSCs. Therefore, LINC00473 could provide a new strategy for the treatment of SONFH. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) show great therapeutic potential for osteoarthritis (OA). However, their low bioavailability through intraarticular injection inhibits the process of clinical application. In the present study, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed as an intraarticular delivery platform for MSC-sEVs. Our results showed that the DAHP hydrogel could be prepared easily and that its gelation properties were suitable for intraarticular administration. In vitro studies demonstrated that the DAHP hydrogel could achieve sustained release of MSC-sEVs mainly by degradation control and preserve the therapeutic functions of sEVs. An in vivo experiment revealed that the DAHP hydrogel could enhance the efficacy of MSC-sEVs for OA improvement. This study provides a suitable delivery platform for MSC-sEVs-based OA therapy. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) have shown a high potential as a cell-free therapeutic factor for treating osteoarthritis (OA). The sustained release of these MSC-sEVs in the joint space is essential for their clinical application. Herein, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed for intraarticular release of MSC-sEVs. The properties of the DAHP hydrogel, namely gelation features, cytocompatibility, sustained release, and functional maintenance of MSC-sEVs, make it suitable for intraarticular injection and delivery of sEVs. The efficacy of MSC-sEVs was enhanced by the intraarticularly injected DAHP hydrogel. Our present study provides a promising sustained delivery platform for MSC-sEVs for treating OA. [Display omitted] [ABSTRACT FROM AUTHOR]

A simple, multiple‐hydrogen‐bond approach to fabricating physically crosslinked, Amylopectin reinforced polyacrylamide/poly(vinyl alcohol) (Amy/PAAm/PVA) double‐network (DN) hydrogels with super toughness in bulk and at solid interfaces is reported. The Amy/PAAm/PVA DN hydrogels exhibit high tensile strength (854.1 kPa), high extensibility (≈eight times), high bulk toughness (4094.8 kJ m−3), good self‐recovery property (≈92% of self‐recovery at room temperature), and strong adhesion to nonporous glass surfaces (≈158 kPa). Such tough and adhesive DN hydrogels have great potential for various applications in engineering artificial soft tissues, flexible electronics, and wearable devices. [ABSTRACT FROM AUTHOR]

Stretchable conductive hydrogels with high strain sensitivity have become hot topics in the area of wearable flexible devices. However, practical applications are limited by their weak mechanical properties and high-water content, especially under low temperature conditions. Deep eutectic solvents (DESs) are known as green solvents owing to the great conductivity, stability and biocompatibility. Although some functional gels have been designed assisted by DES, it has remained a significant challenge to construct composite gels containing DES with various properties. Here, we designed self-healing, stretchable and conductive composite hydrogels based on sodium phytate and DES (acrylic acid/choline chloride). The mechanical, self-healing, conductivity properties and transparency of the resulting gels could be adjusted by the content of sodium phytate. A simple device for information encryption display was built by using the transparency change of the gels. Moreover, flexible strain sensor based on gels could detect human movement like finger bending, facial expressions even human pulse after exercise. In addition, the strain sensor could be used at low temperatures of − 20 °C and still possess great sensitivity after self-healing. [Display omitted] • Composite hydrogels containing deep eutectic solvent and sodium phytate were prepared by radical polymerization. • The properties of composite hydrogels could be modulated by sodium phytate. • The composite hydrogels-based strain sensors can monitor both large motions and subtle physiological activities. • The gels-based strain sensors still have high sensitivity after self-healing and could be used at low temperature. [ABSTRACT FROM AUTHOR]

[Display omitted] Chitosan-based injectable hydrogels were designed and fabricated through the dynamic crosslinking of dual-reversible covalent bonds (imine and phenylboronate ester) for precise insulin release. The hydrogels contain dual glucose-sensors/responsive elements, featuring high sensitivity and rapid responsiveness to glucose level variation in cumulative and half-hourly pulsed insulin release. The hydrogels demonstrated improved cytocompatibility against HSF cells and histological long-term analysis of tissue after implantation. Evaluation of the glycemic control ability in STZ-induced hyperglycemic mice revealed that the hydrogel system showed excellent glycemic control ability in the glucose tolerance test and maintained blood glucose levels in a normal range for up to 11 days after a single administration. Thus, the hydrogel system showed applicable potential in insulin replacement therapy for diabetes mellitus. [ABSTRACT FROM AUTHOR]

In glaucoma, astrocytes within the optic nerve head (ONH) rearrange their actin cytoskeleton, while becoming reactive and upregulating intermediate filament glial fibrillary acidic protein (GFAP). Increased transforming growth factor beta 2 (TGF β2) levels have been implicated in glaucomatous ONH dysfunction. A key limitation of using conventional 2D culture to study ONH astrocyte behavior is the inability to faithfully replicate the in vivo ONH microenvironment. Here, we engineer a 3D ONH astrocyte hydrogel to better mimic in vivo mouse ONH astrocyte (MONHA) morphology, and test induction of MONHA reactivity using TGF β2. Primary MONHAs were isolated from C57BL/6J mice and cell purity confirmed. To engineer 3D cell-laden hydrogels, MONHAs were mixed with photoactive extracellular matrix components (collagen type I, hyaluronic acid) and crosslinked for 5 minutes using a photoinitiator (0.025% riboflavin) and UV light (405-500 nm, 10.3 mW/cm2). MONHA-encapsulated hydrogels were cultured for 3 weeks, and then treated with TGF β2 (2.5, 5.0 or 10 ng/ml) for 7 days to assess for reactivity. Following encapsulation, MONHAs retained high cell viability in hydrogels and continued to proliferate over 4 weeks as determined by live/dead staining and MTS assays. Sholl analysis demonstrated that MONHAs within hydrogels developed increasing process complexity with increasing process length over time. Cell processes connected with neighboring cells, coinciding with Connexin43 expression within astrocytic processes. Treatment with TGF β2 induced reactivity in MONHA-encapsulated hydrogels as determined by altered F-actin cytoskeletal morphology, increased GFAP expression, and elevated fibronectin and collagen IV deposition. Our data sets the stage for future use of this 3D biomimetic ONH astrocyte-encapsulated hydrogel to investigate astrocyte behavior in response to injury. • Optic nerve head astrocytes (ONHA) retain viability and proliferate in photo-crosslinked biopolymer hydrogels. • The hydrogel system allows for astrocytes to achieve stellate morphology and develop process complexity. • TGFB2 induces astrogliosis in ONHA-hydrogels consistent with 2D models. • This novel 3D biomimetic hydrogel system can be used to further investigate ONHA behavior under glaucomatous insult. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel strategy for preparing bioactive and self-healable macroporous hydrogel was proposed. • The macroporous hydrogel was proved to be conductive for cell/vessel infiltration and hydrogel-tissue integration. • The macroporous hydrogel was proved to improve the survival rate of HUVECs or MAECs when used as a cell delivery system. • The macroporous hydrogel could accelerate wound healing by promoting vascularization and collagen deposition. Macroporous hydrogels have been attracting increasingly attention in cell delivery and tissue regeneration. Assembling microgels is an effective method for preparing macroporous hydrogels. However, current methods are limited to specific requirements to devices and hydrogel inherent properties. In addition, most of macroporous hydrogels lack self-healing abilities due to the permanent covalent crosslink of microgels. In this study, we proposed an effective strategy for preparing a bioactive macroporous self-healable hydrogel by producing microgels through squeezing methacrylated hyaluronic acid (MeHA) and 3-aminophenylboronic acid modified sodium alginate (SABA) nanoporous hydrogels through steel meshes and assembling the MeHA-SABA microgels under alkaline condition created by bioglass (BG) ionic products. Results demonstrated that the obtained macroporous hydrogels have significant larger pore size than nanoporous hydrogels, which facilitated cell infiltration, viability and proliferation. Meanwhile, the macroporous hydrogels had good self-healing abilities with the formation of dynamic B-O bonds. Furthermore, with the bioactivity of BG, the hydrogels could induce cell migration and ingrowth of cells and blood vessels. Thus, bioactivity and macroporous structure of the hydrogels can work synergistically to stimulate tissue regeneration. Taken together, this strategy is effective, simple and can be widely applied in fabricating binary components self-healable macroporous hydrogels as long as the two components are crosslinkable, indicating a great application potential in fabricating macroporous hydrogels for cell delivery and tissue regeneration. [ABSTRACT FROM AUTHOR]

Hydrogels that possess adequate toughness in bulk and at soft interface are highly desirable. We report a fully physically crosslinked dual Amylopectin (Amy, the first network)/poly(N-hydroxyethyl acrylamide) (PHEAA, the second network) hydrogel, where both networks were hydrogen bonding (H-bonding) crosslinked, with super toughness in bulk and tunable adhesion at hydrogel-soft tissue interface. Through adjustment of hydrogen bond density, strong and tough hydrogels were prepared that exhibited different levels of adhesion strength and three adhesive failure mechanisms. We replaced Amy with oxidized starch (OSA) to synthesize dual and hybrid chemically/physically crosslinked OSA/PHEAA double network (DN) hydrogels that were capable of forming Schiff's bases at hydrogel-hydrogel or hydrogel-tissue interfaces, aside from interfacial H-bonding, incurring sustained, high interfacial toughness (1850 J m−2 hydrogel-hydrogel and 610 J m−2 hydrogel-tissue) in wet environments. Such tough and adhesive DN hydrogels have great potential in various applications such as engineering of artificial soft tissues or implantable devices that are intended to adhere to internal organs or tissues. • Fully physically crosslinked hydrogels via H-bonding. • Tunable adhesion and three adhesive failure mechanisms of hydrogels. • The sacrificial bonds including H-bonds and reversible Schiff's bases at the interface. • High interfacial toughness at hydrogel-hydrogel or hydrogel-tissue interfaces in wet environments. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a common and serious manifestation after myocardial infarction (MI). Despite their clinical importance, current treatments for MI still have several limitations. Revascularization has been proven to have positive effects on MI-induced damage. Currently biomaterial-based angiogenesis strategies represent potential candidates for MI treatment. Bioglass (BG) is a commercially available family of bioactive glasses. BG has angiogenic properties and thus might be an attractive alternative for MI treatments. Here, we loaded BG in sodium alginate (BG SA), locally injected it into peri-infarct myocardial tissue and examined its suitability for inducing cardiac angiogenesis and eventually improving cardiac function following MI. Cardiac function was evaluated via echocardiography. Infarct morphometry, angiogenesis, apoptosis and angiogenic protein expression were all analysed 4 weeks after BG SA injection. Compared with the control treatment, BG SA was sufficient to prompt angiogenesis, suppress apoptosis, up-regulate the expression of angiogenic proteins, attenuate infarct size, preserve wall thickness and eventually improve cardiac function. Our results demonstrate the feasibility and effectiveness of BG SA in myocardial regeneration via angiogenesis, suggesting that BG SA is a potential therapeutic strategy for post-infarct myocardial regeneration. [ABSTRACT FROM AUTHOR]