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The natural extracellular matrix, with its heterogeneous structure, provides a stable and dynamic biophysical framework and biochemical signals to guide cellular behaviors. It is challenging but highly desirable to develop a synthetic matrix that emulates the heterogeneous fibrous structure with macroscopic stability and microscopical dynamics and contains inductive biochemical signals. Herein, we introduce a peptide fiber-reinforced hydrogel in which the stiff ß-sheet fiber functions as a multivalent cross-linker to enhance the hydrogel's macroscopic stability. The dynamic imine cross-link between the peptide fiber and polymer network endows the hydrogel with a microscopically dynamic network. The obtained fibrillar nanocomposite hydrogel, with its cell-adaptable dynamic network, enhances cell-matrix and cell-cell interactions and therefore significantly promotes the mechanotransduction, metabolic energetics, and osteogenesis of encapsulated stem cells. Furthermore, the hydrogel can codeliver a fiber-attached inductive drug to further enhance osteogenesis and bone regeneration. We believe that our work provides valuable guidance for the design of cell-adaptive and bioactive biomaterials for therapeutic applications.
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Hidrogeles , Mecanotransducción Celular , Hidrogeles/química , Biomimética , Regeneración Ósea , Péptidos/química , OsteogénesisRESUMEN
BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.
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Lesión Pulmonar Aguda , Fibrosis Pulmonar , Lesión Pulmonar Aguda/tratamiento farmacológico , Alginatos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/química , Inflamación , Nanogeles , Tamaño de la Partícula , Quercetina/farmacología , Quercetina/uso terapéutico , RatasRESUMEN
The dynamic conformational changes in the secondary structures of proteins are essential to their functions and can regulate diverse cellular events. Herein we report the design of a synthetic polymer-based secondary structure analogue of a zinc finger (ZnF) by introducing a zinc coordination motif to overcome the free energy barrier predicted by theoretical calculations and fold-free polymer chains. The conformational switching between unfolded and folded state of the ZnF analogue can be triggered in situ to drastically manipulate the accessibility of conjugated cell adhesive ligands to the cell membrane receptors, thereby effectively controlling the adhesion, spreading, mechanosensing, and differentiation of stem cells. We believe that emulating the dynamic secondary structures of proteins via rational design of a folded synthetic polymer-cation complex is a promising strategy for developing bioactive materials to mediate desired cellular functions.
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Células Madre , Dedos de Zinc , Diferenciación Celular , Ligandos , PolímerosRESUMEN
Hydrogels are emerging biomaterials with desirable physicochemical characteristics. Doping of metal ions such as Ca2+ , Mg2+ , and Fe2+ provides the hydrogels with unique attributes, including bioactivity, conductivity, and tunability. Traditionally, this doping is achieved by the interaction between metal ions and corresponding ligands or the direct incorporation of as-prepared metal-based nanoparticles (NPs). However, these approaches rely on a complex and laborious preparation and are typically restricted to few selected ion species. Herein, by mixing aqueous solutions of ligands (bisphosphonates, BPs), polymer grafted with ligands, and metal ions, a series of self-assembled metallic-ion nanocomposite hydrogels that are stabilized by the in situ formed ligand-metal ion (BP-M) NPs are prepared. Owing to the universal coordination between BPs and multivalent metal ions, the strategy is highly versatile and can be generalized for a wide array of metal ions. Such hydrogels exhibit a wide spectrum of mechanical properties and remarkable dynamic properties, such as excellent injectability, rapid stress relaxation, efficient ion diffusion, and triggered disassembly for harvesting encapsulated cells. Meanwhile, the hydrogels can be conveniently coated or patterned onto the surface of metals via electrophoresis. This work presents a universal strategy to prepare designer nanocomposite materials with highly tunable and dynamic behaviors.
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Osteoporotic bone defects pose a significant challenge for bone regeneration as they exhibit impaired healing capacity and delayed healing period. To address this issue, this study introduces a hydrogel that creates a rejuvenating microenvironment, thereby facilitating efficient bone repair during the initial two weeks following bone defect surgery. The hydrogel, named GelHFS, was created through host-guest polymerization of gelatin and acrylated ß-cyclodextrin. Incorporation of the human fetal mesenchymal stem cell secretome (HFS) formed GelHFS hydrogel aimed at mimicking a rejuvenated stem cell niche. Our results demonstrated that GelHFS hydrogel promotes cell stellate spreading and osteogenic differentiation via integrin ß1-induced focal adhesion pathway. Implantation of GelHFS hydrogel in an osteoporotic bone defect rat model recruited endogenous integrin ß1-expressing cells and enhanced new bone formation and bone strength. Our findings reveal that GelHFS hydrogel provides a rejuvenating niche for endogenous MSCs and enhances bone regeneration in osteoporotic bone defect. These findings highlight the potential of GelHFS hydrogel as an effective therapeutic strategy for addressing challenging bone healing such as osteoporotic bone regeneration.
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Effective and easy regulation of hydrogel surface properties without changing the overall chemical composition is important for their diverse applications but remains challenging to achieve. We report a generalizable strategy to reconfigure hydrogel surface networks based on hydrogel-substrate interface dynamics for manipulation of hydrogel surface wettability and bioadhesion. We show that the grafting of hydrophobic yet flexible polymeric chains on mold substrates can significantly elevate the content of hydrophobic polymer backbones and reduce the presence of polar groups in hydrogel surface networks, thereby transforming the otherwise hydrophilic hydrogel surface into a hydrophobic surface. Experimental results show that the grafted highly dynamic hydrophobic chains achieved with optimal grafting density, chain length, and chain structure are critical for such substantial hydrogel surface network reconfiguration. Molecular dynamics simulations further reveal the atomistic details of the hydrogel network reconfiguration induced by the dynamic interface interactions. The hydrogels prepared using our strategy show substantially enhanced bioadhesion and transdermal delivery compared with the hydrogels of the same chemical composition but fabricated via the conventional method. Our findings provide important insights into the dynamic hydrogel-substrate interactions and are instrumental to the preparation of hydrogels with custom surface properties.
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Cellular energetics plays an important role in tissue regeneration, and the enhanced metabolic activity of delivered stem cells can accelerate tissue repair and regeneration. However, conventional hydrogels with limited network cell adaptability restrict cell-cell interactions and cell metabolic activities. In this work, it is shown that a cell-adaptable hydrogel with high network dynamics enhances the glucose uptake and fatty acid ß-oxidation of encapsulated human mesenchymal stem cells (hMSCs) compared with a hydrogel with low network dynamics. It is further shown that the hMSCs encapsulated in the high dynamic hydrogels exhibit increased tricarboxylic acid (TCA) cycle activity, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) biosynthesis via an E-cadherin- and AMP-activated protein kinase (AMPK)-dependent mechanism. The in vivo evaluation further showed that the delivery of MSCs by the dynamic hydrogel enhanced in situ bone regeneration in an animal model. It is believed that the findings provide critical insights into the impact of stem cell-biomaterial interactions on cellular metabolic energetics and the underlying mechanisms.
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Hidrogeles , Cicatrización de Heridas , Animales , Humanos , Regeneración Ósea , Comunicación Celular , Proliferación Celular , Diferenciación CelularRESUMEN
Coacervation driven liquid-liquid phase separation of biopolymers has aroused considerable attention for diverse applications, especially for the construction of microstructured polymeric materials. Herein, a coacervate-to-hydrogel transition strategy is developed to create macroporous hydrogels (MPH), which are formed via the coacervation process of supramolecular assemblies (SA) built by the host-guest complexation between γ-cyclodextrin and anthracene dimer. The weak and reversible supramolecular crosslinks endow the SA with liquid-like rheological properties, which facilitate the formation of SA-derived macroporous coacervates and the subsequent transition to MPH (pore size ≈ 100 µm). The excellent structural dynamics (derived from SA) and the cytocompatible void-forming process of MPH can better accommodate the dramatic volumetric expansion associated with colony growth of encapsulated multicellular spheroids compared with the non-porous static hydrogel with similar initial mechanical properties. The findings of this work not only provide valuable guidance to the design of biomaterials with self-evolving structures but also present a promising strategy for 3D multicellular spheroid culture and other diverse biomedical applications.
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Hidrogeles , Esferoides Celulares , Hidrogeles/química , Polímeros/química , Materiales BiocompatiblesRESUMEN
BACKGROUND: There is great interest to engineer in vitro models that allow the study of complex biological processes of the microvasculature with high spatiotemporal resolution. Microfluidic systems are currently used to engineer microvasculature in vitro, which consists of perfusable microvascular networks (MVNs). These are formed through spontaneous vasculogenesis and exhibit the closest resemblance to physiological microvasculature. Unfortunately, under standard culture conditions and in the absence of co-culture with auxiliary cells as well as protease inhibitors, pure MVNs suffer from a short-lived stability. METHODS: Herein, we introduce a strategy for stabilization of MVNs through macromolecular crowding (MMC) based on a previously established mixture of Ficoll macromolecules. The biophysical principle of MMC is based on macromolecules occupying space, thus increasing the effective concentration of other components and thereby accelerating various biological processes, such as extracellular matrix deposition. We thus hypothesized that MMC will promote the accumulation of vascular ECM (basement membrane) components and lead to a stabilization of MVN with improved functionality. RESULTS: MMC promoted the enrichment of cellular junctions and basement membrane components, while reducing cellular contractility. The resulting advantageous balance of adhesive forces over cellular tension resulted in a significant stabilization of MVNs over time, as well as improved vascular barrier function, closely resembling that of in vivo microvasculature. CONCLUSION: Application of MMC to MVNs in microfluidic devices provides a reliable, flexible and versatile approach to stabilize engineered microvessels under simulated physiological conditions.
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Lacking self-repair abilities, injuries to articular cartilage can lead to cartilage degeneration and ultimately result in osteoarthritis. Tissue engineering based on functional bioactive scaffolds are emerging as promising approaches for articular cartilage regeneration and repair. Although the use of cell-laden scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Acellular approaches through the recruitment of endogenous cells offer great promise for in situ articular cartilage regeneration. In this study, we propose an endogenous stem cell recruitment strategy for cartilage repair. Based on an injectable, adhesive and self-healable o-alg-THAM/gel hydrogel system as scaffolds and a biophysio-enhanced bioactive microspheres engineered based on hBMSCs secretion during chondrogenic differentiation as bioactive supplement, the as proposed functional material effectively and specifically recruit endogenous stem cells for cartilage repair, providing new insights into in situ articular cartilage regeneration.
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Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor-targeting and enzyme-activatable cell-material interface system based on DDDEEK-pY-phenylboronic acid (SAP-pY-PBA) conjugates. Using this tandem-activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP-pY-PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme-responsive biointerface combining supramolecular hydrogels with biomineralization.
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Neoplasias Óseas , Osteosarcoma , Niño , Humanos , Adolescente , Biomineralización , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Hidrogeles/farmacología , Neoplasias Óseas/tratamiento farmacológico , BiomarcadoresRESUMEN
Long-term maintenance of embryonic stem cells (ESCs) in the undifferentiated state is still challenging. Compared with traditional 2D culture methods, 3D culture in biomaterials such as hydrogels is expected to better support the long-term self-renewal of ESCs by emulating the biophysical and biochemical properties of the extracellular matrix (ECM). Although prior studies showed that soft and degradable hydrogels favor the 3D growth of ESCs, few studies have examined the impact of the structural dynamics of the hydrogel matrix on ESC behaviors. Herein, we report a gelatin-based structurally dynamic hydrogel (GelCD hydrogel) that emulates the intrinsic structural dynamics of the ECM. Compared with covalently crosslinked gelatin hydrogels (GelMA hydrogels) with similar stiffness and biodegradability, GelCD hydrogels significantly promote the clonal expansion and viability of encapsulated mouse ESCs (mESCs) independent of MMP-mediated hydrogel degradation. Furthermore, GelCD hydrogels better maintain the pluripotency of encapsulated mESCs than do traditional 2D culture methods that use MEF feeder cells or medium supplementation with GSK3ß and MEK 1/2 inhibitors (2i). When cultured in GelCD hydrogels for an extended period (over 2 months) with cell passaging every 7 days, mESCs preserve their normal morphology and maintain their pluripotency and full differentiation capability. Our findings highlight the critical role of the structural dynamics of the hydrogel matrix in accommodating the volume expansion that occurs during clonal ESC growth, and we believe that our dynamic hydrogels represent a valuable tool to support the long-term 3D culture of ESCs.
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Gelatina , Hidrogeles , Animales , Materiales Biocompatibles , Diferenciación Celular , Proliferación Celular , Células Madre Embrionarias , Gelatina/química , Glucógeno Sintasa Quinasa 3 beta , Hidrogeles/química , Ratones , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
The development from stem cells to adult tissues requires the delicate presentation of numerous crucial inductive cues and the activation of associated signaling pathways. The Notch signaling pathways triggered by ligands such as Jagged-1 have been demonstrated to be essential in various development processes especially in osteogenesis and ossification. However, few studies have capitalized on the osteoinductivity of the Jagged-1 mimetic ligands to enhance the osteogenesis and skeleton regeneration. In this study, we conjugate the porous hyaluronic acid hydrogels with a Jagged-1 mimetic peptide ligand (Jagged-1) and investigate the efficacy of such biomimetic functionalization to promote the mechanotransduction and osteogenesis of human mesenchymal stem cells by activating the Notch signaling pathway. Our findings indicate that the immobilized Jagged-1 mimetic ligand activates Notch signaling via the upregulation of NICD and downstream MSX2, leading to the enhanced mechanotransduction and osteogenesis of stem cells. We further demonstrate that the functionalization of the Jagged-1 ligand in the porous scaffold promotes angiogenesis, regulates macrophage recruitment and polarization, and enhances in situ regeneration of rat calvarial defects. Our findings provide valuable guidance to the design of development-inspired bioactive biomaterials for diverse biomedical applications.
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Materiales Biocompatibles , Receptores Notch , Humanos , Ratas , Animales , Proteína Jagged-1/metabolismo , Materiales Biocompatibles/farmacología , Receptores Notch/metabolismo , Ligandos , Mecanotransducción Celular , Biomimética , Regeneración Ósea , Transducción de SeñalRESUMEN
The presentation of development-relevant bioactive cues by biomaterial scaffolds is essential to the guided differentiation of seeded human mesenchymal stem cells (hMSCs) and subsequent tissue regeneration. Wnt5a is a critical non-canonical Wnt signaling ligand and plays a key role in the development of musculoskeletal tissues including cartilage. Herein we investigate the efficacy of biofunctionalizing the hyaluronic acid hydrogel with a synthetic Wnt5a mimetic ligand (Foxy5 peptide) to promote the chondrogenesis of hMSCs and the potential underlying molecular mechanism. Our findings show that the conjugation of Foxy5 peptide in the hydrogels activates non-canonical Wnt signaling of encapsulated hMSCs via the upregulation expression of PLCE1, CaMKII-ß, and downstream NFATc1, leading to enhanced expression of chondrogenic markers such as SOX9. The decoration of Foxy5 peptide also promotes the metabolic activities of encapsulated hMSCs as evidenced by upregulated gene expression of mitochondrial complex components and glucose metabolism biomarkers, leading to enhanced ATP biosynthesis. Furthermore, the conjugation of Foxy5 peptide activates the non-canonical Wnt, PI3K-PDK-AKT and IKK/NF-κB signaling pathways, thereby inhibiting the hypertrophy of the chondrogenically induced hMSCs in the hydrogels under both in vitro and in vivo conditions. This enhanced chondrogenesis and attenuated hypertrophy of hMSCs by the biomaterial-mediated bioactive cue presentation facilitates the potential clinical translation of hMSCs for cartilage regeneration. Our work provides valuable guidance to the rational design of bio-inductive scaffolds for various applications in regenerative medicine.
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Condrogénesis , Células Madre Mesenquimatosas , Materiales Biocompatibles/metabolismo , Diferenciación Celular , Células Cultivadas , Humanos , Hidrogeles/química , Hipertrofia/metabolismo , Ligandos , Péptidos/química , Células Madre/metabolismo , Vía de Señalización Wnt , Proteína Wnt-5a/metabolismoRESUMEN
Osteoarthritis (OA) is a degenerative disease associated with joint inflammation, articular cartilage degeneration and subchondral hypertrophy. Small molecules which both ameliorate chondrocyte OA phenotype and activate bone marrow-derived mesenchymal stem cells (BMSCs) chondrogenesis under inflammatory conditions have the therapeutical potential for OA treatment. In this study, we characterized a novel small molecule which could ameliorate OA progression via novel regulating mechanisms. Docosahexaenoic acid (DHA), a bioactive molecule, was screened from a small molecule library and showed anti-inflammatory and chondroprotective effects in OA chondrocytes, as well as ameliorated IL-1ß impaired BMSCs chondrogenesis in Wnt/ß-catenin and NF-κB signaling dependent manners. Furthermore, Malat1 was found to be the key mediator of DHA-mediating anti-inflammation chondroprotection and chondrogenesis. DHA also rescued cartilage loss and damage in a surgery-induced OA mice model. The elevation of serum Malat1 levels caused by OA was also downregulated by DHA treatment. Taken together, our findings demonstrated that DHA, with a dual-signaling repression property, exerted its anti-inflammation, chondroprotection and chondrogenesis function possibly via regulating Malat1 level, suggesting that it may be a possible drug candidate for OA patients with elevated MALAT1 expression levels.
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Cartílago Articular , Osteoartritis , ARN Largo no Codificante , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Cartílago Articular/metabolismo , Células Cultivadas , Condrocitos/metabolismo , Condrogénesis , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Ratones , Osteoartritis/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
The intricate dynamic feedback mechanisms involved in bone homeostasis provide valuable inspiration for the design of smart biomaterial scaffolds to enhance in situ bone regeneration. In this work, we assembled a biomimetic hyaluronic acid nanocomposite hydrogel (HA-BP hydrogel) by coordination bonds with bisphosphonates (BPs), which are antiosteoclastic drugs. The HA-BP hydrogel exhibited expedited release of the loaded BP in response to an acidic environment. Our in vitro studies showed that the HA-BP hydrogel inhibits mature osteoclastic differentiation of macrophage-like RAW264.7 cells via the released BP. Furthermore, the HA-BP hydrogel can support the initial differentiation of primary macrophages to preosteoclasts, which are considered essential during bone regeneration, whereas further differentiation to mature osteoclasts is effectively inhibited by the HA-BP hydrogel via the released BP. The in vivo evaluation showed that the HA-BP hydrogel can enhance the in situ regeneration of bone. Our work demonstrates a promising strategy to design biomimetic biomaterial scaffolds capable of regulating bone homeostasis to promote bone regeneration.
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To meet the rising demand of injectable hydrogels with self-healing, robustness and biocompatibility for biomedical engineering, the reversible ketoester-type acylhydrazone linkages was used for the fabrication of novel cellulose-based hydrogel. The ketoester-type acylhydrazone bond exchanged rapidly, endowing the hydrogels with highly efficient self-healing performance without any external stimuli under physiological environment, which was hardly achieved with the widely used arylhydrozone bond. The dynamic hydrogels exhibited tunable mechanical property, pH responsiveness, injectability and biocompatibility, demonstrating immense applications prospect for various biomedicines, such as drug and cell delivery. The pH-responsive controlled release of model drug doxorubicin (DOX) loaded in the hydrogel was demonstrated. In addition, benefitting from the excellent biocompatibility and the reversible ketoester-type acylhydrazone bonds, cells were encapsulated in the hydrogels as 3D carrier. The covalent adaptable network intensified injectability of cell-laden hydrogels and improved the long-lasting viability for cell culture, showing great potential in the biomedical field.
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Celulosa/química , Sistemas de Liberación de Medicamentos/métodos , Hidrazonas/química , Hidrogeles/administración & dosificación , Hidrogeles/química , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Técnicas de Cultivo de Célula , Técnicas de Cultivo Tridimensional de Células/métodos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Inyecciones/métodos , RatonesRESUMEN
Dynamic hydrogels cross-linked by weak and reversible physical interactions enhance the 3-dimensional (3D) spreading and mechanosensing abilities of encapsulated cells in a matrix. However, the highly dynamic nature of these physical cross-links also results in low mechanical stiffness in the hydrogel network and high tether compliance of the cell adhesion motifs attached to the network. The resulting low force feedback of the soft hydrogel network impedes the efficient activation of mechanotransduction signalling in the encapsulated cells. Herein, we demonstrate that the chemical incorporation of acryloyl nanoparticle-based cross-linkers creates regionally stiff network structures in the dynamic supramolecular hydrogels without compromising the dynamic properties of the cell-adaptable inter-nanoparticle hydrogel network. The obtained dynamic hydrogels with a heterogeneous hydrogel network topology expedite the development of adhesion structures, 3D spreading, and mechanosensing of the encapsulated stem cells, as evidenced by the upregulated expression of key biomarkers such as vinculin, FAK, and YAP. This enhanced spreading and mechanotransduction promotes the osteogenic differentiation of the encapsulated stem cells. In contrast, doping with physically entrapped nanoparticles or molecular cross-linkers (PEGDA) cannot locally reinforce the dynamic hydrogel network and therefore fails to facilitate cell mechanosensing or differentiation in the 3D hydrogels. We further show that the dynamic hydrogels with a locally stiffened network promote the in situ regeneration of bone defects in an animal model. Our findings provide valuable insights into the design of the supramolecular dynamic hydrogels with biomimetic hierarchical biomechanical structures as the optimized carrier material for stem cell-based therapies.
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Hidrogeles , Osteogénesis , Animales , Regeneración Ósea , Mecanotransducción Celular , Células MadreRESUMEN
Achieving strong adhesion of bioadhesives on wet tissues remains a challenge and an acute clinical demand because of the interfering interfacial water and limited adhesive-tissue interactions. Here we report a self-gelling and adhesive polyethyleneimine and polyacrylic acid (PEI/PAA) powder, which can absorb interfacial water to form a physically cross-linked hydrogel in situ within 2 seconds due to strong physical interactions between the polymers. Furthermore, the physically cross-linked polymers can diffuse into the substrate polymeric network to enhance wet adhesion. Superficial deposition of PEI/PAA powder can effectively seal damaged porcine stomach and intestine despite excessive mechanical challenges and tissue surface irregularities. We further demonstrate PEI/PAA powder as an effective sealant to enhance the treatment outcomes of gastric perforation in a rat model. The strong wet adhesion, excellent cytocompatibility, adaptability to fit complex sites, and easy synthesis of PEI/PAA powder make it a promising bioadhesive for numerous biomedical applications.
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Membraneless coacervate compartments in the intracellular and pericellular space mediate critical cellular functions. Developing synthetic coacervates that emulate the morphological, physical, and functional complexity of these natural coacervates is challenging but highly desirable. Herein, a generalizable nanoparticle assembly (NPA) strategy is developed, which is applicable to interactive core-shell nanoparticles with different chemical makeups, to fabricate vacuolated coacervates. The obtained NPA coacervates contain stable internal vacuoles to provide segregated microcompartments, which can mediate the spatially heterogeneous distribution of diverse macromolecules via restricted diffusion. It is further shown that the vacuolated NPA coacervates can harbor and retain macromolecular medium supplements to regulate the functions of cells encapsulated in vacuoles. Furthermore, the restricted macromolecule diffusion can be abolished on demand via the triggered coacervate-hydrogel transition, thereby altering the exposure of encapsulated cells to environmental factors. It is believed that the NPA strategy provides new insights into the design principles of hierarchical coacervates that hold promising potential for a wide array of biomedical applications.