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Fully restoring the lost population of cardiomyocytes and heart function remains the greatest challenge in cardiac repair post myocardial infarction. In this study, a pioneered highly ROS-eliminating hydrogel was designed to enhance miR-19a/b induced cardiomyocyte proliferation by lowering the oxidative stress and continuously releasing miR-19a/b in infarcted myocardium in situ. In vivo lineage tracing revealed that â¼20.47 % of adult cardiomyocytes at the injected sites underwent cell division in MI mice. In MI pig the infarcted size was significantly reduced from 40 % to 18 %, and thereby marked improvement of cardiac function and increased muscle mass. Most importantly, our treatment solved the challenge of animal death--all the treated pigs managed to live until their hearts were harvested at day 50. Therefore, our strategy provides clinical conversion advantages and safety for healing damaged hearts and restoring heart function post MI, which will be a powerful tool to battle cardiovascular diseases in patients.
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Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.
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Together, tumor and virus-specific tissue-resident CD8+ memory T cells (TRMs) of hepatocellular carcinoma (HCC) patients with Hepatitis B virus (HBV) infection can provide rapid frontline immune surveillance. The quantity and activity of CD8+ TRMs were correlated with the relapse-free survival of patients with improved health. However, HBV-specific CD8+ TRMs have a more exhausted phenotype and respond more actively under anti-PDL1 or PD1 treatment of HBV+HCC patients. Vaccination strategies that induce a strong and sustained CD8+ TRMs response are quite promising. Herein, a biodegradable poly(D,L-lactide-co-glycolide) microsphere and nanosphere particle (PLGA N.M.P) delivery system co-assembled by anti-PD1 antibodies (aPD1) and loaded with ovalbumin (OVA-aPD1 N.M.P) was fabricated and characterized for size (200 nm and 1 µm diameter), charge (-15 mV), and loading efficiencies of OVA (238 µg mg-1 particles) and aPD1 (40 µg mg-1 particles). OVA-aPD1 N.M.P could stimulate the maturation of BMDCs and enhance the antigen uptake and presentation by 2-fold compared to free OVA. The nanoparticles also induced the activation of macrophages (RAW 264.7) to produce a high level of cytokines, including TNF-α, IL-6 and IL-10. In vivo stimulation of mice using OVA-aPD1 N.M.P robustly enhanced IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and the secretion of IgG and IgG2a/IgG1 antibodies. OVA-aPD1 N.M.P delivered OVA to increase the activation and proliferation of OVA-specific CD8+ TRMs, and its combination with anti-PD1 antibodies promoted complete tumor rejection by the reversal of tumor-infiltrating CD8+ T cell exhaustion. Thus, PLGA N.M.P could induce a strong CD8+ TRMs response, further highlighting its therapeutic potential in enhancing an antitumor immune response.
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Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Ratones , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Ovalbúmina/química , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/química , Células T de Memoria/inmunología , Vacunación , Humanos , Células RAW 264.7 , Memoria InmunológicaRESUMEN
Temporomandibular joint (TMJ) cartilage repair poses a considerable clinical challenge, and tissue engineering has emerged as a promising solution. In this study, we developed an injectable reactive oxygen species (ROS)-responsive multifunctional hydrogel (RDGel) to encapsulate dental pulp stem cells (DPSCs/RDGel in short) for the targeted repair of condylar cartilage defect. The DPSCs/RDGel composite exhibited a synergistic effect in the elimination of TMJ OA (osteoarthritis) inflammation via the interaction between the hydrogel component and the DPSCs. We first demonstrated the applicability and biocompatibility of RDGel. RDGel encapsulation could enhance the anti-apoptotic ability of DPSCs by inhibiting P38/P53 mitochondrial apoptotic signal in vitro. We also proved that the utilization of DPSCs/RDGel composite effectively enhanced the expression of TMJOA cartilage matrix and promoted subchondral bone structure in vivo. Subsequently, we observed the synergistic improvement of DPSCs/RDGel composite on the oxidative stress microenvironment of TMJOA and its regulation and promotion of M2 polarization, thereby confirmed that M2 macrophages further promoted the condylar cartilage repair of DPSCs. This is the first time application of DPSCs/RDGel composite for the targeted repair of TMJOA condylar cartilage defects, presenting a novel and promising avenue for cell-based therapy.
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Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective wound healing without scar formation. This study focuses on the fabrication of electrospun ROS-responsive selenium-containing polyurethane nanofibers incorporating deferoxamine mesylate (Def), indomethacin (Indo), and gold nanorods (AuNRs) as proangiogenesis, anti-inflammatory, and antibacterial agents for synchronized delivery to a full-thickness wound in vivo. The structure of the fabricated nanofibers was analyzed by various techniques. Toxicity was checked by CCK-8 and hemolytic assays. The efficiency of wound healing in vitro was verified by a transwell assay and cell scratch assay. The wound healing efficiency of the nanofibers was assayed in full-thickness wounds in a rat model. The multifunctional nanofibers had a porous structure, enhanced antioxidation, antibacterial activity, and promoted wound healing. They eradicated TNF-α and IL-6, increased IL-10 expression, and revealed the angiogenic potential by increased expression of HIF-1α, VEGF, and CD31.
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Oro , Nanofibras , Poliuretanos , Especies Reactivas de Oxígeno , Selenio , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Poliuretanos/química , Poliuretanos/farmacología , Animales , Nanofibras/química , Selenio/química , Selenio/farmacología , Especies Reactivas de Oxígeno/metabolismo , Oro/química , Oro/farmacología , Ratas , Nanotubos/química , Antibacterianos/farmacología , Antibacterianos/química , Deferoxamina/farmacología , Deferoxamina/química , Ratas Sprague-Dawley , Humanos , Indometacina/farmacología , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/químicaRESUMEN
Despite of the recent advances in regulatory T cell (Treg) therapy, a limited number of available cells and specificity at the desired tissue site have severely compromised their efficacy. Herein, an injectable drug-releasing (MTK-TK-drug) microgel system in response to in situ stimulation by reactive oxygen species (ROS) was constructed with a coaxial capillary microfluidic system and UV curing. The spherical microgels with a size of 150 µm were obtained. The MTK-TK-drug microgels efficiently converted the pro-inflammatory Th17 cells into anti-inflammatory regulatory T cells (Treg) cells in vitro, and the ROS-scavenging materials synergistically enhanced the effect by modulating the inflammation microenvironment. Thus, the microgels significantly reduced cardiomyocyte apoptosis and decreased the inflammatory response in the early stages of post-myocardial infarction (MI) in vivo, thereby reducing fibrosis, promoting vascularization, and preserving cardiac function. Overall, our results indicate that the MTK-TK-drug microgels can attenuate the inflammatory response and improve MI therapeutic effects in vivo.
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Microgeles , Infarto del Miocardio , Humanos , Especies Reactivas de Oxígeno , Infarto del Miocardio/tratamiento farmacológico , Linfocitos T Reguladores , MicrofluídicaRESUMEN
Shape-memory materials hold great potential to impart medical devices with functionalities useful during implantation, locomotion, drug delivery, and removal. However, their clinical translation is limited by a lack of non-invasive and precise methods to trigger and control the shape recovery, especially for devices implanted in deep tissues. In this study, the application of image-guided high-intensity focused ultrasound (HIFU) heating is tested. Magnetic resonance-guided HIFU triggered shape-recovery of a device made of polyurethane urea while monitoring its temperature by magnetic resonance thermometry. Deformation of the polyurethane urea in a live canine bladder (5 cm deep) is achieved with 8 seconds of ultrasound-guided HIFU with millimeter resolution energy focus. Tissue sections show no hyperthermic tissue injury. A conceptual application in ureteral stent shape-recovery reduces removal resistance. In conclusion, image-guided HIFU demonstrates deep energy penetration, safety and speed.
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Ultrasonido Enfocado de Alta Intensidad de Ablación , Poliuretanos , Animales , Perros , Calefacción , Imagen por Resonancia Magnética/métodos , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , UreaRESUMEN
Wound management is an important issue that places enormous pressure on the physical and mental health of patients, especially in cases of infection, where the increased inflammatory response could lead to severe hypertrophic scars (HSs). In this study, a hydrogel dressing was developed by combining the high strength and toughness, swelling resistance, antibacterial and antioxidant capabilities. The hydrogel matrix was composed of a double network of polyvinyl alcohol (PVA) and agarose with excellent mechanical properties. Hyperbranched polylysine (HBPL), a highly effective antibacterial cationic polymer, and tannic acid (TA), a strong antioxidant molecule, were added to the hydrogel as functional components. Examination of antibacterial and antioxidant properties of the hydrogel confirmed the full play of the efficacy of HBPL and TA. In the in vivo studies of methicillin-resistant Staphylococcus aureus (MRSA) infection, the hydrogel had shown obvious promotion of wound healing, and more profoundly, significant suppression of scar formation. Due to the common raw materials and simple preparation methods, this hydrogel can be mass produced and used for accelerating wound healing while preventing HSs in infected wounds.
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Both bacteria-infection and excessive inflammation delay the wound healing process and even create non-healing wound, thus it is highly desirable to endow the wound dressing with bactericidal and anti-oxidation properties. Herein an antibacterial and antioxidation hydrogel based on Carbomer 940 (CBM) and hydroxypropyl methyl cellulose (HPMC) loaded with tea polyphenols (TP) and hyperbranched poly-l-lysine (HBPL) was designed and fabricated. The hydrogel killed 99.9 % of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) at 107 CFU mL-1, and showed strong antioxidation against H2O2 and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH) radicals without noticeable cytotoxicity in vitro. The CBM/HPMC/HBPL/TP hydrogel significantly shortened the inflammatory period of the MRSA-infected full-thickness skin wound of rats in vivo, with 2 orders of lower MRSA colonies compared with the blank control, and promoted the wound closure especially at the earlier stage. The inflammation was suppressed and the vascularization was promoted significantly as well, resulting in reduced pro-inflammatory factors including interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), and increased anti-inflammatory factors such as interleukin-4 (IL-4) and interleukin-10 (IL-10).
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Antioxidantes , Staphylococcus aureus Resistente a Meticilina , Animales , Ratas , Antioxidantes/farmacología , Hidrogeles/farmacología , Polilisina/farmacología , Escherichia coli , Peróxido de Hidrógeno , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Derivados de la Hipromelosa , Inflamación , Interleucina-1beta , TéRESUMEN
Myocardial infarction (MI) has a characteristic inflammatory microenvironment due to the overproduction of reactive oxygen species (ROS) and causes the extraordinary deposition of collagen and thereby fibrosis. An on-demand adaptive drug releasing hydrogel is designed to modulate the inflammatory microenvironment and inhibit cardiac fibroblasts (CFs) proliferation post MI by scavenging the overproduced ROS and releasing 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) to maintain the expression of hypoxia-inducible factor 1α (HIF-1α). DPCA is prefabricated to a prodrug linked with disulfide bond (DPCA-S-S-OH). The DPCA-S-S-OH and carboxylated calixarene (CSAC4A) are grafted onto the backbone of methacrylated hyaluronic acid (HAMA) to obtain HAMA-S-S-DPCA and HAMA-CA, respectively, which are further reacted to form a dual network hydrogel (R+ /DPCA(CA)) with covalent linking and host-guest interaction between DPCA and CSAC4A. The ROS-triggered hydrolysis of ester bond and subsequently sustaining release of DPCA from the cavity of CSAC4A jointly cause the constant expression of HIF-1α, which significantly restricts the CFs proliferation, leading to suppressed fibrosis and promoted heart repair.
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Hidrogeles , Infarto del Miocardio , Humanos , Ácidos Carboxílicos , Liberación de Fármacos , Fibrosis , Ácido Hialurónico , Infarto del Miocardio/tratamiento farmacológico , Especies Reactivas de OxígenoRESUMEN
The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed.
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Bacterial infection causes lung inflammation and recruitment of several inflammatory factors that may result in acute lung injury (ALI). During bacterial infection, reactive oxygen species (ROS) and other signaling pathways are activated, which intensify inflammation and increase ALI-related mortality and morbidity. To improve the ALI therapy outcome, it is imperative clinically to manage bacterial infection and excessive inflammation simultaneously. Herein, a synergistic nanoplatform (AZI+IBF@NPs) constituted of ROS-responsive polymers (PFTU), and antibiotic (azithromycin, AZI) and anti-inflammatory drug (ibuprofen, IBF) was developed to enable an antioxidative effect, eliminate bacteria, and modulate the inflammatory milieu in ALI. The ROS-responsive NPs (PFTU NPs) loaded with dual-drugs (AZI and IBF) scavenged excessive ROS efficiently both in vitro and in vivo. The AZI+IBF@NPs eradicated Pseudomonas aeruginosa (PA) bacterial strain successfully. To imitate the entry of bacterial-derived compounds in body, a lipopolysaccharide (LPS) model was adopted. The administration of AZI+IBF@NPs via the tail veins dramatically reduced the number of neutrophils, significantly reduced cell apoptosis and total protein concentration in vivo. Furthermore, nucleotide oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) and Interleukin-1 beta (IL-1ß) expressions were most effectively inhibited by the AZI+IBF@NPs. These findings present a novel nanoplatform for the effective treatment of ALI.
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Lesión Pulmonar Aguda , Infecciones Bacterianas , Nanopartículas , Humanos , Azitromicina , Especies Reactivas de Oxígeno , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Polímeros , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Inflamación , Nanopartículas/uso terapéuticoRESUMEN
Advanced elastomers are highly in demand for the fabrication of medical devices for minimally invasive surgery (MIS). Herein, a shape memory and self-healing polyurethane (PCLUSe) composed of semi-crystalline poly(ε-caprolactone) (PCL) segments and interchangeable and antioxidative diselenide bonds was designed and synthesized. The excellent shape memory of PCLUSe contributed to the smooth MIS operation, leading to less surgical wounds than in the case of sternotomy. The diselenide bonds of PCLUSe contributed to the rapid self-healing under 405 nm irradiation within 60 s, and the alleviation of tissue oxidation post injury. After being delivered through a 10 mm diameter trocar onto a beating canine heart by MIS, two shape-recovered PCLUSe films self-assembled (self-healing) into a larger single patch (20 × 10 × 0.2 mm3) under the trigger of laser irradiation in situ, which could efficiently overcome the limited-size problem within MIS and meet a larger treatment area. The diselenide bonds in the PCLUSe cardiac patches protected the myocardium under oxidative stress post myocardial infarction (MI), and significantly maintained the cardiac functions.
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Infarto del Miocardio , Poliuretanos , Animales , Perros , Poliuretanos/química , Elastómeros , MiocardioRESUMEN
Tumor necrosis factor α (TNF-α) is a leading proinflammatory cytokine as the master regulator of inflammation in chronic inflammation diseases. Although TNF-α antagonists such as small molecules and peptides are in development, comparable effectiveness in TNF-α neutralization is hardly achieved only with TNF-α capture. In this study, simplified α2-macroglobulin (SM) as a novel TNF-α inhibitor was fabricated to relieve inflammation response by TNF-α capture and internalization with lysosomal degradation. SM was prepared by conjugating a TNF-α-targeting peptide with a receptor binding domain (RBD) derived from α2-macroglobulin through a synthetic biology strategy. SM exhibited effective capture and bioactivity inhibition of TNF-α. Improved endocytosis of TNF-α into lysosomes was observed with SM in macrophages. Even challenged with LPS/IFNγ, the macrophages showed relieved inflammation response with SM treatment. When administrated in chronic inflammation injury in vivo, SM achieved comparable therapeutic efficacy with Infliximab, showing ameliorated cartilage degeneration with relieved inflammation in osteoarthritis (OA) and preserved cardiac function with mitigated myocardium injury in myocardial infarction (MI). These results suggest that SM functioning in TNF-α capture-internalization mechanism might be promising therapeutic alternatives of TNF-α antibodies.
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Infarto del Miocardio , Osteoartritis , alfa 2-Macroglobulinas Asociadas al Embarazo , Embarazo , Femenino , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Inflamación/tratamiento farmacológico , Factores InmunológicosRESUMEN
Diagnostic and therapeutic illumination on internal organs and tissues with high controllability and adaptability in terms of spectrum, area, depth, and intensity remains a major challenge. Here, we present a flexible, biodegradable photonic device called iCarP with a micrometer scale air gap between a refractive polyester patch and the embedded removable tapered optical fiber. ICarP combines the advantages of light diffraction by the tapered optical fiber, dual refractions in the air gap, and reflection inside the patch to obtain a bulb-like illumination, guiding light towards target tissue. We show that iCarP achieves large area, high intensity, wide spectrum, continuous or pulsatile, deeply penetrating illumination without puncturing the target tissues and demonstrate that it supports phototherapies with different photosensitizers. We find that the photonic device is compatible with thoracoscopy-based minimally invasive implantation onto beating hearts. These initial results show that iCarP could be a safe, precise and widely applicable device suitable for internal organs and tissue illumination and associated diagnosis and therapy.
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Óptica y Fotónica , Fototerapia , Fibras Ópticas , Fármacos Fotosensibilizantes , Diseño de EquipoRESUMEN
Osteochondral tissue involves cartilage, calcified cartilage and subchondral bone. These tissues differ significantly in chemical compositions, structures, mechanical properties and cellular compositions. Therefore, the repairing materials face different osteochondral tissue regeneration needs and rates. In this study, we fabricated an osteochondral tissue-inspired triphasic material, which was composed of a poly(lactide-co-glycolide) (PLGA) scaffold loaded with fibrin hydrogel, bone marrow stromal cells (BMSCs) and transforming growth factor-ß1 (TGF-ß1) for cartilage tissue, a bilayer poly(L-lactide-co-caprolactone) (PLCL)-fibrous membrane loaded with chondroitin sulfate and bioactive glass, respectively, for calcified cartilage, and a 3D-printed calcium silicate ceramic scaffold for subchondral bone. The triphasic scaffold was press-fitted into the osteochondral defects in rabbit (cylindrical defects with a diameter of 4 mm and a depth of 4 mm) and minipig knee joints (cylindrical defects with a diameter of 10 mm and a depth of 6 mm). The µ-CT and histological analysis showed that the triphasic scaffold was partly degraded, and significantly promoted the regeneration of hyaline cartilage after they were implanted in vivo. The superficial cartilage showed good recovery and uniformity. The calcified cartilage layer (CCL) fibrous membrane was in favor of a better cartilage regeneration morphology, a continuous cartilage structure and less fibrocartilage tissue formation. The bone tissue grew into the material, while the CCL membrane limited bone overgrowth. The newly generated osteochondral tissues were well integrated with the surrounding tissues too.
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Biomimética , Andamios del Tejido , Conejos , Porcinos , Animales , Andamios del Tejido/química , Porcinos Enanos , Cartílago , HuesosRESUMEN
Traumatic brain injury (TBI), a major public health problem accompanied with numerous complications, usually leads to serve disability and huge financial burden. The adverse and unfavorable pathological environment triggers a series of secondary injuries, resulting in serious loss of nerve function and huge obstacle of endogenous nerve regeneration. With the advances in adaptive tissue regeneration biomaterials, regulation of detrimental microenvironment to reduce the secondary injury and to promote the neurogenesis becomes possible. The adaptive biomaterials could respond and regulate biochemical, cellular, and physiological events in the secondary injury, including excitotoxicity, oxidative stress, and neuroinflammation, to rebuild circumstances suitable for regeneration. In this review, the development of pathology after TBI is discussed, followed by the introduction of adaptive biomaterials based on various pathological characteristics. The adaptive biomaterials carried with neurotrophic factors and stem cells for TBI treatment are then summarized. Finally, the current drawbacks and future perspective of biomaterials for TBI treatment are suggested.
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Materiales Biocompatibles , Lesiones Traumáticas del Encéfalo , Humanos , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/uso terapéutico , Lesiones Traumáticas del Encéfalo/terapia , Lesiones Traumáticas del Encéfalo/complicaciones , Regeneración Nerviosa , Neurogénesis , Células MadreRESUMEN
Ocular alkali burn is a serious ophthalmic emergency. Highly penetrative alkalis cause strong inflammatory responses leading to persistent epithelial defects, acute corneal perforation and severe scarring, and thereby persistent pain, loss of vision and cicatricial sequelae. Early and effective anti-inflammation management is vital in reducing the severity of injury. In this study, a double network biomaterial was prepared by compounding electrospinning nanofibres of thioketal-containing polyurethane (PUTK) with a reactive oxygen species (ROS)-scavenging hydrogel (RH) fabricated by crosslinking poly(poly(ethylene glycol) methyl ether methacrylate-co-glycidyl methacrylate) with thioketal diamine and 3,3'-dithiobis(propionohydrazide). The developed PUTK/RH patch exhibited good transparency, high tensile strength and increased hydrophilicity. Most importantly, it demonstrated strong antioxidant activity against H2O2 and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH). Next, a rat corneal alkali burn model was established, and the PUTK/RH patch was transplanted on the injured cornea. Reduced inflammatory cell infiltration was revealed by confocal microscopy, and lower expression levels of genes relative to inflammation, vascularization and scarring were identified by qRT-PCR and western blot. Fluorescein sodium dyeing, hematoxylin and eosin (H&E) staining and immunohistochemical staining confirmed that the PUTK/RH patch could accelerate corneal wound healing by inhibiting inflammation, promoting epithelial regeneration and decreasing scar formation. STATEMENT OF SIGNIFICANCE: Ocular alkali burn is a serious ophthalmic emergency, characterized with persistent inflammation and irreversible vision loss. Oxidative stress is the main pathological process at the acute inflammatory stage, during which combined use of glucocorticoids and amniotic membrane transplantation is the most widely accepted treatment. In this study, we fabricated a polyurethane electrospun nanofiber membrane functionalized with a ROS-scavenging hydrogel. This composite patch could be a promising amniotic membrane substitute, possessing with a transparent appearance, elasticity and anti-inflammation effect. It could be easily transplanted onto the alkali-burned corneas, resulting in a significant inhibition of stromal inflammation and accelerating the recovery of corneal transparency. The conception of ROS-scavenging wound patch may offer a new way for ocular alkali burn.
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Quemaduras Químicas , Lesiones de la Cornea , Quemaduras Oculares , Ratas , Animales , Cicatriz/patología , Especies Reactivas de Oxígeno/metabolismo , Quemaduras Químicas/terapia , Hidrogeles/farmacología , Hidrogeles/metabolismo , Peróxido de Hidrógeno/farmacología , Poliuretanos/farmacología , Córnea/patología , Cicatrización de Heridas , Lesiones de la Cornea/metabolismo , Inflamación/patología , Quemaduras Oculares/metabolismo , Quemaduras Oculares/patologíaRESUMEN
Infection can disturb the wound healing process and lead to poor skin regeneration, chronic wound, septicemia and even death. To combat the multi-drug resistance bacteria or fungi, it is urgent and necessary to develop advanced antimicrobial wound dressings. In this study, a composite hydrogel dressing composed of polyvinyl alcohol (PVA), agarose, glycerol and antibacterial hyperbranched polylysine (HBPL) was prepared by a freeze-thawing method. The hydrogel showed robust mechanical properties, and the HBPL in the hydrogel displayed effective and broad-spectrum antimicrobial properties to bacteria and fungi as well as biofilms. The composite hydrogel exhibited good biocompatibility with respect to the levels of cells, blood, tissue and main organs. In an animal experiment of an infected wound model, the hydrogel significantly eliminated the infection and accelerated the wound regeneration with better tissue morphology and angiogenesis. The hydrogel also successfully achieved scalable production of over 600 g with a yield over 90 %, suggesting the great potential for the application in practice.
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Antiinfecciosos , Hidrogeles , Animales , Hidrogeles/farmacología , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Vendajes , Antiinfecciosos/farmacologíaRESUMEN
Spinal cord injury (SCI) is an overwhelming and incurable disabling event accompanied by complicated inflammation-related pathological processes, such as excessive reactive oxygen species (ROS) produced by the infiltrated inflammatory immune cells and released to the extracellular microenvironment, leading to the widespread apoptosis of the neuron cells, glial and oligodendroctyes. In this study, a thioketal-containing and ROS-scavenging hydrogel was prepared for encapsulation of the bone marrow derived mesenchymal stem cells (BMSCs), which promoted the neurogenesis and axon regeneration by scavenging the overproduced ROS and re-building a regenerative microenvironment. The hydrogel could effectively encapsulate BMSCs, and played a remarkable neuroprotective role in vivo by reducing the production of endogenous ROS, attenuating ROS-mediated oxidative damage and downregulating the inflammatory cytokines such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), resulting in a reduced cell apoptosis in the spinal cord tissue. The BMSCs-encapsulated ROS-scavenging hydrogel also reduced the scar formation, and improved the neurogenesis of the spinal cord tissue, and thus distinctly enhanced the motor functional recovery of SCI rats. Our work provides a combinational strategy against ROS-mediated oxidative stress, with potential applications not only in SCI, but also in other central nervous system diseases with similar pathological conditions.