Hydrogel-based bioadhesives have emerged as alternatives for sutureless wound closure, since they can mimic the composition and physicochemical properties of the extracellular matrix. However, they are often associated with poor mechanical properties, low adhesion to native tissues, and lack of antimicrobial properties. Herein, a new sprayable, elastic, and biocompatible composite hydrogel, with broad-spectrum antimicrobial activity, for the treatment of chronic wounds is reported. The composite hydrogels were engineered using two ECM-derived biopolymers, gelatin methacryloyl (GelMA) and methacryloyl-substituted recombinant human tropoelastin (MeTro). MeTro/GelMA composite hydrogel adhesives were formed via visible light-induced crosslinking. Additionally, the antimicrobial peptide Tet213 was conjugated to the hydrogels, instilling antimicrobial activity against Gram (+) and (-) bacteria. The physical properties (e.g. porosity, degradability, swellability, mechanical, and adhesive properties) of the engineered hydrogel could be fine-tuned by varying the ratio of MeTro/GelMA and the final polymer concentration. The hydrogels supported in vitro mammalian cellular growth in both two-dimensional and three dimensional cultures. The subcutaneous implantation of the hydrogels in rats confirmed their biocompatibility and biodegradation in vivo. The engineered MeTro/GelMA-Tet213 hydrogels can be used for sutureless wound closure strategies to prevent infection and promote healing of chronic wounds.
Photocrosslinkable materials have been frequently used for constructing soft and biomimetic hydrogels for tissue engineering. Although, ultraviolet (UV) light is commonly used for photocrosslinking such materials, its use has been associated with several biosafety concerns such as DNA damage, accelerated aging of tissues, and cancer. Here we report an injectable visible light crosslinked gelatin-based hydrogel for myocardium regeneration. Mechanical characterization revealed that the compressive moduli of the engineered hydrogels could be tuned in the range of 5–56 kPa, by changing the concentrations of the co-initiator and co-monomer in the precursor formulation. In addition, the average pore sizes (26–103 μm) and swelling ratio (7–13%) were also shown to be tunable by varying the hydrogel formulation. In vitro studies showed that visible light crosslinked GelMA hydrogels supported the growth and function of primary cardiomyocytes (CMs). In addition, the engineered materials were shown to be biocompatible in vivo, and could be successfully delivered to the heart after myocardial infarction in an animal model to promote tissue healing. The developed visible light crosslinked hydrogel could be used for the repair of various soft tissues such as the myocardium, and for the treatment of cardiovascular diseases with enhanced therapeutic functionality.
Surgical sealants have been used for sealing or reconnecting ruptured tissues but often have low adhesion, inappropriate mechanical strength, cytotoxicity concerns, and poor performance in biological environments. To address these challenges, we engineered a biocompatible and highly elastic hydrogel sealant with tunable adhesion properties by photocrosslinking the recombinant human protein tropoelastin. The subcutaneous implantation of the methacryloyl-substituted tropoelastin (MeTro) sealant in rodents demonstrated low toxicity and controlled degradation. All animals survived surgical procedures with adequate blood circulation by using MeTro in an incisional model of artery sealing in rats, and animals showed normal breathing and lung function in a model of surgically induced rat lung leakage. In vivo experiments in a porcine model demonstrated complete sealing of severely leaking lung tissue in the absence of sutures or staples, with no clinical or sonographic signs of pneumothorax during 14 days of follow-up. The engineered MeTro sealant has high potential for clinical applications because of superior adhesion and mechanical properties compared to commercially available sealants, as well as opportunity for further optimization of the degradation rate to fit desired surgical applications on different tissues.
Corneal injuries are common causes of visual impairment worldwide. Accordingly, there is an unmet need for transparent biomaterials that have high adhesion, cohesion, and regenerative properties. Herein, we engineer a highly biocompatible and transparent bioadhesive for corneal reconstruction using a visible light cross-linkable, naturally derived polymer, GelCORE (gel for corneal regeneration). The physical properties of GelCORE could be finely tuned by changing prepolymer concentration and photocrosslinking time. GelCORE revealed higher tissue adhesion compared to commercial adhesives. Furthermore, in situ photopolymerization of GelCORE facilitated easy delivery to the cornea, allowing for bioadhesive curing precisely according to the required geometry of the defect. In vivo experiments, using a rabbit stromal defect model, showed that bioadhesive could effectively seal corneal defects and induce stromal regeneration and re-epithelialization. Overall, GelCORE has many advantages including low cost and ease of production and use. This makes GelCORE a promising bioadhesive for corneal repair.
Conventional surgical techniques to seal and repair defects in highly stressed elastic tissues are insufficient. Therefore, this study aimed to engineer an inexpensive, highly adhesive, biocompatible, and biodegradable sealant based on a modified and naturally derived biopolymer, gelatin methacryloyl (GelMA). We tuned the degree of gelatin modification, prepolymer concentration, photoinitiator concentration, and crosslinking conditions to optimize the physical properties and adhesion of the photocrosslinked GelMA hydrogels. Following ASTM standard tests that target wound closure strength, shear resistance, and burst pressure, GelMA sealant was shown to exhibit adhesive properties that were superior to clinically used fibrin- and poly(ethylene glycol)-based glues. Chronic in vivo experiments in small as well as translational large animal models proved GelMA to effectively seal large lung leakages without the need for sutures or staples, presenting improved performance as compared to fibrin glue, poly(ethylene glycol) glue and sutures only. Furthermore, high biocompatibility of GelMA sealant was observed, as evidenced by a low inflammatory host response and fast in vivo degradation while allowing for adequate wound healing at the same time. Combining these results with the low costs, ease of synthesis and application of the material, GelMA sealant is envisioned to be commercialized not only as a sealant to stop air leakages, but also as a biocompatible and biodegradable hydrogel to support lung tissue regeneration.
Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR‐223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti‐inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local‐targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR‐223 5p mimic (miR‐223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR‐223* in J774A.1 macrophages demonstrates increased expression of the anti‐inflammatory gene Arg‐1 and a decrease in proinflammatory markers, including TNF‐α, IL‐1β, and IL‐6. The therapeutic potential of miR‐223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cover the wounds during the healing process in an acute excisional wound model. Histological evaluation and quantitative polymerase chain reaction (qPCR) analysis show that local delivery of miR‐223* efficiently promotes the formation of uniform vascularized skin at the wound site, which is mainly due to the polarization of macrophages to the M2 phenotype. Overall, this study demonstrates the potential of nanoparticle‐laden hydrogels conveying miRNA‐223* to accelerate wound healing.
Bioprinting has gained significant attention for creating biomimetic tissue constructs with potential to be used in biomedical applications such as drug screening or regenerative medicine. Ideally, biomaterials used for three-dimensional (3D) bioprinting should match the mechanical, hydrostatic, bioelectric, and physicochemical properties of the native tissues. However, many materials with these tissue-like properties are not compatible with printing techniques without modifying their compositions. In addition, integration of cell-laden biomaterials with bioprinting methodologies that preserve their physicochemical properties remains a challenge. In this work, a biocompatible conductive hydrogel composed of gelatin methacryloyl (GelMA) and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) was synthesized and bioprinted to form complex, 3D cell-laden structures. The biofabricated conductive hydrogels were formed by an initial crosslinking step of the PEDOT:PSS with bivalent calcium ions and a secondary photopolymerization step with visible light to crosslink the GelMA component. These modifications enabled tuning the mechanical properties of the hydrogels, with Young's moduli ranging from ∼40−150 kPa, as well as tunable conductivity by varying the concentration of PEDOT:PSS. In addition, the hydrogels degraded in vivo with no substantial inflammatory responses as demonstrated by haematoxylin and eosin (H&E) and immunofluorescent staining of subcutaneously implanted samples in Wistar rats. The parameters for forming a slurry of microgel particles to support 3D bioprinting of the engineered cell-laden hydrogel were optimized to form constructs with improved resolution. High cytocompatibility and cell spreading were demonstrated in both wet-spinning and 3D bioprinting of cell-laden hydrogels with the new conductive hydrogel-based bioink and printing methodology. The synergy of an advanced fabrication method and conductive hydrogel presented here is promising for engineering complex conductive and cell-laden structures.
Conventional methods to engineer electroconductive hydrogels (ECHs) through the incorporation of conductive nanomaterials and polymers exhibit major technical limitations. These are mainly associated with the cytotoxicity, as well as poor solubility, processability, and biodegradability of their components. Here, we describe the engineering of a new class of ECHs through the functionalization of non-conductive polymers with a conductive choline-based bio-ionic liquid (Bio-IL). Bio-IL conjugated hydrogels exhibited a wide range of highly tunable physical properties, remarkable in vitro and in vivo biocompatibility, and high electrical conductivity without the need for additional conductive components. The engineered hydrogels could support the growth and function of primary cardiomyocytes in both two dimentinal (2D) and three dimensional (3D) cultures in vitro. Furthermore, they were shown to be efficiently biodegraded and possess low immunogenicity when implanted subcutaneously in rats. Taken together, our results suggest that Bio-IL conjugated hydrogels could be implemented and readily tailored to different biomedical and tissue engineering applications.
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