The Photo-responsive And Tissue Adhesive Hydrogel For Soft Tissues Repair And Regeneration

Soft tissues,including the skin,muscles,tendons,ligaments,cartilage,and blood vessels,are often prone to damages.At present,the repair of soft tissue injuries depends on self-healing;there is no ideal treatment,which severely affects people's daily life and work.For cartilage defects,the treatment options are very limited,because the cartilage has no blood vessels,no nerves,no lymphatics,and poor self-healing capabilities Currently,some traditional therapies,such as bone marrow stimulation and joint replacement,are effective in alleviating pain.Still,they are incapable of regenerating healthy hyaline cartilage with normal morphology and functions.Severe muscle damage is often accompanied by uncontrollable bleeding;if not treated in time,it will seriously threaten the patient's life.Large-scale skin traumas(such as third-degree burns and full-thickness defects of the dermis)are also difficult to heal because of their limited self-healing ability.Autologous skin transplantation is commonly used for the treatment of large-scale skin trauma;however,the outcome is limited or failed due to insufficient donors or skin graft necrosis.The development of tissue engineering(scaffold materials,cells,and bioactive molecules)provides a better option for solving the above problems and has broad prospects in the treatment of soft tissue damage.The extracellular matrix of human soft tissues is composed of hydrogels,here,different biomimetic hydrogels were designed,and its functionalities were investigated for different type of soft tissue repairThe goal of this study is to design hydrogels and treatments for three different soft tissues repair:(1)developing a more effective and straightforward method for cartilage repair;(2)developing a rapid cross-linking and strong wet surface adhesion hydrogel for cardiovascular tissues repair under bleeding conditions;(3)using rapid 3D printing to fabricate functional living soft tissues to solve the shortage of transplantable donor tissues and organs.Therefore,this study is divided into three parts:(1)a photo-responsive and tissue adhesive hydrogel for cartilage defect repair;(2)a photo-responsive and tissue adhesive hydrogel with super-fast gelation for repairing heart defects under bleeding conditions;(3)Complex structure fabrication via 3D printing combining with super-fast gelation,photo-responsive and tissue adhesive hydrogel for skin repair1.A photo-responsive and tissue adhesive hydrogel for cartilage defect repairArticular cartilage repair remains a significant challenge in today's clinical practice due to its poor self-healing capacity.Current treatment options are limited,traditional therapies such as marrow stimulating techniques and joint replacement are effective in alleviating pain,but they are incapable of regenerating healthy hyaline cartilage with normal morphology and functions.Therefore,it is essential to develop a promising strategy to achieve a one-step cartilage repair for patients suffering from joint diseases and traumas.Inspired by the complex composition and microscopic architecture of native articular cartilage,an injectable hydrogel(M-O-G)with tough mechanical property and strong tissue adhesiveness is developed.All hydrogel material compositions are natural polymers,or their derivatives,resembling the healthy cartilage extracellular matrix(ECM).This hydrogel showed superior tunable mechanical properties(mechanical strength?270 kPa,compressibility?70%),and rapid recovery ability.Moreover,it exhibited strong adhesiveness and enhanced integration with tissues,which is more beneficial for tissue repair.Further,in vivo studies demonstrated that the hydrogel had excellent biocompatibility and superior performance in cartilage defect regeneration,thus promote the interface healing between neo-tissue and normal cartilage.Therefore,the presented hydrogel is a promising biomaterial for clinical cartilage regeneration and other biomedical applications.2.A photo-responsive and tissue adhesive hydrogel with super-fast gelation for repairing heart defects under bleeding conditionsUncontrollable bleeding is a major problem in surgical procedures and after major trauma.Existing hemostatic agents poorly control hemorrhaging from traumatic arterial and cardiac wounds because of their weak adhesion to wet and mobile tissues.Here we design a photoreactive adhesive(Ge1MA/HA-NB)that mimics the extracellular matrix(ECM)composition.This biomacromolecule-based matrix hydrogel can undergo rapid gelling and fixation to adhere and seal bleeding arteries and cardiac walls after UV light irradiation.These repairs can withstand up to 290 mm Hg blood pressure,significantly higher than blood pressures in most clinical settings(systolic BP 60-160 mm Hg).Most importantly,the hydrogel can stop high-pressure bleeding from pig carotid arteries with 4?5mm-long incision wounds and from pig hearts with 6 mm diameter cardiac penetration holes.Treated pigs survived after hemostatic treatments with this hydrogel.The above results showed that this hydrogel has excellent hemostatic properties,and the hydrogel itself can be used as a biomaterial scaffold to guide tissue repair and regeneration,which has superior advantages compared with current clinical gel products.3.Complex structure fabrication via 3D printing combining with super-fast gelation,photo-responsive and tissue adhesive hydrogel for skin repairIt is still a challenge for existing bioprinting technologies to fabricate organs suitable for implantation due to the inability to recapitulate the complex anatomical structures,mechanical properties,and biological functions of target tissues and organs.Also,failure to create 3D constructs with interconnected microchannels for long-range mass transportation limits the clinical applications of 3D printing.Here,a new method was developed to 3D print functional living skin(FLS)using a newly designed biomimetic bioink(GelMA/HA-NB)and digital light processing(DLP)-based 3D printing technology.The FLS possesses interconnected microchannels that facilitate cell migration,proliferation,and neo-tissue formation.The GelMA/HA-NB bioink,composed of gelatin methacrylate(GelMA)and N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide(NB)linked hyaluronic acid(HA-NB),has demonstrated its rapid gelation kinetics,tunable mechanical properties,excellent biocompatibility,and tissue adhesion.The DLP-based 3D printing technology provides a rapid method to precise position clusters of human skin fibroblasts(HSFs)and human umbilical vein endothelial cells(HUVECs)with high cell viability to form FLS.The FLS promotes skin regeneration and efficient neovascularization by mimicking the physiological structure of natural skin,and it can also be easily handled and implanted onto the wound site due to its strong mechanical and bio-adhesive properties.In addition,in vivo study demonstrated that the living skin exhibited instant defense function in skin irritation assay and had superior performance in promoting dermal regeneration with skin appendages in large animals.This study provides a rapid and mass production method of functional living organs for future clinical applications.