Biomimetic Collagen-Based Tissue Adhesives For Biomedical Applications

Tissue adhesives have been used in place of sutures and electrocoagulation in clinical practice to join tissues together,promote healing,control or prevent bleeding,or prevent gas or fluid leakage.Tissue adhesives are easier to use and cause minimal tissue damage compared to traditional wound closure methods.However,pressing problems with existing tissue adhesives for clinical use include weak adhesion to moist tissue surfaces,inadequate mechanical strength,poor haemostasis,cytotoxicity and after-effects.There is an urgent need to develop a medical tissue adhesive that can be easily manipulated,has good shape adaptation,high adhesive sealing capacity,excellent biocompatibility,high haemostatic efficiency and accelerated wound healing.Inspired by the secretion of glue by various plants and animals in nature and the culinary arts in life,this PhD thesis combines the principles of wet-surface adhesion mechanisms,the principles of tissue adhesive design,and the development of two powerful wet tissue adhesives based on the synthesis of collagen and starch biopolymers.We have explored their synthetic mechanisms,tested their various properties,and used them for skin and spinal cord tissue engineering applications.The main research in this thesis can be divided into three sections:1.Inspired by the bio-glue secreted by the natural flora and fauna of the mussel,ivy and oyster,this part combines the key adhesive characteristics of the three flora and fauna to design and prepare a strong hydrogel tissue adhesive based on collagen and starch materials-CoSt.CoSt combines unique drainage,molecular chain penetration and enhanced interfacial cross-linking features for rapid removal of interfacial water,enhanced toughness dissipation and involves multiple reversible CoSt offers excellent injectability,self-healing and shape adaptation,as well as repeatable strong wet tissue adhesion(62±4.8 KPa)and high sealing performance(153.2±35.1 mmHg).In vitro haemostasis experiments also showed that CoSt has accelerated blood clotting properties,thanks to its ability to form a rapid haemostatic barrier upon contact with blood.We also constructed a rat tail break haemorrhage model,a hepatic incision haemorrhage model,a major liver defect haemorrhage model and an emergency abdominal aortic haemorrhage model to verify the haemostatic properties of CoSt in vivo,and the experimental results showed that CoSt completed haemostasis within 1 min in all haemorrhage models,and the haemostasis time and bleeding volume were significantly lower compared to commercial medical fibrin.2.To further validate the properties of CoSt in promoting wound repair,we constructed a 2-cm skin incision model and a 1-cm skin circular notch model in rats.For the skin incision model,fibrin glue was also selected as a control group and characterised by H&E staining.Similar results were obtained for the circular skin notch model,with wound closure rates and relative thickness of new skin in the CoSt treatment group significantly exceeding those of the control group.Quantitative analysis of markers in the new skin also showed that the CoSt treatment group had greater levels of blood vessels,hair follicles and sebaceous glands in the new skin than the control group.These results suggest that CoSt tissue adhesives can effectively close broken skin without sutures and accelerate the regenerative healing of skin tissue in rats.3.Inspired by the art of cooking,CSSA tissue adhesives with modulus(～1KPa)and electroactivity(～9.88×10-4S/cm)matching that of natural spinal cord were synthesised rapidly(～25s)using catecholated collagen,oxidised starch and mixed ion(CaCl2 and LiCl)solutions by a low-temperature heating one-pot method,faster and stronger adhesion(>100KPa),and enhanced bonding properties thanks to chain enhancement caused by a merad chemical reaction at high cooking temperatures.Due to these advanced properties,CSSA can be effectively injected into the spinal cord injury site and achieve non-compressible neurological haemostasis and seamless filling of the connecting lesion cavity.Combined with the formation of high mobility Li+-quinone based redox pairs,this allows for continuous and stable electrical signalling.In combination with electrical stimulation treatment,we demonstrate that injectable functional conductive CSSA can effectively modulate the local microenvironment of spinal cord injury,reduce fibrotic scar formation,promote neurogenesis,facilitate myelin regeneration and enhance axonal regeneration.More importantly,we propose a new integrated repair concept where multifunctional CSSA tissue adhesives can be integrated to achieve haemostasis,non-destructive connection and filling of defective lesion sites and promote regeneration of spinal cord injury.