Bio-multifunctional Hydrogel Patches For Repairing Full-thickness Abdominal Wall Defect

Abdominal wall defects,caused by congenital rupture,trauma,and removal of primary or metastatic tumors,are a common surgical issue affecting millions of people worldwide in recent years and patient populations are still increasing.Abdominal wall defects may result in hernia formation,intestinal incarceration,necrosis,and even death.Tension-free abdominal wall defect repair using implantable materials is the gold standard for treating these problems because direct silk sutures can lead to a high recurrence rate.General surgeons commonly use permanent synthetic meshes(e.g.,polypropylene(PP)meshes)to achieve maximum reinforcement of the defect area.However,this kind of mesh can induce significant foreign body reactions(FBR)and accelerate fibrosis,which may cause chronic pain and further restrict movement.Moreover,the mesh does not have adhesion properties and requires silk thread fixation,extending the operation time.Non-biodegradable synthetic patches are associated with complications including intestinal erosion,serious inflection,and limited physical activity of the patient due to the retention of patching material after abdominal wall defect treatment.In addition,the use of acellular extracellular matrix(AECM),such as porcine small intestinal submucosa(SIS)and dermal matrix,is an alternative strategy to repair abdominal wall defects.However,the application of AECM is still limited by its complex decellularization process,loss of remodeling strength,and high cost.Therefore,the development of bio-instructive multifunctional patches is emerging as a promising strategy to trigger full-thickness abdominal wall defects to undergo a regenerative process.In recent years,functional hydrogels have gained increasing attention in biomedical applications,particularly tissue repair and regeneration,owing to their natural extracellular matrix-like structure,tunable mechanical properties,suitable diffusion nature due to their elastic networks,wound exudate absorption,etc.The formation of chemically cross-linked hydrogels has been carried out by using small cross-linking agent molecules,hybrid polymer networks,enzyme-catalyzed reactions,photosensitive agents,and so forth.Among these preparation strategies,dynamic Schiff bases are very attractive owing to rapid gelation and self-healing under physiological conditions without any stimulation,and they have good fatigue resistance and biocompatibility,therefore they have been used in biomedical applications,such as drug delivery systems,wound healing,tissue regeneration,tissue adhesives and so forth.In response to the above clinical problems and needs,we have developed a bio-functional carboxymethyl chitosan(CMCS)and four-arm poly(glycol)aldehyde(4-arm-PEG-CHO)hydrogel patch based on the Schiff alkali reaction for full-layer abdominal wall defect repair.Our results by 1H NMR spectroscopy showed the presence of peaks of aldehyde groups(10.04 ppm),benzene rings(8.14-8.16,7.88-7.90 ppm)and ester groups(4.45 ppm)protons,indicating that 4-arm-PEG-CHO was successfully synthesized and hydrogels with different composition ratios were formed within 5 minutes at room temperature.Blast pressure experiments show that the average burst pressures of hydrogels 1,2 and 3 are 217.5,150.0 and 90.0 mmHg,respectively,and the burst pressure of all hydrogels is significantly higher than the normal intra-abdominal pressure(5 mmHg),and even higher than that of grade Ⅳ abdominal compartment syndrome(25 mmHg),which can be excellent for the role of the physical barrier of abdominal wall defects.In the simulated in vivo physiological environment,the hydrogel still shows good adhesion to wet skin after 6 days,which can effectively prevent the hydrogel from shifting after surgery.Through macroscopic self-healing observation and rheological self-healing testing,the cleaved hydrogel can be combined again into a complete butterfly-shaped hydrogel without any external stimulation,and the hydrogel strength after healing is strong enough to support its own weight,when the rheology recovery test they recover their original values immediately after stress recovery,and after many similar cycles,G’ does not drop significantly,which makes if the patient’s postoperative incision is damaged,the mesh ruptures,and the hydrogel can self-heal,effectively preventing recurrence.The antimicrobial activity of hydrogels against E.coli and Staphylococcus aureus was studied by in vitro antimicrobial assays and colony(CFU)tests,showing that all hydrogels showed some antibacterial effect on both bacteria.To accelerate tissue repair,rb-bFGF was introduced into hydrogel patch,live dead cell staining was performed to assess the cytotoxicity of hydrogels,scratch tests were used to study the effects of hydrogels on cell migration,and gel+rb-bFGF samples significantly promoted cell proliferation and migration,showing great potential for abdominal wall defect repair.Histomorphological experiments have shown that compared with the commercial PP mesh commonly used in clinical practice,the developed hydrogel mesh can promote the repair and thickening of abdominal wall tissue by upregulating the production of Ki67,promote collagen formation,induce neovascularization,and inhibit inflammation by reducing the expression of IL-6,TNF-α and IL-1β.Our results show that this novel bio-functional hydrogel patch has great potential in the treatment of full-thickness abdominal wall defects.