Microneedle Assisted Controlled Release Of Zinc Based Nanoparticles For Accelerating Wound Healing In Diabetes

Background:Diabetes patients will lead to hyperglycemia and various complications,including cardiovascular disease,nerve damage（neuropathy）,kidney damage（kidney disease）,eye damage（retinopathy）,hearing impairment,dementia,especially delayed wound healing,which is one of the most serious complications of diabetes wound healing.It is reported that up to 15%of diabetes patients will eventually suffer from chronic skin wound ulcers,which is the most common cause of nontraumatic amputation worldwide.Chronic wounds caused by diabetes are exposed to the environment for a long time,with a high risk of infection.In addition,compared with the healing process of normal wounds,diabetes wounds obviously show slow and persistent inflammation,healing obstacles,new vessel obstruction and lack of extracellular matrix components.At present,clinical treatment includes blood glucose control,surgical debridement,graft transplantation and wound dressing.However,there is still no effective and widely applicable treatment method to treat chronic non healing wounds of diabetes.These wounds are increasingly severe,with high rates of mortality and disability,threatening human health worldwide.Objective:Based on the multiple superimposed factors of diabetes patients’wound surface,such as bacterial infection,oxidative stress,regulation of the immune system and other aspects,we hope that through the use of new carrier microneedles for combined treatment that nano drugs can play a role in different stages of diabetes patients’wound healing.Methods:Using AA-[Zn（OH）₄]^2-（denoted as ZO）as the precursor,AA-[Zn（OH）₄]^2-/Ce（denoted ZCO）was synthesized by ion exchange method.The ZCO was encapsulated in the enzyme reactive natural polymer hyaluronic acid microneedle,then the ZCO-HA microneedle was obtained.The physical and chemical properties of the synthetic material were studied by electron microscopy,laser confocal microscopy and other experiments,Flow cytometry and laser confocal microscopy were used to study cell uptake and ROS effect of cells,CCK-8,cell scratch,in vitro tube formation and other experiments were used to study cell proliferation,migration and angiogenesis,BALB/C mice were used to establish diabetes wound models,and hyaluronic acid microneedle drug system was used to study the wound healing effect of diabetes.Results:ZCO-HA micro-needle patch was successfully prepared and has good mechanical properties,has the effect of promoting diabetes wound healing.In terms of bacteria,the micro-needle uses the enzyme sensitivity of HA to slowly release ZCO at the wound site.At the same time,Zn²⁺will be rapidly released to break the oxidation balance of bacteria,causing oxidative stress to destroy DNA,protein and lipid,thus killing drug-resistant bacteria;At the cellular leve,the slowly released Zn²⁺and Ce³⁺/Ce⁴⁺alleviate oxidative stress by clearing ROS,thus reduces the inflammatory state of macrophages and showing the anti-inflammatory ability（inflammatory stage）;In addition,metal ions(Zn²⁺,Ce³⁺/Ce⁴⁺)promote the proliferation and migration of endothelial cells and angiogenesis in vitro（proliferation stage）.At the animal level,ZCO-HA microneedles alleviate wound inflammation,promote the proliferation and migration of fibroblasts and endothelial cells into the wound by promoting the expression of VEGF and CD31,and promotes the formation of granulation tissue and collagen deposition,finally accelerates the wound healing of diabetes.Conclusion:We have successfully developed system which nano drug ZCO was loaded by a hyaluronic acid microneedle for diabetes wound healing to achieve the targeted and slowed release of nano drugs in the microenvironment of diabetes wound.ZCO-HA cooperatively promotes wound healing in diabetes by inhibiting bacterial growth,clearing reactive oxygen species from diabetes wounds,alleviating oxidative stress,promoting endothelial cell proliferation,migration,angiogenesis and other effects.This system provides a new strategy for solving the complex and dynamic problems of wound surface in diabetes patients and promoting the effect of wound healing.