The Construction Of Metal-organic Framework/electrospun Fiber Composite Material With Controlled Release Of Nitric Oxide And Its Research On Promoting Diabetic Wound Healing

Diabetic foot ulcer is a typical chronic wound disease and one of the major complications of diabetes.And the related medical costs have continued to rise in recent years with the rising incidence of diabetes.The physical and psychological pain caused by the disease and the consumption of social resources have made it a major challenge for global public health.Nitric oxide(NO)has proven to be an important messenger molecule in the human body in recent years,and has played a vital role in the cardiovascular system,nervous system and immune system.In addition,the introduction of exogenous NO during wound healing can also promote angiogenesis and collagen deposition at the wound bed.However,although the use of NO for the treatment of diabetic wounds has achieved some significant results,as a gas drug whose therapeutic effect is directly related to its concentration,the control of the release behavior of NO during the treatment process has always been a major challenge.As a new type of porous nanoparticles with metal ions as the center and organic ligands as the framework,metal-organic frameworks(MOFs)are widely used in gas storage due to their extremely high specific surface area.And its high drug loading capacity and biosafety have also gradually attracted people's attention.In this paper,we used a copper-based MOF named HKUST-1 as the carrier of NO,and modified the secondary amino group inside HKUST-1 by post-modification method to achieve the purpose of stable and quantitative loading of NO.And the construction of NO slow-release system was realized through electrostatic spinning technology.Tissue engineering scaffolds prepared by electrospinning nanofibers have the similar micro-nano structures to natural extracellular matrix,and their specific surface area and porosity are extremely high.When used as a wound dressing,it can provide cells with a suitable growth environment to promote their proliferation and differentiation,and can also play a role in filling wound defects to promote regeneration of wound tissue.In addition,the scaffolds can be built into a drug sustained release system by encapsulating the drug inside the nanofiber,so that the drug can be slowly released as the fiber degraded in the wound site,and the degradation rate of fibers can be controlled by its base material and microstructure,so it is an emerging drug supply system with excellent performance.In addition,we also applied this NO sustained-release system to the treatment of wounds in diabetic mice,and further studied the effects of composite scaffold on cell behavior in vitro and angiogenesis,collagen deposition and inflammatory during wound healing.The results showed that NO could be quantitatively and stably supported in HKUST-1 nanoparticles modified with secondary amino groups,and the amount of NO could be controlled by parameters such as loading pressure and loading time during the loading process.NO was stable in HKUST-1 and could be stored for a long time in a dry environment.NO@HKUST-1 nanoparticles could be uniformly wrapped inside the coaxial nanofiber scaffold,so that NO could be slowly released as the fiber scaffold degrades.Compared with the burst release produced by the direct release of NO@HKUST-1,the release rate of NO from the composite fiber scaffold was significantly controlled,and NO could be continuously released as an average rate of 1.7 nmol L~-11 h~-11 for up to 14 days.In addition,with the decomposition of HKUST-1 inside the fiber,copper ions could also be continuously released within 14days.In terms of wound healing effects,copper ions released from the fiber scaffold could synergize with NO to regulate the expression levels of various proteins and genes related to wound healing at the cytokine level,thus regulate the various behaviors of endothelial cells,such as adhesion,proliferation,migration and tube formation.Therefore,at the macro level,the scaffold could promote the regeneration of blood vessels and the deposition of collagen,and reduction the inflammation at the wound site,which greatly shortened the wound healing period.These results demonstrate that such a composite fiber scaffold based on MOF and electrospinning as a slow-release system of NO for the treatment of diabetic wounds is a very effective method and has important research significance.