Experimental Study Of A Biomimetic Stent With Hydrogel And Nano-Fiber Membrane For The Treatment Of Esophageal Fistula

Objective:As a muscular digestive tract organ,the esophagus is easy to be damaged by mechanical damage,digestive juice erosion,tumor ulceration,etc.,therefore esophageal fistula could be formed.The treatment and fistula repair are clinical difficulties and are also the direction of tissue engineering.There are currently no mature interventional implant materials for esophagus.The purpose of this study is to reconstruct traditional esophageal stents using material science techniques to achieve degradable biomimetic esophageal stent with hydrogel and nano-fiber membrane for interventional implantation.The reliability,degradability,compatibility and treatment effect of the stent are evaluated on the material level both in vitro and in vivo to achieve interventional and regenerative repair of esophageal fistula.Methods:Degradable polydioxanone(PDO)silk was used to braid the stent framework,and the specifications and supporting forces were screened.Using oriented microsol electrospinning technology,oriented polylactic acid-glycolic acid(PLGA)copolymer fibers were formed on the surface of the stent.By encapsulating TGF-?1 factor in fibers,it achieved the effects of fistula plugging,slow drug release,and guidance of the orientated growth of cells.Using gelatin methacrylate(GelMA)and photo-crosslinking technology,primary bone marrow mesenchymal stem cells(BMSCs)extracted from rabbit bone marrow were carried and wrapped on the outer surface of the stent membrane to serve as seeds for tissue repair.The compatibility of various materials,orientation of cell growth,and gene expression changes during the process of inducing differentiation were verified in vitro.In a rabbit esophageal fistula model,the degradation of the stent,the treatment efficiency of esophageal fistula,and complications were verified in vivo.Results:The bionic scaffold could provide up to 6.92 N sufficient radial support force.It could be significantly compressed into a stent conveyor.After repeated compression and release,the mechanical performance decreases less.PDO slowly degrades in the acidic environment of the esophagus,the residual weight was 82.9%after 98 d,and no secondary surgery was required to remove it.The PLGA fiber membrane could be uniformly covered on the surface of the stent.With a certain tensile effect,the maximum tensile force could reach 1.38 MPa,and the residual weight was 80.6%under the enzymatic environment after 4 weeks.The speed of drug release was slow and controllable,and the accumulative release percent was 92.53%in 10 days,which could gradually induce the differentiation of stem cells.GelMA could encapsulate and be cross-linked with primary BMSCs,it lost 44.4%weight after 4 weeks therefore could be used as a stem cell carrier.Each material of the bionic stent had good biocompatibility,and the cell viability all maintained over 90%.BMSCs on the oriented fiber membrane could achieve uniform growth.After induction by TGF-?1,BMSCs got myoblast differentiation along with the increasion of ?-SMA expression and decreasion of CD44 expression.In a rabbit esophageal fistula model,the bionic stent was sent into the esophageal fistula site through interventional intraluminal stent implantation,which could effectively block the fistula.After 30 days,the stent was still intact and had mechanical support,the membrane maintained basic coverage.The fistula repair effect was observed obviously,and it significantly improved the survival rate of the animal(78%).Except for the slightly higher displacement rate,the stenosis rate and the recurrence rate of esophageal fistula were significantly lower than those of the nickel-titanium stent.Histopathology also confirmed the repair effect on esophageal muscle layer was better in bionic stent group than that of control group.Conclusion:The biomimetic esophageal stent with hydrogel and fiber membrane could be implanted in the fistula,which could realize the functions of supporting the esophagus,blocking off the fistula,maintaining the unobstruction of digestive tract,and completing self-repair and regeneration of tissue.It could improve esophageal healing rate and reduce the complications.The whole stent and attaching materials could be degraded and no sencondary surgery was needed.In a word,the biomimetic stent is an ideal material which brings new possibilities for the intraluminal treatment of clinically complicated esophageal fistula.