| Abdominal wall hernias（AWH）are prevalent pathologies in the abdomen.It has been reported that one in four people might develop congenital or acquired AWH.Around 1 million adults have AWH repair every year in China.AWH can cause severe complications,such as abdominal distension,abdominal pain,intestinal obstruction,and peritonitis,which can reduce the patient’s quality of life and even cause death if not treated quickly enough.Hernias are challenging to heal on their own and mostly require surgical treatment.Currently,mesh repair for AWH has been reckoned as the gold standard.Among various synthetic meshes,polypropylene（PP）is the most widely used material for herniorrhaphy.Despite the PP mesh repair can decline the recurrence rate and abdominal pain significantly,the risk of adhesion formation between the mesh and viscera remains a prevalent problem.Various physical barriers have been incorporated into PP mesh to achieve anti-adhesion effects by isolating the interaction between PP and viscera.Among them,solid films and gels were employed widely.While the former has poor permeability and flexibility,likely to inhibit wound healing and affect mesh compliance.The latter is difficult to combine with PP mesh;its stability is poor and even limited to cover an irregular wound,thus inducing abdominal adhesions.Thereby,it is urgently needed to further improve the anti-adhesion barrier materials,then combined with PP meshes to endow them with excellent anti-adhesion properties and tissue compatibility.For solving the above problems,we here firstly develop different anti-adhesion nanofiber barriers by incorporating functional components ibuprofen or lecithin into poly（lactic-co-glycolic acid）（PLGA）and polycaprolactone（PCL）through electrospinning,subsequently a series of studies including physical properties and biological characterization to reveal the anti-adhesive mechanism.Afterward,we construct composite meshes with anti-adhesion efficiency by employing lightweight PP meshes to support the abdominal defect and wound healing,NFM layers consisting of PLGA and PCL to protect PP prostheses from the viscera and improve tissue-mesh integration,and alginate hydrogen（AH）to achieve interfacial bonding and facilitate adhesion prevention.The composite meshes were characterized by studies of physical properties,mechanical properties,performances,in vitro biodegradability,and biocompatibility.In vivo experiments in a rabbit model were further conducted to evaluate the anti-adhesion properties and tissue compatibility.The correlation between PP substrates features and composite mesh characteristics was also explored.The research contents are summarized as follows:（1）To improve the anti-adhesion effect of electrospun nanofibrous membranes,we developed a novel sandwiched electrospun scaffold loaded with ibuprofen（Sandwich）serving as an anti-adhesion barrier.The surface characteristics,chemical compositions,mechanical properties,drug release behaviors,and in vitro biological evaluations were investigated to explore the practical feasibility of Sandwich for anti-adhesion applications.The middle layer of Sandwich is the PLGA/PCL NFMs loading with ibuprofen,acting as an effectual drug carrier.The outer layer is the pure PLGA/PCL NFMs,expected to improve the drugs’ utilization and effectiveness.For all scaffolds,the addition of ibuprofen had no harmful effect on surface characteristics,mechanical properties,protein adsorption,and blood compatibility.The Sandwich exhibited significantly a reduced initial burst of drug release in the first hour and a prolonged delivery for ibuprofen over 14 days.In vitro study on fibroblasts showed that incorporation of ibuprofen effectively inhibited their adhesion and proliferation,and the Sandwich group maintained the least adhesion of L-929 after 5 days of culture.For RAW 264.7 macrophages,worse cell adhesion and poorer TNF-α production of Sandwich indicated superior anti-inflammatory effects.（2）To provide PLGA/PCL NFMs with improved anti-adhesion efficiency,a functional element phospholipid was readily incorporated into NFMs barriers.Concretely,lecithin was added to PLGA/PCL blend solutions at a different ratio（0,2.5,5,and 10 wt%）,and the phospholipid functionalized NFMs（denoted as NFM,NFM-2.5Lec,NFM-5Lec,and NFM-10Lec）were developed by one-step electrospinning of polymer solutions.Their surface morphology,chemical characterization,and in vitro biological assessment were investigated to examine the feasibility of the obtained NFMs as anti-adhesion barriers.The optimized phospholipid NFMs were shown to be drastically decreased fiber diameter,high porosity,superior hydrophilicity,and excellent cytocompatibility.Moreover,the NFM-10 Lec group exhibited significantly reduced fibroblasts after incubation of 3 days compared to that of the NFMs,indicating the lasting-long anti-adhesion capability against fibroblasts.Meanwhile,the phospholipid NFMs showed superior anti-inflammatory effects.Thus,the facile phospholipid functionalized nanofibers provided a promising strategy for anti-adhesion applications.（3）We adopted the optimized PLGA/PCL nanofibrous membranes（NFM）as a physical barrier and utilized the alginate component as a bonding media to firmly combine the NFM barrier and the warp-knitted PP substrate to yield the composite mesh.The in vitro studies were conducted to investigate the feasibility of the anti-adhesion composite mesh for AWH repair.The results showed that the NFM barriers were firmly attached to PP substrates with the alginate agent,effectively eliminating the delamination without unwanted damage to the nanofiber barrier.The whole process will not damage the inherent properties of the mesh,and the obtained PP/AH-NFM mesh has good performance in all aspects,likely to be used for implantation in the body safely.（4）A rabbit model was used to assess the potential application of anti-adhesion composite mesh.The prosthetic meshes were implanted intra-abdominally against the peritoneum in rabbits.After 7 days and 30 days of implantation,each group was investigated for postoperative complications and abdominal adhesions.All the animals had routine feeding and recovery,and none exhibited postoperative complications and adverse reactions to the surgical procedure.However,the bare PP mesh adhered to the omentum or viscera severely.The adherent sites always required traction and even sharp dissection to be separated.The PP/AH-NFM group showed a lower adhesion degree,similar to the control Proceed.In comparison,the PP/AH-NFM mesh shows a milder inflammation reaction,superior histocompatibility,suggesting great potential in repairing AWH as an anti-adhesion composite mesh.（5）For deeply exploring the influence of the PP substrate on the performance of anti-adhesion composite mesh,three kinds of warp-knitted PP mesh were selected as the substrate material（identified as PP1,PP2,and PP3）,which were integrated with the NFM physical barriers to obtaining the composite meshes（namely C-PP1,C-PP2,and C-PP3）,using alginate hydrogel as the bonding media.Studies on the physicochemical properties,mechanical performances,in vitro biocompatibility,in vivo anti-adhesion effects,and tissue compatibility were investigated.The results show that the PP substrate is the critical component of composite meshes,especially playing a dominant role in mechanical support.There is a significant correlation between the porosity of PP prostheses and the meshes’ mechanical strength.Both PP substrates and their composite meshes have good biocompatibility,but the PP substrate structure,especially the porosity,notably affects cell growth and proliferation.In vivo experiments indicated that the bare substrates PP1 and PP3 displayed severe adhesion levels,and there was no significant difference between them.In comparison,the lowest adhesion grade was detected in the C-PP1 group,similar to the commercial Proceed meshes while notably less than C-PP3 samples.Moreover,the C-PP1 showed a milder inflammation reaction.These results prove that the PP substrate has s significant impact on the performance of the anti-adhesion composite meshes.We conclude that the NFM barrier can be incorporated into the lightweight PP mesh with sufficient mechanical support to yield the composite mesh with better anti-adhesion properties and tissue compatibility. |
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