Construction Of Nanofibrous Composite Membranes And Composite Microspheres For Blood Purification And Its Removal Mechanism Of Biological Toxins

Kidney disease has become an increasingly serious and common problem with the rapid development of society and gradually transforms into uremia at the late stage of kidney failure with high morbidity and mortality in the world.The kidney transplantation technology is limited by the severe shortage of donors,and the blood purification technology has become the main method to treat the patients with kidney diseases.At present,the most widely used blood purification technology is hemodialysis,hemoperfusion or the combination of these two technologies.The core component of hemodialysis is dialysis membrane,but the uremic toxins removal efficiency especially for medium molecular uremic toxins is not satisfactory for current dialysis membranes.At present,hemoperfusion is the most effective treatment for the removal of medium molecular uremic toxins,which is better than hemodialysis.Therefore,the development of high performance hemodialysis membrane with more efficient toxin removal and new adsorbents,as well as the improvement of their biocompatibility,is the most urgent task to improve the quality of life of patients with renal failure.In recent years,a new type of thin film nanofibrous composite?TFNC?ultrafiltration membrane with two-tier structure has been demonstrated to be applied to hemodialysis.Ultrathin functional hydrogel barrier layer is prepared by coating method and the the mesh size of the pure PVA hydrogel was tuned difficultly due to its very narrow casting window for preparing hydrogel barrier layer.In addition,the current adsorption material applied to the blood perfusion is single,thus a new type of nanomaterials with specific adsorption on uremic toxin is urgently needed.Blood dialysis and blood perfusion work together to build new dialysis/adsorption double function for the blood purification,and constructing a small portable artificial kidney device is very important to extend the life of the patients with kidney failure,as well as a far-reaching important exploration in blood purification field at present.Herein,novel TFNC ultrafiltration?UF?membranes consisting of PVA-based hydrogel barrier layer and electrospun polyacrlonitrile?PAN?nanofibrous supporting layer were designed and fabricated by combining electrospinning and conventional surface coating techniques.After modifying PVA,self-assembling on functional hydrogel barrier layer and constructing biomimetic nanochannels in functional hydrogel layer,the hydrophilicity and anti-fouling performance of hydrogel functional layer were systematically studied,and the biocompatibility of composite membrane as blood contacting material was also studied.The mesh size of hydrogel layer was tuned to analysis and research the effect on uremic toxin removal efficiency.According to the dialysis performance,the mesh size of hydrogel layer was optimized to obtain the excellent nanofibrous composite membrane.In addition,in order to make hemodialysis and hemoperfusion work together,gelatin/metal organic framework composite microspheres were prepared by freezing casting technology as adsorption materials for hemoperfusion,and their adsorption properties to biological toxins were studied,laying a foundation for the construction of portable?artificial kidney?.All details were as follows:Novel TFNC ultrafiltration?UF?membranes consisting of sulfonated poly?vinyl alcohol??s-PVA?blended PVA hydrogel barrier layer and electrospun PAN nanofibrous supporting layer were designed and fabricated by combining electrospinning and conventional surface coating techniques.The mesh sizes of hydrogel network of s-PVA/PVA barrier layer could be tuned by varying the blending content of s-PVA.The optimized s-PVA/PVA TFNC UF membrane?S-P-TFNC-1-3?possessed high pure water flux up to 380 Lm^-2h^-1bar^-1 with high bovine serum albumin?BSA?rejection?>90%?.Besides,the introduction of s-PVA into the hydrogel barrier layer endowed the TFNC membranes with enhanced hydrophilicity,antifouling property and biocompatibility?decreased protein adsorption,prolonged clotting time,suppressed platelet adhesion,lower hemolysis ratio and more benefits for cell proliferation?due to the presence of sulfonic groups.The dialysis simulation experiment results of S-P-TFNC-1-3 showed that 84.2%of urea and 60.9%of lysozyme were cleaned and over 95%of BSA was retained after 4h dialysis process.Especially,the removal of middle-molecule uremic toxin was more efficient than conventional hemodialysis membranes reported so far,and high retention of big proteins was achieved simultaneously.Zwitterionic multilayers on poly?vinyl alcohol??PVA?thin-film nanofibrous composite?TFNC?substrate were constructed via a facile surface engineered layer-by-layer?LBL?assembly of poly?sulfobetaine methacrylate??PSBMA?and tannic acid?TA,a polyphenol?,which endowed the modified membranes with multifunctionality for filtration of proteins and dyes and potential biomedical application.Characterizations of surface chemical structure and morphology of the modified membranes confirmed the successful zwitterionic self-assembly modification.The LBL-assembled membranes showed superior separation performance for filtration of proteins and dyes.Especially when the number of TA/PSBMA bilayer was 6,the PVA-6BL-M possessed high permeate flux(311.7 L m^-22 h^-1)and excellent rejection?99.9%?for 0.1 g/L Direct Red 80 solution at 0.6 MPa.After being covered more TA/PSBMA bilayers,the LBL-assembled membranes could not only sieve smaller molecules of proteins and dyes well,but also exhibit better anti-biofouling properties?higher water flux recovery ratio and the less BSA,E.coli and S.aureus bacteria adsorption?.In addition,the LBL-assembled membranes presented excellent blood compatibility?greatly reduced platelet adhesion,significantly increased clotting time and lower hemolysis ratio?.Finally,the clearance efficiency of LBL-assembled membranes to small and medium molecules toxins during the hemodialysis process is comparable with that of currently reported hemodialysis membranes,but LBL-assembled membranes hardly lose beneficial proteins,which is significantly better than the current dialysis membrane.Biomacromolecules and their assemblies exhibit the great potential for biomimetic construction of novel and functional nanomaterials.Sulfated silk nanofibrils?SSNFs?were firstly prepared with special designed sulfated silk fibroin molecule by a facile self-assembly technique,which were incorporated into the PVA hydrogel.Then they were together coated on the electrospun PAN nanofibrous scaffold to fabricate a novel PVA/SSNFs/PAN TFNC membranes for hemodiafiltration.Combining the results from filtration and hemodiafiltration tests,it could be deduced that the formation of nanogaps between PVA matrix and SSNFs provided more nanochannels for water and uremic toxins to transport rapidly through the functional layer.Especially the incorporation of SSNFs into PVA hydrogel layer endowed PVA/SSNFs TFNC hemodiafiltration membranes with rapid mid-molecule toxins removal channels.PVA/SSNFs-5could clear 65.7%of lysozyme,also maintaining 85.0%clearance of urea and 94.7%interception of BSA after 4 h of dialysis.In addition,the blood compatibility of PVA/SSNFs TFNC membranes was also enhanced after the introduction of biomimetic SSNFs due to the heparin-like structure of sulfated silk fibroin?SSF?.Hemoperfusion is superior to hemodialysis in the removal of medium molecular toxins,and is often combined with hemodialysis in the treatment of renal failure.We successfully synthesized the UiO-66 and UiO-66-NH₂ particles with octahedral structure.The diameters of UiO-66 and UiO-66-NH₂ particles were ranged from 200 to 300 nm.Then we blended the metal organic frameworks?MOFs?well with gelatin solution.The blended solution was suck by syringe and trickled into the liquid nitrogen drop by drop,and the liquid drop was dried by vacuum freeze drying.The dry microspheres were immersed in the dopamine solution for crosslinking to form the stable hydrogel microspheres.The interior of the composite beads had a structure similar to"honeycomb"containing a large number of micropores,and the sizes of the pores were very uniform,and the thickness of the honeycomb wall is also relatively uniform.The gelatin-based composite microspheres had good anticoagulant ability,good adsorption effect on small and medium molecular toxins in the body of patients with renal failure,and excellent adsorption ability on excessive bilirubin in the body of patients with liver failure.These results indicate that the gelatin/MOF composite beads had great potential in clinical hemoperfusion and provided a novel adsorbent material for the construction of portable artificial kidney.Consequently,the above series of studies have shown that the hydrogel barrier layer of thin film nanofibrous composite membrane can be tuned and modified for blood purification.The antifouling performance and biocompatibility can be improved and the mesh size of hydrogel layer can be optimized to design a high performance hemodialysis membrane.Then the hydrogel composite beads with high adsorption ability were constructed to remove toxins and work together with blood dialysis membranes,preparing double-function wearable portable artificial kidney devices for blood purification.