Preparation And Properties Of Thin-Film Nanofibrous Composite Membranes For Hemodialysis

At present,kidney disease has affected more than 10%of the worldwide population and become one of the major threats to public health.Chronic/acute kidney malfunction will result in the increase of toxins in human body,and then lead to uremia.Hemodialysis is the most viable and efficient clinical therapy for the patients with end stage renal diseases.It is the process of removing blood from a patient,purifying that blood through the hemodialysis equipment(also called as artificial kidney),and then returning it to the patient's blood stream.The core element of a hemodialysis equipment is the hemodialysis membrane,which can eliminate toxic metabolites and excess water from blood via diffusive and convective transport across the membrane and prevent loss of necessary proteins due to the pore size exclusion of the membrane.Therefore,the research and development of high-performance hemodialysis membranes is the pivotal issue to enhance the quality of hemodialysis treatment and increase the patients'longevity.However,most relevant hemodialysis membranes are prepared by classical non-solvent induced phase separation(NIPS)process.Hemodialysis membranes prepared according to this method suffer from a typical tradeoff:it is paradoxical to reconcile the desire of high removal of middle-molecular toxic substances and high retention of big proteins simultaneously because of their broad pore size distribution.Besides,these hemodialysis membranes also suffer from a series of issues as membrane fouling,thrombus generation,and cytotoxicity,which will lead to an adverse effect on the patient health.In addition,dialysis fluid may be contaminated with biological contaminants(e.g.endotoxin),and using high-flux hemodialysis membranes also increases the risk of transfer of these contaminants from dialysate circuit into bloodstream.Herein,a thin-film nanofibrous composite(TFNC)membrane,consisting of a two-tier structure,i.e.,an ultrathin separation layer,and an electrospun nanofibrous supporting layer,was demonstrated as the hemodialysis membrane for the first time.On this basis,novel high-performance TFNC hemodialysis membranes were developed by adjusting the pore structure,surface morphology,and chemical composition of the separation layer and designing the material of the support layer.Meanwhile,the relationship between the material,structure,and performance of the TFNC hemodialysis membranes was studied systematically.Detailed studies are as follow:1.TFNC membranes,consisting of a two-tier composite structure,i.e.,an ultrathin separation layer and an electrospun nanofibrous supporting layer,were demonstrated as the hemodialysis membranes for the first time.Herein,an electrospun PAN nanofibrous scaffold was employed as the supporting layer due to its excellent thermal stability,chemical stability,and electro-spinnability,PVA with good hydrophilicity and biocompatibility was used as the material for the separation layer.The ultrathin hydrophilic crosslinked PVA separation layer with a narrow pore-size distribution provided the high selectivity(the sieving coefficient for urea,lysozyme and bovine serum albumin(BSA)was 1.0,0.75 and 0.05,respectively),and the PAN nanofibrous support layer with a highly interconnected pore structure offered the high permeability(290 L/m~2h pure water flux).The optimized PVA/PAN TFNC membrane exhibited excellent dialysis performances(88.2%urea clearance,58.6%lysozyme clearance,and 98.4%BSA retention in a4?h simulating dialysis).In addition,the PVA/PAN TFNC membrane also possessed excellent overall mechanical properties(the tensile strength of 13.9 MPa and the elongation at break of 55%)and comparable hemocompatibility properties.2.Heparin functionalized MWCNTs(Hep-g-MWCNTs)were incorporated into the crosslinked PVA separation layer of the TFNC membranes to prepare a novel TFNC hemodialysis membrane containing directional toxin transport nanochannels.For the preparation of Hep-g-pMWCNTs,dopamine(DA)was spontaneously adhered to MWCNTs by pH-induced polymerization and then heparin was grafted onto the polydopamine(PDA)adhered MWCNTs through catechol chemistry.Combining dialysis simulation experiments and pore-flow model,we demonstrated that the formation of free nanogaps at the interface between Hep-g-pMWCNTs and PVA matrix provided additional directional nanochannels for toxins to transport.The Hep-g-pMWCNTs/PVA/PAN TFNC membranes showed efficient toxins removal without sacrificing selectivity,especially for the middle-molecule uremic toxin removal,which was much more effective than the conventional hemodialysis membranes reported so far(with the urea clearance of 88.2%,lysozyme clearance of 58.6%,and BSA retention of 98.4%in a 4?h simulating dialysis).Besides,the Hep-g-pMWCNTs/PVA/PAN TFNC membranes also exhibited excellent hemocompatibility:high resistance to protein adsorption,suppressed platelet adhesion,favorable anticoagulant activity,limited hemolysis ratio,and low complement activation.3.The addition of heparin in the PVA coating solution could not only decrease the solution viscosity(from 9.1±0.4 to 6.4±0.3 mPa s),but also lead to the faster gel point of the solution(from 19.0 min to 14.2 min).By performing heparin-PVA mixture coating solution with relatively low viscosity but fast gelling process,a new kind of sub-micron ridged heparinized TFNC hemodialysis membranes were successfully fabricated.The formation of the sub-micron ridge structure could be attributed to the coating solution rheology variation caused by the heparin/PVA ratio change.Besides,the introduced heparin would covalently bind to PVA chains via Schiff-base reaction.Thus,the sub-micron ridged surface topography and heparin chemical modification synergistically endowed the membranes with excellent permeability,protein antifouling properties,anticoagulant activity,cytocompatibility,and hemodialysis performances.4.By using poly(ethyleneimine)(PEI)/poly(ether sulfones)(PES)nanofibrous affinity membrane as the supporting layer,a novel TFNC hemodialysis membrane with combined removal of uremic toxins from blood and endotoxins from dialysate were successfully fabricated.The PEI/PES nanofibrous affinity membrane was fabricated by electrospinning technique followed by solvent etching in crosslinking solution.The maximum absorption capacity(from Freundlich isotherm data)of the optimized PEI/PES nanofibrous affinity membrane for endotoxin was 5667EU/g,and the adsorption processes became saturated after 4 h.The application of PEI/PES nanofibrous affinity membrane as the supporting layer of the TFNC hemodialysis membrane not only achieved the combined removal of uremic toxins from blood and endotoxins from dialysate(180.5×10~3 EU/m~2 endotoxin removal at 4?h simulating dialysis),but also avoided the transport of endotoxin from the dialysate to the bloodstream during hemodialysis.To sum up,this study represented the first attempt of the TFNC membranes for their potential application in hemodialysis.The unique two-tier structure broke the universal upper bound relationship between the permeability and selectivity of the conventional polymeric hemodialysis membranes.Besides,directional toxin transport nanochannels were incorporated into the separation layer of the TFNC membranes to achieve efficient toxins removal without sacrificing selectivity.Moreover,by combining physical surface topography with chemical composition modification,the TFNC membranes showed excellent permeability,protein antifouling properties,anticoagulant activity,cytocompatibility,and hemodialysis performances.In addition,nanofibrous affinity membrane was employed as the supporting layer of the TFNC membrane to achieve the combined removal of uremic toxins from blood and endotoxins from dialysate.Given this,we anticipate that this study will provide new insights and inspirations for constructing novel high-performance hemodialysis membranes.