Elsevier

Journal of Membrane Science

Volume 582, 15 July 2019, Pages 151-163
Journal of Membrane Science

Novel thin-film nanofibrous composite membranes containing directional toxin transport nanochannels for efficient and safe hemodialysis application

https://doi.org/10.1016/j.memsci.2019.04.006Get rights and content

Highlights

  • Novel TFNC membranes containing toxin transport nanochannels were obtained.

  • Heparin functionalized MWCNTs were synthesized via a biomimetic approach.

  • The membranes exhibited efficient toxins removal without sacrificing selectivity.

  • The membranes showed low protein adsorption and good blood compatibility.

Abstract

Polymeric hemodialysis (HD) membranes with limited porosities, tortuous pores, and broad pore size distributions suffer from a trade-off between permeability-i.e., how fast toxins pass through the membranes-and selectivity-i.e., to what extent necessary proteins are retained. Here, a novel thin-film nanofibrous composite (TFNC) membrane, composed of an electrospun polyacrylonitrile (PAN) nanofibrous support layer and a chemically cross-linked polyvinyl alcohol (PVA) separation layer filled with heparin functionalized multi-walled carbon nanotubes (Hep-g-pMWCNTs), was demonstrated for efficient and safe HD application. 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 membranes showed efficient toxins removal without sacrificing selectivity (with the urea clearance of 88.2%, lysozyme clearance of 58.6%, and bovine serum albumin retention of 98.4% in a 4 h simulating dialysis). Especially, the efficiency in removing middle molecule toxins increased obviously compared with the values reported to date. Besides, the membranes exhibited excellent hemocompatibility: high resistance to protein adsorption, suppressed platelet adhesion, favorable anticoagulant activity, limited hemolysis ratio, and low complement activation. These facts suggested that the Hep-g-pMWCNTs/PVA/PAN TFNC membranes with superior comprehensive performances presented great potential for HD application.

Introduction

Worldwide, kidney failure has become an increasing problem and millions of patients suffer from end stage renal disease (ESRD). Chronic/acute kidney malfunction will result in the increase of toxins in human body, and then lead to adverse effects or even uremia [1]. Hemodialysis (HD), which has been established for more than 50 years, is deemed as the most popular and viable clinical therapy [2]. In a dialyzer, HD membranes separate the bloodstream from dialysate stream. The toxins in blood of patients are removed via diffusive and convective transport across membranes, while essential plasma proteins are retained due to the pore size exclusion of membranes [3]. However, recent studies reported that due to the unsatisfactory toxins removal ratio, especially for the so-called middle molecule toxins (the size between 5000 and 60,000 Da), the mortality rates of patients with the duration longer than 3.7 years on HD ranged from 30% to 50%, without substantial improvement in the past few decades [4,5]. Therefore, the development of high performance membranes with higher and faster clearance of toxins has become a pivotal issue in HD treatment to improve the outcome of dialysis patients.

With the development of modern science, various materials and technologies have been applied in the fabrication of HD membranes. Cellulose and its derivatives were the first generation of materials used as HD membranes. These membranes only allowed the toxic molecules with the size below 2000 Da to pass slowly, as their structures were dense and homogeneous [6,7]. To allow the removal of higher molecular weight toxins, cellulose-based materials, in the past few years, have been replaced by the synthetic polymers such as polysulfone (PSf), polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene difluoride (PVDF), polylactic acid (PLA), and polyvinyl alcohol (PVA) [[8], [9], [10], [11], [12]]. These synthetic polymeric HD membranes with asymmetric structure were capable of eliminating the toxins of up to 5000 Da but rejecting nearly 100% middle molecule toxins. For example, Irfan et al. demonstrated that only 1.2% of lysozyme (14.4 kDa) could be cleaned out by pure PES membranes in a 4 h simulating dialysis [9]. To improve the removal ratio of these toxins, recent researchers concentrated on the optimization of membrane fabrication processes or the exploitation of new additives. Meyer et al. have demonstrated that poly(ethylene oxide)-block-poly(methyl methacrylate) (PEO-b-PMMA) could effectively be used as a functional additive to increase the separation performance of PVDF membranes [13]. Gao et al., Yu et al., and Zhu et al. prepared high-flux PLA membranes by incorporating poly(ethylene oxide) (PEO), polysulfone-graft-poly(lactic acid) (PSf-g-PLA), and poly(lactic acid)-block-poly(2-hydroxyethyl methacrylate) (PLA-PHEMA) [[14], [15], [16]]. Nevertheless, all these membranes fabricated by nonsolvent induced phase separation (NIPS) processes (i.e., polymers were dissolved in the solvent and precipitations took place in the nonsolvent bath) usually faced a trade-off between permeability and selectivity due to their broad pore size distributions [17]. Consequently, the presence of these additives improved the clearance of middle molecule toxins to some extent (∼30%), as they increased the pore size of membranes, at the expense of selectivity (proteins retention decrease to ∼90%) [[14], [15], [16]]. To break this universal upper bound relationship, we have demonstrated a new kind of thin-film nanofibrous composite (TFNC) HD membranes in our earlier report [18]. For our TFNC membranes, the nanofiber support layer with interconnected pores structure improved the permeability for middle molecule toxins (∼45% removal), and the ultrathin separation layer with narrow pore size distribution provided the high selectivity for proteins (∼98% retention). However, the transport rate of toxins remained limited due to the limited porosities and tortuous pores of the polymeric separation layers (i.e., the pores were only a small fraction and restricted by polymer chains in a tortuous manner). In this perspective, increasing the transport rate of toxins further while maintaining the high selectivity of the state-of-the-art TFNC HD membranes is a great challenge.

Recently, Yang et al. reported a self-assembled membrane composed of amyloid-like proteins for efficient dialysis, and molecules could be transported along the nanochannels formed in the voids of lysozyme oligomer aggregates [19]. Actually, the concept of “nanochannels” has attracted considerable interest in recent years because it provided a new strategy for regulating substance transportation. This concept was inspired by the aquaporin proteins of nature and the evolution of nanomaterials has enabled it to be used in various applications, including filtering, energy utilization, and biomedical uses [[20], [21], [22], [23]]. The carbon nanomaterials with different morphologies could exhibit unique physical, chemical, and biological properties [[24], [25], [26]]. In particular, multi-walled carbon nanotubes (MWCNTs) have shown tremendous potential in polymeric membrane systems due to their unique structure. According to Gusev's simulation [27], the interfacial regions constructed between nanotubes and polymer matrix could provide highly efficient nanochannels for molecular transport, which was predicted to be the most promising approach to increase the permeability of polymeric membranes without compromising selectivity. And the results of recent studies for the applications such as forward osmosis, reverse osmosis, and nanofiltration apparently supported this expectation [[28], [29], [30]]. These cases motivate us to incorporate MWCNTs into the polymeric separation layer of our TFNC membranes generating nanovoids as additional nanochannels to promote the transportation of toxins across the membranes. However, two challenges should be addressed to fabricate this novel nanostructured TFNC membranes. The incompatibility between inorganic MWCNTs and organic polymer is the first problem, which may lead large interfacial gaps and reduce the selectivity of membranes. Second, the favorable blood compatibility for these membranes is required because the potential toxicity of MWCNTs may cause adverse effects on HD patients. Dopamine (DA), a biological neurotransmitter molecule, is able to self-polymerize under alkaline conditions to form polydopamine (PDA) that can strongly adhere onto any solid surface [31]. More importantly, the adhered PDA can further covalently immobilize amine or thiol-based biopolymers under mild reaction conditions [32], rendering it an effective method of MWCNTs modification to overcome the limitations mentioned above.

This study aims to design the HD membranes with integrated efficient uremic toxins removal and high blood compatibility by incorporating biopolymer functionalized MWCNTs into the polymeric separation layer of TFNC membranes. Herein, an electrospun PAN nanofibrous scaffold is employed as the supporting layer due to its excellent thermal stability, chemical stability and electro-spinnability, and PVA with good hydrophilicity and biocompatibility is used as the material for the separation layer. Heparin is chosen as the model biopolymer because it has been widely used as a biocompatible anticoagulant in clinical HD [33]. Novel heparin functionalized MWCNTs (Hep-g-pMWCNTs) were synthesized and then used to modify the PVA/PAN TFNC membranes (Scheme 1). For the preparation of Hep-g-pMWCNTs, DA was spontaneously adhered to MWCNTs by pH-induced polymerization and then heparin was grafted onto the PDA adhered MWCNTs through catechol chemistry. Details about the reaction mechanism between the adhered PDA and heparin were shown in Fig. S1 in Supporting Information (SI). Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), and dynamic light scattering (DLS) were used to evaluate the as-prepared Hep-g-pMWCNTs. Then, the surface chemical components, morphology, permeability, mean effective pore size, surface porosity, simulating dialysis performance, and mechanical properties of the Hep-g-pMWCNTs/PVA/PAN TFNC membranes were systematically investigated. Moreover, the blood compatibility of the membranes was evaluated with protein adsorption, platelet adhesion, plasma recalcification time, hemolysis ratio, and complement activation.

Section snippets

Materials

PAN (Mw = 120 kDa) was supplied by Shanghai Jinshan Co., Ltd., China. PVA (Mw = 146–186 kDa), dopamine hydrochloride (purity 98%), and heparin sodium salt (>140 USP units/mg) were purchased from Sigma-Aldrich. Urea (purity 98%), lysozyme, bovine serum albumin (BSA), and p-dimethylaminobenzaldehyde (PDAB, purity 99%) were obtained from J&K Scientific Ltd., China. N,N′-dimethylformamide (DMF, purity>99.8%), glutaraldehyde (GA, 25 wt% aqueous solution), hydrochloric acid (HCl, CP), boric acid

Characterization of heparin functionalized MWCNTs

The chemistry of pristine MWCNTs, pMWCNTs, and Hep-g-pMWCNTs were characterized by FTIR spectrum. The results were shown in Fig. 1A. In terms of the pMWCNTs, there were three new adsorption bands at 3440, 1620, and 1506 cm−1, which corresponded to the hydroxy, indole, and indoline groups of PDA, respectively [11]. This result indicated that PDA had adhered onto MWCNTs successfully. After grafting of heparin, the new peaks appeared at 1190 and 1035 cm−1 were attributed to the asymmetric valence

Conclusions

In summary, a new class of TFNC membranes consisting of an electrospun PAN nanofibrous support layer and a cross-linked PVA separation layer filled with heparin functionalized MWCNTs (Hep-g-pMWCNTs) had been successfully fabricated for HD application. The aqueous stable Hep-g-pMWCNTs were prepared by a facile and green (no toxic reagent was used) approach. The Hep-g-pMWCNTs/PVA/PAN TFNC membranes could favorably combine highly efficient toxins removal with high plasma proteins retention (the

Acknowledgments

This work was supported by National Science Foundation of China (51273042), Program of Shanghai Science and Technology Innovation International Exchange and Cooperation (15230724700), Program for Innovative Research Team in University of Ministry of Education of China (IRT_16R13), Fundamental Research Funds for the Central Universities, and Graduate Student Innovation Fund of Donghua University (BCZD2018004).

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