Portable, wearable and implantable artificial kidney systems:needs, opportunities and challenges

Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon footprint. Innovative dialysis technologies such as portable, wearable and implantable artificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An important challenge for these technologies is the need for continuous regeneration of a small volume of dialysate. Dialysate recycling systems based on sorbents have great potential for such regeneration. Novel dialysis membranes composed of polymeric or inorganic materials are being developed to improve the removal of a broad range of uraemic toxins, with low levels of membrane fouling compared with currently available synthetic membranes. To achieve more complete therapy and provide important biological functions, these novel membranes could be combined with bioartificial kidneys, which consist of artificial membranes combined with kidney cells. Implementation of these systems will require robust cell sourcing; cell culture facilities annexed to dialysis centres; large-scale, low-cost production; and quality control measures. These challenges are not trivial, and global initiatives involving all relevant stakeholders, including academics, industrialists, medical professionals and patients with kidney disease, are required to achieve important technological breakthroughs.</p

Achievements and challenges in bioartificial kidney development

Bioartificial kidneys (BAKs) combine a conventional hemofilter in series with a bioreactor unit containing renal epithelial cells. The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions. Currently, primary human renal proximal tubule cells are most relevant for clinical applications. However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges. BAKs have been applied in Phase I/II and Phase II clinical trials for the treatment of critically ill patients with acute renal failure. Significant effects on cytokine concentrations and long-term survival were observed. A subsequent Phase IIb clinical trial was discontinued after an interim analysis, and these results showed that further intense research on BAK-based therapies for acute renal failure was required. Development of BAK-based therapies for the treatment of patients suffering from end-stage renal disease is even more challenging, and related problems and research approaches are discussed herein, along with the development of mobile, portable, wearable and implantable devices

Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon footprint. Innovative dialysis technologies such as portable, wearable and implantable artificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An important challenge for these technologies is the need for continuous regeneration of a small volume of dialysate. Dialysate recycling systems based on sorbents have great potential for such regeneration. Novel dialysis membranes composed of polymeric or inorganic materials are being developed to improve the removal of a broad range of uraemic toxins, with low levels of membrane fouling compared with currently available synthetic membranes. To achieve more complete therapy and provide important biological functions, these novel membranes could be combined with bioartificial kidneys, which consist of artificial membranes combined with kidney cells. Implementation of these systems will require robust cell sourcing; cell culture facilities annexed to dialysis centres; large-scale, low-cost production; and quality control measures. These challenges are not trivial, and global initiatives involving all relevant stakeholders, including academics, industrialists, medical professionals and patients with kidney disease, are required to achieve important technological breakthroughs

Design of Peptoid-Based Coating to Reduce Biofouling in Gas Exchange Devices

In recent decades, membrane technology has been used commonly in biomedical area. However, membrane fouling is a widespread problem in different applications. One method to minimize fouling is through surface modification of membranes. My research explores a novel polymer to minimize nonspecific protein adsorption in biomedical applications. It firstly focuses on grafting the electrically neutral NMEG peptoid, containing 2-methoxyethyl side chains, to polysulfone (PSU) membrane via polydopamine. Contact angle measurements indicated that the hydrophilicity of the peptoid-grafted membranes was significantly improved while the pore size and strength of the membranes remained unchanged. The modified membranes showed an improved fouling resistance when tested with bovine serum albumin, lysozyme and fibrinogen proteins. To further investigate the low fouling surfaces, peptoid length was varied length of peptoids (NMEG5, NMEG10, NMEG15 and NMEG20). The effect of peptoid length and grafting density on fouling resistance of the membranes was studied. Static adsorption experiments with bovine serum albumin revealed that there is an optimal grafting density to improve fouling resistance of peptoid modified membranes, which was dependent on the length and amount of the grafted peptoids. To evaluate the application of modified hollow fibers in the biomedical field, a gas exchange system was designed and built. The peptoid-grafted hollow fiber membranes could preserve an excellent oxygen gas transmission compared with PSU membranes after exposure to bovine serum solution (35 mg/ml in PBS). To expand the understanding about dynamic fouling resistance of peptoid grafted surfaces, cross-flow filtration tests using bovine serum solution as the feed, was designed and built. According to the cross-flow filtration results, NMEG modified membranes showed a significant improvement in antifouling ability. Furthermore, flux recovery ratios obtained from NMEG modified membranes were much higher than unmodified membranes. The outcome of this study suggests that peptoids are a promising material for fouling-resistant membrane surface modificatio

A portable artificial kidney system using microfluidics and multi-step filtration

Natural kidney filtration is a compact, multi-step filtration process which passes wastes and exceeded fluids via microscale vessels in glomerulus and tubules. The principal renal replacement therapy (RRT), commonly called dialysis, is a single-step filtration process based on diffusion to replace kidney failure. Conventional dialysis is limited in its effectiveness (not a continuous treatment), its impact on quality of life (typically requiring patients to spend several days per week in a clinic), and its cost (large systems, requiring frequent membrane replacement). This thesis is an investigation into the feasibility of using microfluidics and membrane technology to create portable alternatives to dialysis systems. It starts with a comprehensive review of the state-of-the-art in portable artificial kidneys, microfluidics, membrane science, and other related fields. An innovative, multi-step process was designed to mimic kidney filtration using two membranes; one to filter out large particles and one to remove urea and recycle water, thus mitigating the need for a dialysate system. The underlying physics (the mixing and shear stress) of the mechanisms which could enhance filtration performance at microscale was then studied. It was found that by adding microspacers into narrow-channel flows, it is possible to significantly enhance filtration. Optimized 3D-printed spacer designs (e.g., a ‘gyroid’ spacer) showed flux enhancement of up to 93% (compared to a plain channel) when using a plasma mimicking solution. The use of different blood and plasma mimicking solutions also suggested a prior step to separate large biological components (e.g., cells, proteins) is helpful to reduce cell contact and fouling in membrane filtration. The potential use of microfluidic diode valves and micropumps for pressure and flowrate regulation in the proposed small-format system was discussed. Membrane processes which mimic the filtration function of the tubules and have the potential for integration into portable systems (e.g., reverse osmosis and membrane distillation) are demonstrated to be useful potential alternatives to dialysis in toxin removal and in returning clean water to the blood stream

A High Cell-Bearing Capacity Multibore Hollow Fiber Device for Macroencapsulation of Islets of Langerhans

Macroencapsulation of islets of Langerhans is a promising strategy for transplantation of insulin-producing cells in the absence of immunosuppression to treat type 1 diabetes. Hollow fiber membranes are of interest there because they offer a large surface-to-volume ratio and can potentially be retrieved or refilled. However, current available fibers have limitations in exchange of nutrients, oxygen, and delivery of insulin potentially impacting graft survival. Here, multibore hollow fibers for islets encapsulation are designed and tested. They consist of seven bores and are prepared using nondegradable polymers with high mechanical stability and low cell adhesion properties. Human islets encapsulated there have a glucose induced insulin response (GIIS) similar to nonencapsulated islets. During 7 d of cell culture in vitro, the GIIS increases with graded doses of islets demonstrating the suitability of the microenvironment for islet survival. Moreover, first implantation studies in mice demonstrate device material biocompatibility with minimal tissue responses. Besides, formation of new blood vessels close to the implanted device is observed, an important requirement for maintaining islet viability and fast exchange of glucose and insulin. The results indicate that the developed fibers have high islet bearing capacity and can potentially be applied for a clinically applicable bioartificial pancreas

Sulfonated polyethersulfone and functionalized multiwall carbon nanotubes/polyvinylpyrrolidone nanocomposite based hemodialysis membrane

Chemical modification of polymer and blending of suitable additives are the common methods used to improve the properties of polyethersulfone (PES) based hemodialysis membranes. In this research work, both methods are adopted and novel nanocomposite based additives were synthesized and blended with PES alone; and then with chemically modified PES (sulfonated PES (S-PES)). The whole research work was divided into three phases. In the first phase, the nanocomposites (NCs) were formed by mixing together the acid functionalized multiwall carbon nanotubes (f-MWCNT) and two different grades of polyvinylpyrrolidone (PVP-k90 and PVP-k30) in dimethylformamide and subsequently blended with PES. The f-MWCNT contained some hydrophilic functional groups (–COOH, and –OH) and heredity hydrophobic carbon part, which made it dual nature. On one side, it carbon part created sites for attachment for the hydrophobic polymer (PES) by hydrophobic–hydrophobic interaction and p–p stacking, whereas on the other side, its hydrophilic acid and hydroxyl groups attracted the hydrophilic sides of PVP by hydrogen bonding, dipole–dipole interaction and dispersion forces. Thus, f-MWCNT acted as the anchoring material between the PVP and PES in the membrane that also greatly reduced the leaching process of the additives and stabilize the membrane composition as shown by elution ratio test. The Fourier transform infrared spectroscopy spectra of fabricated membranes revealed that both types of NCs were physically bonded with PES by hydrogen bonding and the addition of NCs to PES, improved the internal capillary system of membranes as confirmed by field emission scanning electron microscope analysis. The results showed that f-MWCNT/PVP-k90 based membranes exhibited better performance than f-MWCNT/PVP-k30 based membranes in terms of flux rate, rejection rate and biocompatibility. The results from dialysis of uremic solutes unveiled that membrane formed by PVP-k90 based NCs demonstrated superior performance with 56.30%, 55.08% and 27.90% clearance ratio of urea, creatinine and lysozyme solutes, respectively. In the second phase, two best performance membranes of f-MWCNT/PVP-k90 NCs based were selected and then blended with variable ratio of S-PES. The outcome indicated that the blending of S-PES polymer, further enhanced the membrane biocompatibility and reduced the protein adsorption (bovine serum albumin, 55% and lysozyme, 65%), hemolysis process (74.80%) and illustrated longer clotting times than pristine and non-sulfonated membranes. The clearance ratio of uremic solutes was also improved and reached up to 57.3%, 57.1% and 32.4% of urea, creatinine and lysozyme, respectively. Thus, the blending of S-PES and NCs in the PES membrane greatly improved the biocompatibility and removal ability of uremic solutes. In the third and final phase, the hollow fiber (HF) membranes were spun using S-PES and PVPk90/f-MWCNT based NCs and the HF membrane characteristics and dialysis performances were evaluated. The results showed that HF membrane had a good flux rate (29.8l/h.m2.bar), low molecular weight cut off (29-34 kDa) than pristine PES membranes. The dialysis tests confirmed that the HF membranes illustrated 72.7%, 75.1% and 35.4% clearance ratio of urea, creatinine and lysozyme solutes, especially. Thus, the blending of S-PES and NCs in the PES membrane highly improved the biocompatibility and removal ability of uremic solutes and it can be used in commercial grade dialyzers