An innovative fabrication technology of hollow fiber membrane via nanopore size modality control for high clearance of uremic toxins in hemodialysis

Abstract

While the incidence of geriatric diseases is steadily increasing due to the aging population, the number of patients with end-stage kidney disease is also increasing significantly every year. Contrary to the increase in patients with kidney disease, the effectiveness of treatment modalities has not been developed significantly. Besides, a large number of patients with kidney disease are suffering from difficulties in maintaining a healthy life for a long period of time, or dying because their health does not fully recover. A normal kidney filters 120 liters of blood per day from the kidneys and removes various uremic toxins from the blood and excretes them in the urine. However, in the case of patients with kidney failure the kidneys do not function and it is impossible to eliminate uremic toxins without dialysis or kidney transplantation treatment. Although there are some kinds of kidney disease treatment, the majority of patients with end-stage kidney disease receive hemodialysis treatment, which is the representative treatment, to maintain life 2-3 times a week for 4 hours each time. The hemodialysis membrane, which is the most important factor in determining the efficiency of hemodialysis, is excellent in removing uremic toxins with small molecular weight, comparable to a healthy kidney. Nevertheless, the performance to sufficiently remove large-middle molecular weight of uremic toxins is still insufficient. Moreover, so-called protein-bound uremic toxins are difficult to remove due to its size similar with albumin and characteristic binding to protein. Since they are directly associated with an increased risk of cardiovascular disease and death, removal efficiency of protein-bound uremic toxins has necessity of improvement. In order to increase the removal efficiency including from small molecular weight to protein-bound uremic toxins, it is necessary to study the pathway of uremic toxins removal, and possess a high-performance hemodialysis membranes are required to realize it. This work aimed, in chapter 3, to fabricate novel hemodialysis membranes under different inner diameters with approaching two classes: high-flux (M#1, M#2) and high molecular weight retention onset (M#3, M#4). The results showed that membrane with smaller inner diameter (M#1: 218 µm) performed a superior removal of small molecules i.e., urea: 266,394 mg/m^2 and creatinine: 11,985 mg/m^2. Spinning conditions, such as bore and dope solution flowrate, had a significant impact on pore size distribution, porosity, and dimensions, but not entirely on the membrane structure. These factors are crucial to govern the efficiency of uremic toxin clearance and the level of protein loss/leaking. Consequently, a high molecular weight retention onset of M#4 at 13,998 Da favored enhanced removal of middle molecules, resulting in lysozyme removal of 5,120 mg/m^2 and a high sieving coefficient of β2-microglobulin (0.91). A minimized loss (2.46 g/session) and minor leaking (0.08 g/session) of protein were attained in M#4 e.g., molecular weight retention onset class. Notably, we first explored the removal pathway of protein-bound uremic toxins with i) Free Form-protein-bound uremic toxins removal by diffusion ii) Free Form-protein-bound uremic toxins removal by adsorption iii) Bovine serum albumin (BSA)-protein-bound uremic toxins conjugate adsorption on a membrane, and iv) Leaking of BSA-protein-bound uremic toxins conjugate to the dialysate. Our high-flux and molecular weight retention onset membranes removed hippuric acid of 2,911 mg/m^2; 3,476 mg/m^2, indoxyl sulfate of 1,640 mg/m^2; 1,452 mg/m^2, p-cresol of 3,1469 mg/m^2; 3,702 mg/m^2, respectively. Overall, our study proposes a promising membrane for hemodialysis application that exhibited either higher flux or high molecular weight retention onset compared to the commercial membranes. Their properties facilitate an increase in the removal of middle molecules but still retain a minimized loss of protein and minor leakage. To realize improvement in hemodialysis hollow fiber membrane, we aimed to control pores and internal structure of hollow fiber membrane by fabricating a dual-layer using a triple nozzle. Two different pore formers i.e., polyethylene glycol (PEG), poly vinyl pyrrolidone (PVP) separately prepared in the polyethersulfone (PES) dope solutions were used for spinning the dual-layer. As an outcome of this work, nanoscale pores could be formed on the lumen side (26.8-33.2 nm), and the open pores continuously increased the size toward the shell side. Thanks to outstanding pore structure, our fabricated membrane was able to possess a remarkable water permeability of 296.2±5.7 L/m^2·h·bar and an extremely low BSA loss rate of 0.06±0.02 % e.g., high BSA retention of 99.94%. As a result of these properties, the studied membranes are well suited for use in either blood purification or molecular sieving of biomedical materials and valuable source recovery from advanced water treatment.