Liu Fu Team: Series made progress in the field of anticoagulation self dialyzer

According to the report, \”The Lancet\” latest \”1990–2017 global, regional and national burden of chronic kidney disease: Global Burden of Disease Study 2017 system analysis\” that, as of 2017, the global number of people with chronic kidney disease patients up to 697 500 000 which amounted to 132.3 million the number of Chinese kidney disease, the prevalence rate of 10%. Chinese end-stage kidney patients in 2014 (ESRD) patients with nearly 200 million people, according to the US Renal Data System statistics chronic kidney disease and finally the development of ESRD ratio of 1.5% were estimated in 2030 will reach 315 million this staggering figure. ESRD patients requiring dialysis for life to maintain normal life needs, but affected by various factors, the proportion of China ESRD patients receiving hemodialysis treatment is only about 15%, far lower than the global cure rate of 37%. With health insurance coverage and improve the penetration of instruments, the number of patients treated with hemodialysis China continued to grow, become great potential blue ocean market, expected to reach 100 billion. At present, the domestic high-end market mainly hemodialysis Fresenius occupied by Germany, the United States Campbell, Japan Nipro and so on. High blood dialyzer belonging to \”strangle hold\” in the field of medical devices and materials technology, research and development of dialyzers with independent intellectual property rights and market competitiveness has an important livelihood and social significance. Mainstream types of hemodialysis membranes on the market polysulfone membrane PS (Fresenius, Braun, Toray, Belk, Weigao), polyether sulfone film PES (European race, Penny, Nipro, Belk ), polymethyl methacrylate PMMA (Toray). However, poor blood compatibility of polymer materials, upon contact with blood coagulation cascade triggered easily lead to thrombosis formation on the surface of a dialysis membrane, leading to clogging of the membrane, the membrane flux substantially attenuated, reducing the clearance of toxins; and also will trigger complement activation in vivo, the hemodialysis membrane attack the body\’s immune system. In clinical applications, generally require injection of heparin (unfractionated heparin or low molecular weight heparin) to inhibit the formation of thrombus within the dialyzer. But the metabolism of heparin difficulties, which for some patients had bleeding is not applicable, and long-term heparin also lead to thrombocytopenia, hyperkalemia, and osteoporosis. Thereby increasing the blood compatibility of dialysis membrane material developed from anticoagulant dialysis, heparin-free dialysis is hemodialysis trends. Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences Liu, researchers group from Membrane Science began systematic study dialysis membrane areas 2014, has passed the membrane surface dopamine fixed heparin (Journal of 2014 , 452, 390-399), zwitterionic film surface (Journal of membrane Science 2015, 475, 469-479), surface hydrophilizing (ACS Biomaterials Science & Engineering, 2016, 2 (12), 2207-2216), hirudin membrane surface modifying (Journal of membrane Science 2017, 523, 505-514), etc. to improve the blood compatibility of the material, disclosed mechanism of resistance to surface membrane protein adsorption and heparin anticoagulant molecule inhibits the coagulation cascade effect , as shown in FIG. Based on this, the development of a series of anticoagulant coating strategy, at home and abroad from the first to achieve a preparation of anticoagulation dialyzer, for extracorporeal blood contact material (such as artificial kidney, artificial lung and lines ECMO) with blood design and fabrication of the capacitive coating is of great significance.

FIG 1 the inner wall of the hollow fiber membranes extracorporeal blood coagulation / anticoagulation schematic mechanism

1) Preparation of swollen cross-linked interfacial anticoagulant from the dialyzer: a hollow fiber 10000 by the dialyzer of hollow fiber membrane encapsulation composition, typically less than the inner diameter of the yam 200 μm, and the hydrophilic modification anticoagulation achieved with very large molecules in challenging the confinement micron channel. Many of the current research improved anticoagulant properties of materials through physical blending or chemical grafting manner, but the complexity and controllable modifying substance, and compatibility with the modified step difference of the base material, so that these studies limited to flat sheet membranes to carry out work. To solve this problem, the team developed a Top-down interface migration and cross-linking functional strategies (Journal of Membrane Science 2016 based microporous membrane,520, 769-778, Journal of Membrane Science 2016, 513, 166-176), to achieve a modified anticoagulant molecules microporous membrane surface, further having a hydrophilic group was synthesized by controlled radical polymerization techniques (vinylpyrrolidone ) and anticoagulant group (sulfonic acid group and carboxylic acid groups), the copolymer having the structure of sequence alignment, a uniform distribution of the polymer in the dialyzer anticoagulant confinement channel by microfluidics, and cross-interface fixing, and finally through anti-protein adsorption mechanism of anticoagulation sulfonic acid groups of the hydrophilic group to improve the blood compatibility synergistic dialyzer. Related work published in the Journal of Membrane Science 2018, 563, 115-125. 2) hydrophobic interaction based dialyzers prepared from anticoagulation: difficult to clean hemodialyzer hollow fiber membrane as much as the number of fine diameter, such that the remaining organic solvent and small molecules unreacted monomer clean. Therefore, to reduce the residual organic solvent molecules or chemical modification process using green solvents and reduce the use of chemical modification process of the monomer solution is extremely effective. Common hemodialyzer plurality of polymer materials (such as polysulfone), hydrophobic character which readily adsorb proteins in the blood coagulation cascade to initiate thrombus. Team synthesized by radical polymerization of an amphiphilic polymer of poly (lauryl methacrylate – styrene sulfonate – acrylic acid) (P (LMA-SSNa-AA)), with long alkyl hydrophobic side chains. The amphiphilic polymer can be well dispersed in N, N- dimethylformamide (DMF) / water (1: 9, V) mixed solvent, using confinement flow control technology in a modified solution hemodialyzer inside the loop, the use of a hydrophobic membrane material properties of the heparin-adsorbed modifying substance adsorbed uniformly on the surface of the dialysis membrane. This modification is simple manner, to form a simple modification of the system, reducing the participation of an organic solvent, while achieving improvement in compatibility dialyzer blood, it is important for the subsequent industrial production and practical application. Related work published in the Journal of Membrane Science, 2020, 595, 117593. 3) Preparation of a gel implant interface from the dialyzer anticoagulant: To achieve the modification process without a solvent,Green, while enhancing the binding of the coating to the modified substrate membrane, modified to prevent falling off of the coating, the antigelling team cortex by interfacial gel implanted uniformly secured within the hollow fiber channel confinement, such as 2 shown in FIG. The whole process is based on modified water systems, completely avoiding organic solvent remaining in the dialyzer cleaning process. Based on a further understanding of the blood coagulation cascade, sodium alginate and research team modified acrylic polymers synthesized a rich source of carboxylate, anticoagulant mechanism is different from heparinoid substances, affinity to the surface of the film material the aqueous improve significantly, and capable of chelating calcium ions in the blood to block the coagulation cascade. Anticoagulation can not only improve the performance of the dialysis membrane, to inhibit complement activity, prevents activation of the immune system also has a very excellent performance. Azobisisobutyronitrile (AIBN) provides a connection point for the carboxylic acid in combination with the matrix polymer material, the gel skin carboxylic controlled thickness and controlled distribution by controlling the distribution and implantation amount of AIBN. This work has been published in the Journal of Membrane Science, 2020, 604, 118082 ..

FIG prepared by interfacial 2

4) Dialysis anticoagulant from the dialyzer renal failure in animal models implanted hydrogel manner: Prior work teams It has been used activated partial thromboplastin time (APTT) and thrombin time (TT) anticoagulant modified dialyzer time do the relevant tests. Based carboxylate and sulfonate-modified heparan dialyzer APTT> 600s, based on carboxylate-modified dialyzer APTT> 360s; time looks for the plasma TT also extended times, after modification proved dialyzer had an excellent anticoagulant properties. Meanwhile, enzyme-linked immunosorbent assay characterized from dialyzer having a low anticoagulation activity complement (C3a and of C5a), based restrictions laboratory conditions, the use of plasma and whole blood team demonstrated modified blood dialyzer having superior phase capacitive. To further demonstrate the self anticoagulation dialyzer has practical value in clinical practice, the team used a pig model of kidney failure provided by the Affiliated Hospital of Zhejiang Medical University (blood urea nitrogen (BUN> 6mmol / L), respectively, for the above-mentioned modified dialyzer when length less / no heparin dialysis 1h, as shown, in the blood after dialysis uremic, creatinine, inorganic phosphorus and β2- FIG microspheres 3Protein content and other small molecules in the toxin was measured, calculated clearance of toxins. Experimental animals characterized by dialysis three modified dialyzer with a reduced amount of injection of heparin or heparin have not successfully completed the dialysis process, compared to the unmodified dialyzer, an outer surface modified dialyzer \”hanging blood \”phenomenon has been significantly improved, and the amount of protein and the inner surface of the hollow fiber thrombus remaining also significantly reduced, as shown in FIG. Due to increased hydrophilicity modified dialyzer three modified in dialyzer clearance for a small molecule toxins has been significantly improved. Compare the performance difference data on Three modified dialyzer has been published in \”Membrane Science and Technology\”, 2020, 40 (1): 84-92.

Fig 3 a schematic flow chart of animal Dialysis
FIG 4 after three kinds of modified animal Dialysis dialyzer dialyzer unmodified the outer surface and an inner surface phenomena linked to blood thrombus adhesion contrast

the research was supported by the national Natural Science Foundation of China (51973230), Zhejiang Province outstanding Youth Science Foundation (LR20E030002), Zhejiang high-level personnel of young top-notch (ZJWR0108020) Youth innovation Promotion outstanding members of the Chinese Academy of sciences (Y201848), Ningbo Science and technology Bureau (2017C110034,2014B81004) funding support.