| Hemoperfusion is one of the most effective methods for removing blood toxins of liver failure, such as bilirubin. The core device of hemoperfusion is the adsorption column. Improving the anticoagulant activity of the adsorption column is the one of the key problems that needs to be solved. Nowadays, the clinical anticoagulant method is the intravenous injection of a high dose of heparin. However, long term use of this method may put the patients at high risk of bleeding or other severe side effects. Since the adsorption colomn consists of two parts, hull and the adsbrbent, the anticoagulant acitivty of the both parts needs to be improved. This paper proposed different heparinization strategies to improve the anticoagulant acitivity of the hull material and the adsbrbent. As for adsorbent, a chitosan/graphene oxide (GO) hyrbrid hydrogel was prepared, and its surface was covalently bonded with heparin so as to improve the anticoagulant activity. As for the surface of hull material, a chitosan/mesoporous silica composite heparin-releasing coating was constructed on the polydopamine (pDA)-modified surface.This first part of this paper focused on preparing the bilirubin adsorbent based on the novel carbon nanomaterials with anticoagulant acitivity. To select the optimal carbon nanomaterial, we firstly investigated the adsorption properties of mult-walled carbon nanotubes (MWCNTs) and graphene oxide (GO) for bilirubin. The MWCNTs and GO were prepared as magnetic MWCNTs and GO hydrogel for easy separation. Both magnetic MWCNTs and grapheme-based hydrogel showed excellent adsorption ability for bilirubin, and the maximum adsorption capacity was higher than250mg/g at30℃. Besides, the adsorption capacities of magnetic MWCNTs and graphene-based hydrogel for bilirubin were enhanced with the increase in temperature and the ionic strength, indicating that the adsorption mechanism between MWCNTs or graphene oxide is π-π. interactions.Since GO has a better dispersion ability, assembly property and larger specific surface areas, we furtherly select GO as an original material to fabricate bilirubin adsorbent. The mixture of chitosan and GO was freeze-dried to form a porous scaffold. The scaffold was neutralized with NaOH, forming a chotsan/GO hydrogel which was then modified with heparin. The resulting hydrogel displayed excellent mechanical flexibility, and can completely recover after more than80%compression. GO played the crucial role in bilirubin adsorption. When9.09%of GO was incorporated, the adsorption capacity of hep-CS/GH increased by2.7times compared with the pure chitosan hydrogel. Besides, hep-CS/GH performed high adsorption selectivity for bilirubin against albumin, and could effectively remove bilirubin from bilirubin-enriched serum with a clearance of16.9%(initial bilirubin concentration305mg/L, and volume ratio of adsorbent to serum1:16). Finally, after the hydrogel was modified with heparin, protein adsorption, platelet adhesion and hemolysis were reduced, and the plasma clotting time was prolonged from6.7to23.6min, indicating a better anticoagulant activity of hep-CS/GH.The second part of this paper is constructing heparin-releasing coating on the materials surface for improving the anticoagulant activity of hull material. We firstly investigated the method for immobilizing the heparin-releasing coating on materials’ surface by using pDA as an adhesive layer. The layer formation of dopamine or DOPA via self-polymerization on the three polymer substrates (PP, PVDF, nylon), and the stability of pDA layer and poly(DOPA) layer in strongly acidic and alkaline solution were explored. The layer formation of dopamine was different from that of DOPA. Dopamine could form thin layer on all the three substrates, but DOPA could not on PP substrate. Besides, the stability of pDA layer in strongly acidic and alkaline solution was also quite different from that of poly(DOPA). After washed in0.1M HCl for six times, the detachment percentage of pDA was30-57%, while that of poly(DOPA) was below10%. After washed in0.1M NaOH for six times, the detachment percentage of pDA was69-95%, while that of poly(DOPA) was about50%. Finally, oxidation of freshly formed films by NaIO4could significantly enhance their stability. For example, the detachment percentage of the fresh formed pDA layer on PP was as high as95%after washed in0.1M NaOH, while that of the NaIO4-oxidized pDA layer was only38%. This research paved the way to constrct the stable adhesive layer.In respect to the substrate-independent adhesive ability of pDA, we furtherly proposed a novel facile method for constructing a chitosan/mesoporous silica composite heparin-releasing coating on pDA-modified surface. Aminilized mesoporous silica SBA-15was used as heparin carrier. Taking advantage of the film-forming property of catechol-modified chitosan (CCS)/heparin and its reactivity with pDA layer, heparin-loaded SBA-15was embedded within the chitosan/heparin film which adhered on pDA-modified surface. SBA-15was firstly aminilized via silane coupling agent, and when the amine density was5.3×10-4mol/g, the adsorption capacity of SBA-15was promoted from32.9mg/gto189.7mg/g, since aminilizatio of SBA-15could enhance the adsorption capacity by electrastaic attraction. The pDA acted as an adhesive interlayer that stabilized the coating on the substrate. The sustained release rates of heparin from the coating ranged from15.8to2.1μg/cm2/h within8h. The heparin-releasing coating showed good blood compatibility and would not induce coagualation within2h. Compared with the direct injection of heparin; heparin releasing coating could significantly reduce the dose of heparin into blood, which improves the satfty of blood purification.In summary, the preparation of novel heparin-modified chitosan/GO hydrogel could also improve the adsorbent’s anticoagulant acitivity as well as the adsorption property. Besides, constructing heparin-releasing coating on the pDA-modifed substrate surface has the potential to significantly improve anticoagulant acitivity of hull material. The above results are very meaningful for reducing the dose of heparin administered during treatment, and pave the way for improving the satfty of blood purification. |
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