Effects of mussel-inspired co-deposition of 2-hydroxymethyl methacrylate and poly (2-methoxyethyl acrylate) on the hydrophilicity and binding tendency of common hemodialysis membranes: Molecular dynamics simulations and molecular docking studies.

Despite advances in the field, hemoincompatibility remains a critical issue for hemodialysis (HD) as interactions between various human blood constituents and the polymeric structure of HD membranes results in complications such as activation of immune system cascades. Adding hydrophilic polymer structures to the membranes is one modification approach that can decrease the extent of protein adsorption. This study conducted molecular dynamics (MD) simulations to understand the interactions between three human serum proteins (fibrinogen [FB], human serum albumin, and transferrin) and common HD membranes in untreated and modified forms. Poly(aryl ether sulfone) (PAES) and cellulose triacetate were used as the common dialyzer polymers, and membrane modifications were performed with 2-hydroxymethyl methacrylate (HEMA) and poly (2-methoxyethyl acrylate) (PMEA), using polydopamine-assisted co-deposition. The MD simulations were used as the framework for binding energy simulations, and molecular docking simulations were also performed to conduct molecular-level investigations between the two modifying polymers (HEMA and PMEA) and FB. Each of the three proteins acted differently with the membranes due to their unique nature and surface chemistry. The simulations show PMEA binds less intensively to FB with a higher number of hydrogen bonds, which reflects PMEA's superior performance compared to HEMA. The simulations suggest PAES membranes could be used in modified forms for blood-contact applications as they reflect the lowest binding energy to blood proteins.

Hemodialysis biocompatibility mathematical models to predict the inflammatory biomarkers released in dialysis patients based on hemodialysis membrane characteristics and clinical practices.

Chronic kidney disease affects millions of people around the globe and many patients rely on hemodialysis (HD) to survive. HD is associated with undesired life-threatening side effects that are linked to membrane biocompatibility and clinical operating conditions. The present study develops a mathematical model to predict the inflammatory biomarkers released in HD patients based on membrane morphology, chemistry, and interaction affinity. Based on the morphological characteristics of two clinical-grade HD membrane modules (CTA and PAES-PVP) commonly used in Canadian hospitals, a molecular docking study, and the release of inflammatory cytokines during HD and in vitro incubation experiments, we develop five sets of equations that describe the concentration of eight biomarkers (serpin/antithrombin-III, properdin, C5a, 1L-1α, 1L-1ß, C5b-9, IL6, vWF). The equations developed are functions of membrane properties (pore size, roughness, chemical composition, affinity to fibrinogen, and surface charge) and HD operating conditions (blood flow rate, Qb, and treatment time, t). We expand our model based on available clinical data and increase its range of applicability in terms of flow rate and treatment time. We also modify the original equations to expand their range of applicability in terms of membrane materials, allowing the prediction and validation of the inflammatory response of several clinical and synthesized membrane materials. Our affinity-based model solely relies on theoretical values of molecular docking, which can significantly reduce the experimental load related to the development of more biocompatible materials. Our model predictions agree with experimental clinical data and can guide the development of novel materials and support evidence-based membrane synthesis of HD membranes, reducing the need for trial-and-error approaches.

Biocompatibility enhancement of hemodialysis membranes using a novel zwitterionic copolymer: Experimental, in situ synchrotron imaging, molecular docking, and clinical inflammatory biomarkers investigations.

The aim of the current research study is to conduct a comparative assessment of biocompatibility of zwitterionic-coated polyether sulfone (PES) clinical hemodialysis (HD) membranes using both theoretical and experimental methods. Fibrinogen plays a key role in assessing membrane hemocompatibility since its membrane-surface adsorption triggers several biological reactions, complete thrombosis and embolism. As a result, adsorption of fibrinogen on the untreated PES surface and novel synthesized PES coated with poly 3-((3-(3-carboxy-2,5-dimethyltridecanamido) propyl) dimethylammonio) propane-1-sulfonate as a zwitterion (ZW) was compared. Specifically, the comparison was conducted using in situ synchrotron based micro computed tomography imaging (SR-µCT), Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy, and Scanning Electron Microscopy (SEM). The in situ SR-µCT showed that fibrinogen adsorption and membrane fouling were intense on PES membrane surface. However, there was insignificant fouling in the middle layer of zwitterion coated PES membrane (PES-ZW). Moderate shifting of peaks was observed in ATR-FTIR spectra of the adsorbed fibrinogen when compared to the bulk protein spectra, which may be due to the conformational transformations occurring during the adsorption process. The spectral features indicate that PES-ZW surface has a lower adsorption affinity for fibrinogen than that for the PES surface. In this innovative study, the use of molecular modeling docking to evaluate the interaction of fibrinogen active pose with PES-ZW and PES models with the aim of gaining an in depth understanding of the functional group responsible for the interactions was explored. The PES and PES/zwitterion hemodialysis membrane models indicated minimum binding energies with fibrinogen by -6.00 and -6.70 kcal/mol, respectively. Docking studies thus suggest that the membrane's sulfone functional groups play an essential key role during the fibrinogen interaction and adsorption. The HD patients' uremic samples were incubated in vitro with PES and PES-ZW membranes for the inflammatory biomarkers released of Serpin/Antithrombin-III, Properdin, C5a, IL-1α, IL-1ß, TNF-α, and IL6. This study's results emphasize that even though a neutral charge of synthesized novel zwitterion PES, which enhances biocompatibility, the sulfone group still significantly affected the interactions with fibrinogen.

Case studies of clinical hemodialysis membranes: influences of membrane morphology and biocompatibility on uremic blood-membrane interactions and inflammatory biomarkers.

End stage renal disease (ESRD) patients depend on hemodialysis (HD) as a life-sustaining treatment, but HD membrane properties play a critical role in blood activation during HD and can lead to severe patient outcomes. This study reports on a series of investigations on the common clinical HD membranes available in Canadian hospitals to explore the key reasons behind their susceptibility to blood activation and unstable cytokine. Clinical HD membranes composed of cellulose triacetate (CTA) and polyvinylpyrrolidone: polyarylethersulfone (PAES: PVP) were thoroughly characterized in terms of morphology and chemical composition. Membrane-surface interactions with uremic blood samples after HD treatment were probed using Fourier Transform Infra-Red (FTIR) and Raman spectroscopic techniques in order to understand changes in chemistry on membrane fibers. In addition, as part of this innovative study, we utilized Molecular Modeling Docking to examine the interactions of human blood proteins and membrane models to gain an in-depth understanding of functional group types responsible for perceived interactions. In-vitro adsorption of fibrinogen on different clinical HD membranes was compared at similar clinical operating conditions. Samples were collected from dialysis patients to ascertain the extent of inflammatory biomarkers released, before, during (30 and 90 min) and after dialysis (4 h). Collected blood samples were analyzed using Luminex assays for the inflammatory biomarkers of Serpin/Antithrombin-III, Properdin, C5a, 1L-1α, 1L-1ß, TNF-α, IL6, and vWF. We have likewise incubated uremic blood in vitro with the two membrane materials to determine the impact that membrane materials pose in favor of activation away from the hydrodynamics influences. The results of our morphological, chemical, spectroscopic, and in vitro incubation analyses indicate that CTA membranes have a smoother surface and higher biocompatibility than PAES: PVP membranes, however, it has smaller pore size distribution, which results in poor clearance of a broad spectrum of uremic toxins. However, the rougher surface and greater hydrophilicity of PAES: PVP membranes increases red blood cell rupture at the membrane surface, which promotes protein adsorption and biochemical cascade reactions. Molecular docking studies indicate sulfone functional groups play an important role in the adsorption of proteins and receptors. PAES: PVP membranes result in slower but greater adsorption of fibrinogen, but are more likely to experience reversible and irreversible fouling as well as backfiltration. Our major finding is that a single dialysis session, even with a more biocompatible membrane such as CTA, increases the levels of complement and inflammation factors, but to a milder extent than dialysis with a PAES membrane.

A surface-enhanced Raman scattering-based approach for rapid and highly sensitive quantitative analysis of 3-carboxy-4-methyl-5-propyl-2-furanpropionate and indole-3-acetic acid in saline, human serum and uremic serum of patients with chronic kidney disease.

3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) and indole-3-acetic acid (IAA) are critical protein-bound uremic toxins that occur during chronic kidney disease (CKD). This study offers the first reported instance of surface-enhanced Raman scattering (SERS) coupled with an Au nanoparticle substrate for the simple quantification of CMPF and IAA in human serum samples. The detection limits of the CMPF and IAA analysis were estimated to be 0.04 nM (S/N = 3) and 0.05 µM (S/N = 3), respectively. The results demonstrate that the SERS technique is fast-acting and highly sensitive when it comes to the simultaneous and individual quantitative detection of CMPF and IAA in biological samples. We believe that this analytical tool could serve as a very useful method for practical applications during the analysis of CMPF and IAA in the serum and urine of patients at all stages of CKD and of healthy volunteers as well as in various reservoirs.