Blood-contacting Applications Research Articles

Design, development and performance of a Fe-Mn-Si-Cu alloy for bioabsorbable medical implants.

Bioabsorbable metallic alloys constitute a very challenging and innovative field, mainly aimed to develop the next generation of temporary medical implants. Degradation data, biological in vitro and in vivo tests are of major importance in particular for complex alloys, in which the individual element additions could enhance material performance and add functionalities. In this study, a novel Fe-Mn-Si-Cu alloy was carefully designed for vascular and blood-contact applications, and its microstructure, mechanical behavior, degradation behavior and biological performances were investigated accordingly. In previous studies, Mn and Si were found to be suitable elements to effectively enhance mechanical properties and accelerate corrosion rate in simulated body fluid. Cu was added for further grain refinement by the formation of small Cu-rich particles, potentially impacting mechanical properties and degradation behavior. In addition, the feasibility of inducing antibacterial effects in a Fe-Mn-Si-Cu alloy with low Cu content was investigated. The alloy was prepared firstly on a small scale by vacuum arc remelting, then on a larger scale by vacuum induction melting and converted into sheets by conventional thermomechanical processing techniques. Heat treatments were explored to find optimal microstructure conditions. The results confirm promising mechanical, degradation and biological performance in testing the material in in vitro conditions, showing that the degradation products are neither systematically cytotoxic nor have any hemotoxic effects. On the other hand, the expected antibacterial effects could not be confirmed.

ISO 10993-4 Compliant Hemocompatibility Evaluation of Gellan Gum Hybrid Hydrogels for Biomedical Applications.

This study examines the hemocompatibility of gellan-gum-based hybrid hydrogels, with varying gellan-gum concentrations and constant sodium alginate and silk fibroin concentrations, respectively, in accordance with ISO 10993-4 standards. While previous studies have focused on cytocompatibility, the hemocompatibility of these hydrogels remains underexplored. Hydrogels were formulated with 0.3%, 0.5%, 0.75%, and 1% gellan gum combined with 3% silk fibroin and 4.2% sodium alginate separately, using physical and ionic cross-linking. Swelling behavior was analyzed in phosphate (pH 7.4) and acetic (pH 1.2) buffers and surface morphology was examined by scanning electron microscopy (SEM). Hemocompatibility tests included complete blood count (CBC), coagulation assays, hemolysis index, erythrocyte morphology, and platelet adhesion analysis. Results showed that gellan gum-sodium alginate hydrogels exhibited faster swelling than gellan gum-silk fibroin formulations. SEM indicated smoother surfaces with sodium alginate, while silk fibroin increased roughness, further amplified by higher gellan-gum concentrations. Hemocompatibility assays confirmed normal profiles in formulations with 0.3%, 0.5%, and 0.75% gellan gum, while 1% gellan gum caused significant hemolytic and thrombogenic activity. These findings highlight the excellent hemocompatibility of gellan-gum-based hydrogels, especially the sodium alginate variants, supporting their potential in bioengineering, tissue engineering, and blood-contacting biomedical applications.

Synthesis, characterization, and surface modification of degradable polar hydrophobic ionic polyurethane nanoparticles for the delivery of therapeutics to vascular tissue

Degradable polar hydrophobic ionic polyurethanes (D-PHI) are an emerging class of biomaterials with particular significance for blood-contacting applications due to their immunomodulatory effects and highly customizable block chemistry. In this manuscript, D-PHI polymer was formulated as a nanoparticle excipient for the first time by inverse emulsion polymerization. The nanoparticles were optimized with consideration of diameter, surface charge, size variability, and yield as a delivery vehicle for a custom vascular therapeutic peptide. A layer-by-layer (LBL) surface modification technique using poly-L-lysine was integrated within the nanoparticle design to optimize therapeutic loading efficiency. Solvent pH played a pivotal role in emulsion micelle formation, LBL polymer secondary structure, and the polymer functional group interactions critical for high therapeutic loading. The resulting nanoparticle platform met target size (200 ± 20 nm), polydispersity (<0.07), and storage stability standards, was nontoxic, and did not affect therapeutic peptide bioactivity in vitro. Surface-modified D-PHI nanoparticles can be reproducibly manufactured at low cost, generating a highly customizable excipient platform suitable for delivery of biomolecular therapeutics. These nanoparticles have potential applications in vascular drug delivery via localized infusion, drug eluting stents, and drug-coated angioplasty balloons. Statement of significanceNanoscale excipients have become critical in the delivery of many therapeutics to enhance drug stability and targeted biodistribution through careful design of nanoparticle composition, surface chemistry, and size. This manuscript describes the development of a nanoparticle excipient derived from an immunomodulatory degradable polar hydrophobic ionic polyurethane, in combination with a layer-by-layer surface modification approach utilizing poly-L-lysine, to transport a mimetic peptide targeting smooth muscle cell migration in vascular disease. The nanoparticle platform draws on the effect of pH to maximize drug loading and tailor particle properties. The low cost and easily reproducible system presents a highly customizable platform that can be adapted for therapeutic delivery across a wide range of clinical indications.

Surface Engineering for Endothelium-Mimicking Functions to Combat Infection and Thrombosis in Extracorporeal Life Support Technologies.

Blood-contacting medical devices routinely fail from the cascading effects of biofouling toward infection and thrombosis. Nitric oxide (NO) is an integral part of endothelial homeostasis, maintaining platelet quiescence and facilitating oxidative/nitrosative stress against pathogens. Recently, it is shown that the surface evolution of NO can mediate cell-surface interactions. However, this technique alone cannot prevent the biofouling inherent in device failure with dynamic blood-contacting applications. This work proposes an endothelium-mimicking surface design pairing controlled NO release with an inherently antifouling polyethylene glycol interface (NO+PEG). This simple, robust, and scalable platform develops surface-localized NO availability with surface hydration, leading to a significant reduction in protein adsorption as well as bacteria/platelet adhesion. Further in vivo thrombogenicity studies show a decrease in thrombus formation on NO+PEG interfaces, with preservation of circulating platelet and white blood cell counts, maintenance of activated clotting time, and reduced coagulation cascade activation. It is anticipated that this bio-inspired surface design will enable a facile alternative to existing surface technologies to address clinical manifestations of infection and thrombosis in dynamic blood-contacting environments.

Construct functional PEGDA/CSMA/CuII photosensitive ink for SLA 3D printing of blood contact appliance

Stereolithography (SLA) is an emerging technology in three-dimensional printing that has garnered significant attention in the biomedical field due to its high printing fidelity, good biocompatibility, and high spatial resolution. Polyethylene glycol diacrylate (PEGDA) is commonly used as a photosensitive printing ink in SLA, and it possesses excellent biocompatibility, photosensitivity, processability, water solubility, and biomechanical tunability. Additionally, PEGDA exhibits unique anti-protein, platelet, and cell adhesion possibilities, making it a promising material for blood contact applications. However, cross-linking PEGDA using chain growth photopolymerization results in a high concentration of reactive functional groups, leading to high print volume shrinkage, decreased precision of the finished product, warping, deformation, and cracking. This study introduces a chemically modified methacryloylated chitosan (CSMA) as a cross-linking agent into the PEGDA ink. This strategy effectively reduces the volume shrinkage of the ink and imparts antimicrobial properties to the final product. The dual anticoagulation properties of PEGDA were achieved by loading divalent copper ion (CuII) into the ink, which better addresses the antimicrobial and anticoagulant needs in the physiological environment of blood. The results show that SLA printable inks based on PEGDA/CSMA/CuII have low swelling, high print fidelity, high stability, and good cell compatibility. Furthermore, by verifying the functionality of PEGDA/CSMA/CuII, the research shows that the bioprinting ink exhibits excellent antibacterial and anticoagulant properties, making it a promising material candidate for SLA 3D printing of blood purification, central venous catheter, and other semi-implanted blood materials. This study provides new ideas for developing multifunctional photosensitive inks in biomedical engineering.

Polyphenolic tannin-based polyelectrolyte multilayers on poly(vinyl chloride) for biocompatible and antiadhesive coatings with antimicrobial properties

Poly(vinyl chloride) (PVC), a synthetic polymer, is used in various biomedical applications, particularly in the development of catheters. PVC-based catheters are engineered for blood-contacting applications. However, these materials lack antimicrobial properties, resulting in bacterial proliferation and subsequent infections. To overcome this disadvantage, blood-compatible and antimicrobial polyphenolic tannin-based surface coatings, known as polyelectrolyte multilayers (PEMs), were adsorbed onto PVC for the first time. PEMs were created on reduced PVC (Red-PVC) or oxidized PVC (Oxi-PVC) substrates using the layer-by-layer (LbL) approach. An amino-functionalized polyphenolic tannin derivative (TN-NH2), commercially known as Tanfloc, and an unmodified polyphenolic tannin (TN), commercially known as Weibull black, were assembled (15 layers) on Oxi-PVC or Red-PVC at pH 5.0. PVC substrates and PEMs were characterized through atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and water contact angle (WCA) measurements. The PEMs showed enhanced wettability compared to the unmodified PVC, with water contact angles ranging from 42° to 38°. The root mean square (Rq) roughness of the PEMs ranged from 64.5 nm to 74.1 nm, while the unmodified PVC surface displayed a relatively smooth surface with a roughness of 5.4 nm. Stability tests demonstrated that the PEMs maintained their integrity in phosphate buffer (pH 7.4) over seven days at 37°C. The obtained PEMs were not toxic to human fibroblasts and human erythrocytes. The Live/Dead antimicrobial assay results indicated that the PEMs possessed biocidal activity against Pseudomonas aeruginosa (P. aeruginosa) and antiadhesive capacity toward Staphylococcus aureus (S. aureus) and P. aeruginosa after 24 h of incubation. Cytocompatible and antimicrobial tannin-based PEMs on modified PVC surfaces can represent a significant advancement in mitigating bacterial infections associated with PVC-based catheters.

In vivo assessment of dual-function submicron textured nitric oxide releasing catheters in a 7-day rabbit model

Catheter-induced thrombosis is a major contributor to infectious and mechanical complications of biomaterials that lead to device failure. Herein, a dualfunction submicron textured nitric oxide (NO)-releasing catheter was developed. The hemocompatibility and antithrombotic activity of vascular catheters were evaluated in both 20 h in vitro blood loop and 7 d in vivo rabbit model. Surface characterization assessments via atomic force microscopy show the durability of the submicron pattern after incorporation of NO donor S-nitroso-N-acetylpenicillamine (SNAP). The SNAP-doped catheters exhibited prolonged and controlled NO release mimicking the levels released by endothelium. Fabricated catheters showed cytocompatibility when evaluated against BJ human fibroblast cell lines. After 20h in vitro evaluation of catheters in a blood loop, textured-NO catheters exhibited a 13-times reduction in surface thrombus formation compared to the control catheters, which had 83% of the total area covered by clots. After the 7 d in vivo rabbit model, analysis on the catheter surface was examined via scanning electron microscopy, where significant reduction of platelet adhesion, fibrin mesh, and thrombi can be observed on the NO-releasing textured surfaces. Moreover, compared to relative controls, a 63% reduction in the degree of thrombus formation within the jugular vein was observed. Decreased levels of fibrotic tissue decomposition on the jugular vein and reduced platelet adhesion and thrombus formation on the texture of the NO-releasing catheter surface are indications of mitigated foreign body response. This study demonstrated a biocompatible and robust dual-functioning textured NO PU catheter in limiting fouling-induced complications for longer-term blood-contacting device applications. Statement of significanceCatheter-induced thrombosis is a major contributor to infectious and mechanical complications of biomaterials that lead to device failure. This study demonstrated a robust, biocompatible, dual-functioning textured nitric oxide (NO) polyurethane catheter in limiting fouling-induced complications for longer-term blood-contacting device applications.The fabricated catheters exhibited prolonged and controlled NO release that mimics endothelium levels. After the 7 d in vivo model, a significant reduction in platelet adhesion, fibrin mesh, and thrombi was observed on the NO-releasing textured catheters, along with decreased levels of fibrotic tissue decomposition on the jugular vein. Results illustrate that NO-textured catheter surface mitigates foreign body response.

Polyvinylpyrrolidone-stabilised gold nanoparticle coatings inhibit blood protein adsorption

Abstract In this work, the ability of polyvinylpyrrolidone (PVP)-stabilised gold nanoparticle (AuNP) coatings to inhibit blood protein adsorption was evaluated by studying time-resolved solid–liquid interactions of the coatings with the model blood protein bovine serum albumin (BSA). Inhibiting unspecific blood protein adsorption is of crucial importance for blood-contacting implant devices, e.g. vascular grafts, stents, artificial joints, and others, as a preventive strategy for bacterial biofilm formation. A quartz crystal microbalance was used in this work to coat the AuNPs on piezoelectric sensors and to follow time-resolved solid–liquid interactions with the proteins. The AuNP coatings were evaluated for their wettability by contact angle measurements, their surface morphology by light- and atomic force microscopy, and their chemical composition by energy-dispersive X-ray spectroscopy. Results revealed a homogeneous distribution of AuNPs on the sensor surface with a dry mass coverage of 3.37 ± 1.46 µg/cm2 and a contact angle of 25.2 ± 1.1°. Solid–liquid interaction studies by quartz crystal microbalance showed a high repellence of BSA from the PVP-stabilised AuNP coatings and the importance of the PVP in the mechanism of repellence. Furthermore, the conformation of the polymer on the coatings as well as its viscoelastic properties were revealed. Finally, the activated partial thrombin time test and fibrinogen adsorption studies revealed that the AuNPs do not accelerate blood coagulation and can partially inhibit the adhesion of fibrinogen, which is a crucial factor in the common blood coagulation cascade. Such AuNPs have the potential to be used in blood-contact medical applications.

HEMOCOMPATIBILITY STUDIES OF LAYER-BY-LAYER POLYELECTROLYTE COMPLEXES FOR BIO-BASED POLYMERS

Thrombogenesis is an important issue that causes blood-contacting biomedical device failure. This study focuses on hemocompatibility studies of novel blood-contacting polyelectrolyte complexes (PECs) for biomedical application designs. PEC films were fabricated from biobased polymers of silk fibroin (SF), chitosan (CH), and sodium alginate (AL) through the solvent casting method as well as Layer-by-Layer (LbL) technique. Characterization was carried out by Fourier-transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Atomic force microscopy (AFM), and Differential scanning calorimetry (DSC) analyses. FTIR spectra displayed all layers’ characteristic peaks of SF, CH, and AL. AFM images indicated that the addition of AL as an outer layer increased surface roughness. DSC analysis suggested that the best thermal stability has been observed with the CH outer layer of PECs. SEM micrograph analysis indicated that the morphologies of PECs were affected by the inclusion of the clopidogrel bisulfate (CLB). Hemocompatibility properties were investigated by complete blood count (CBC), prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), platelet adhesion, erythrocyte morphology analysis, in vitro cholesterol, and albumin level tests. These hemocompatibility analyses demonstrated that the PEC surfaces provide favourable principles to design and develop non-thrombogenic PECs for blood-contacting biomedical applications

Challenge of material haemocompatibility for microfluidic blood-contacting applications.

Biological applications of microfluidics technology is beginning to expand beyond the original focus of diagnostics, analytics and organ-on-chip devices. There is a growing interest in the development of microfluidic devices for therapeutic treatments, such as extra-corporeal haemodialysis and oxygenation. However, the great potential in this area comes with great challenges. Haemocompatibility of materials has long been a concern for blood-contacting medical devices, and microfluidic devices are no exception. The small channel size, high surface area to volume ratio and dynamic conditions integral to microchannels contribute to the blood-material interactions. This review will begin by describing features of microfluidic technology with a focus on blood-contacting applications. Material haemocompatibility will be discussed in the context of interactions with blood components, from the initial absorption of plasma proteins to the activation of cells and factors, and the contribution of these interactions to the coagulation cascade and thrombogenesis. Reference will be made to the testing requirements for medical devices in contact with blood, set out by International Standards in ISO 10993-4. Finally, we will review the techniques for improving microfluidic channel haemocompatibility through material surface modifications-including bioactive and biopassive coatings-and future directions.

Poly(2-hydroxyethyl methacrylate) hydrogels containing graphene-based materials for blood-contact applications: from soft inert to strong degradable material.

Degradable biomaterials for blood-contacting devices (BCDs) are associated with weak mechanical properties, high molecular weight of the degradation products and poor hemocompatibility. Herein, the inert and biocompatible FDA approved poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel was turned into a degradable material by incorporation of different amounts of a hydrolytically labile crosslinking agent, pentaerythritol tetrakis(3-mercaptopropionate). In situ addition of 1wt.% of oxidized graphene-based materials (GBMs) with different lateral sizes/thicknesses (single-layer graphene oxide, and oxidized forms of few-layer graphene materials) was performed to enhance the mechanical properties of hydrogels. An ultimate tensile strength increases up to 0.2 MPa (293% higher than degradable pHEMA) was obtained using oxidized few-layer graphene with 5 μm lateral size. Moreover, the incorporation of GBMs has demonstrated to simultaneously tune the degradation time, which ranged from 2 to 4 months. Notably, these features were achieved keeping not only the intrinsic properties of inert pHEMA regarding water uptake, wettability and cytocompatibility (short and long term), but also the non-fouling behavior towards human cells, platelets and bacteria. This new pHEMA hydrogel with degradation and biomechanical performance tuned by GBMs, can therefore be envisioned for different applications in tissue engineering, particularly for BCDs where non-fouling character is essential. STATEMENT OF SIGNIFICANCE: Suitable mechanical properties, low molecular weight of the degradation products and hemocompatibility are key features in degradable blood contacting devices (BCDs), and pave the way for significant improvement in the field. In here, a hydrogel with outstanding anti-adhesiveness (pHEMA) provides hemocompatibility, the presence of a degradable crosslinker provides degradability, and incorporation of graphene oxide reestablishes its strength, allowing tuning of both degradation and mechanical properties. Notably, these hydrogels simultaneously provide suitable water uptake, wettability, cytocompatibility (short and long term), no acute inflammatory response, and non-fouling behavior towards endothelial cells, platelets and bacteria. Such results highlight the potential of these hydrogels to be envisioned for applications in tissue engineered BCDs, namely as small diameter vascular grafts.

Synthesis and characterization of novel copper-doped modified bioactive glasses as advanced blood-contacting biomaterials

Bioactive glasses (BGs) are among the most popular biomaterial categories. Due to their biocompatibility, bioactivity, antimicrobial, and angiogenesis abilities, they are increasingly utilized in a variety of tissue-engineering applications. Despite the excellent properties of BGs, their use as blood-contact biomaterials has been restricted because of their influence on the activation of the coagulation cascade. In this study, a series of modified borate-based BGs (containing B2O3, MgO, K2O, Na2O, and different concentrations of CuO) were synthesized by a melting-derived method. The synthesized BGs exhibited anticoagulant properties thanks to removing blood-clotting elements including calcium, phosphate, and silica. The results indicated that all of the BGs were in a glassy phase and did not show any significant cytotoxicity. The modified BGs showed antibacterial properties against S. aureus and P. aeruginosa bacteria. The investigation of hemocompatibility also revealed that none of the groups caused red blood cell rupture or initiated the coagulation cascade. This research demonstrated that the incorporation of copper ions into the modified BGs could dramatically improve the endothelial cell proliferation, migration, vascular endothelial growth factor secretion, tube formation, and expression of angiogenesis-related genes (vascular endothelial growth factor , KDR, hypoxia-inducible factor-1α α, and endothelial nitric oxide), resulting in the promotion of angiogenesis properties. According to the findings, it is achievable to synthesize multifunctional BGs for use in blood-contact applications by combining increased angiogenesis, anticoagulant, and antibacterial properties suitable for vascular tissue engineering applications.

Enhanced hemocompatibility and antibacterial activity of biodegradable poly(ester-urethane) modified with quercetin and phosphorylcholine for durable blood-contacting applications.

This work developed innovative poly(ester-urethane) materials double-modified by quercetin (QC) and phosphorylcholine (PC) with improved antibacterial activity and hemocompatibility. The functional monomer of PC-diol was first synthesized via a click reaction between 2-methacryloyloxyethyl phosphorylcholine and α-thioglycerol; the NCO-terminated prepolymer was subsequently prepared by a one-pot condensation method of PC-diol, poly(ε-caprolactone) diol, and excess isophorone diisocyanate; finally, the prepolymer was chain-extended with QC to produce the linear products (PEU-PQs). 1H NMR, FT-IR, and XPS techniques confirmed the successful introduction of PC and QC, and the in-depth characterization of the cast PEU-PQ films was carried out. Although a low crystallinity was demonstrated by XRD and thermal analysis, the films exhibited excellent tensile stress and stretchability due to the interchain multiple hydrogen bonds. The introduction of PC groups enhanced the surface hydrophilicity, water absorption, and the in vitro hydrolytic degradation rate of the film materials. Inhibition zone tests presented that the QC-based PEU-PQs had effective antibacterial activity against E. coli and S. aureus. The biological evaluations of the materials were performed in vitro by protein absorption, platelet adhesion, and cytotoxic test and in vivo by subcutaneous implantation, which demonstrated superior surface hemocompatibility and biocompatibility. Collectively, the PEU-PQ biomaterials hold a prospective application in durable blood-contacting devices.

Improved Polymer Hemocompatibility for Blood-Contacting Applications via S-Nitrosoglutathione Impregnation.

Blood-contacting medical devices (BCMDs) are inevitably challenged by thrombi formation, leading to occlusion of flow and device failure. Ideal BCMDs seek to mimic the intrinsic antithrombotic properties of the human vasculature to locally prevent thrombotic complications, negating the need for systemic anticoagulation. An emerging category of BCMD technology utilizes nitric oxide (NO) as a hemocompatible agent, as the vasculature's endothelial layer naturally releases NO to inhibit platelet activation and consumption. In this paper, we report for the first time the novel impregnation of S-nitrosoglutathione (GSNO) into polymeric poly(vinyl chloride) (PVC) tubing via an optimized solvent-swelling method. Material testing revealed an optimized GSNO-PVC material that had adequate GSNO loading to achieve NO flux values within the physiological endothelial NO flux range for a 4 h period. Through in vitro hemocompatibility testing, the optimized material was deemed nonhemolytic (hemolytic index <2%) and capable of reducing platelet activation, suggesting that the material is suitable for contact with whole blood. Furthermore, an in vivo 4 h extracorporeal circulation (ECC) rabbit thrombogenicity model confirmed the blood biocompatibility of the optimized GSNO-PVC. Platelet count remained near 100% for the novel GSNO-impregnated PVC loops (1 h, 91.08 ± 6.27%; 2 h, 95.68 ± 0.61%; 3 h, 97.56 ± 8.59%; 4 h, 95.11 ± 8.30%). In contrast, unmodified PVC ECC loops occluded shortly after the 2 h time point and viable platelet counts quickly diminished (1 h, 85.67 ± 12.62%; 2 h, 54.46 ± 10.53%; 3 h, n/a; 4 h, n/a). The blood clots for GSNO-PVC loops (190.73 ± 72.46 mg) compared to those of unmodified PVC loops (866.50 ± 197.98 mg) were significantly smaller (p < 0.01). The results presented in this paper recommend further investigation in long-term animal models and suggest that GSNO-PVC has the potential to serve as an alternative to systemic anticoagulation in BCMD applications.

Blood-incompatibility in haemodialysis: alleviating inflammation and effects of coagulation.

ABSTRACTBlood-incompatibility is an inevitability of all blood-contacting device applications and therapies, including haemodialysis (HD). Blood leaving the environment of blood vessels and the protection of the endothelium is confronted with several stimuli of the extracorporeal circuit (ECC), triggering the activation of blood cells and various biochemical pathways of plasma. Prevention of blood coagulation, a major obstacle that needed to be overcome to make HD possible, remains an issue to contend with. While anticoagulation (mainly with heparin) successfully prevents clotting within the ECC to allow removal of uraemic toxins across the dialysis membrane wall, it is far from ideal, triggering heparin-induced thrombocytopenia in some instances. Soluble fibrin can form even in the presence of heparin and depending on the constitution of the patient and activation of platelets, could result in physical clots within the ECC (e.g. bubble trap chamber) and, together with other plasma and coagulation proteins, result in increased adsorption of proteins on the membrane surface. The buildup of this secondary membrane layer impairs the transport properties of the membrane to reduce the clearance of uraemic toxins. Activation of complement system-dependent immune response pathways leads to leukopenia, formation of platelet–neutrophil complexes and expression of tissue factor contributing to thrombotic processes and a procoagulant state, respectively. Complement activation also promotes recruitment and activation of leukocytes resulting in oxidative burst and release of pro-inflammatory cytokines and chemokines, thereby worsening the elevated underlying inflammation and oxidative stress condition of chronic kidney disease patients. Restricting all forms of blood-incompatibility, including potential contamination of dialysis fluid with endotoxins leading to inflammation, during HD therapies is thus still a major target towards more blood-compatible and safer dialysis to improve patient outcomes. We describe the mechanisms of various activation pathways during the interaction between blood and components of the ECC and describe approaches to mitigate the effects of these adverse interactions. The opportunities to develop improved dialysis membranes as well as implementation strategies with less potential for undesired biological reactions are discussed.

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.

Monolithic polymeric porous superhydrophobic material with pneumatic plastron stabilization for functionally durable drag reduction in blood-contacting biomedical applications

Superhydrophobic (SHP) surfaces can provide substantial reductions in flow drag forces and reduce blood damage in cardiovascular medical devices. However, strategies for functional durability are necessary, as many SHP surfaces have low durability under abrasion or strong fluid jetting or eventually lose their air plastron and slip-flow capabilities due to plastron gas dissolution, high fluid pressure, or fouling. Here, we present a functional material that extends the functional durability of superhydrophobic slip flow. Facile modification of a porous superhydrophobic polytetrafluoroethylene (PTFE, Teflon) foam produced suitable surface structures to enable fluid slip flow and resist protein fouling. Its monolithic nature offered abrasion durability, while its porosity allowed pressurized air to be supplied to resist fluid impalement and to replenish the air plastron lost to the fluid through dissolution. Active pore pressure control could resist high fluid pressures and turbulent flow conditions across a wide range of applied pressures. The pneumatically stabilized material yielded large drag reductions (up to 50%) even with protein fouling, as demonstrated from high-speed water jetting and closed loop pressure drop tests. Coupled with its high hemocompatibility and impaired protein adsorption, this easily fabricated material can be viable for incorporation into blood-contacting medical devices.

Fabrication of Zwitterion TiO2 Nanomaterial-Based Nanocomposite Membranes for Improved Antifouling and Antibacterial Properties and Hemocompatibility and Reduced Cytotoxicity.

Although zwitterion nanomaterials exhibit outstanding antifouling property, hemocompatibility, and antibacterial activity, their poor solubility in organic solvents limits their practical applications. In the present study, natural lysine (amino acids) was surface-grafted onto one-dimensional (1D) TiO2 nanofibers (NFs) through an epoxy ring opening in which the 3-glycidyloxypropyl (dimethoxy) methyl silane was used as a coupling agent. Chemical binding and morphological studies, such as Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy, were conducted to confirm the successful grafting of lysine onto the TiO2 NFs. The lysine-grafted TiO2 NF-polyethersulfone (PES) membrane induced electrostatic interactions and increased the surface charges from −28 to 16 mV in ζ-potential analysis. The lysine exhibited zwitterion characteristics owing to the presence of amino (cations) and carboxyl (anions) functional groups. Moreover, the modified TiO2-PES zwitterion membranes exhibited good water flux performances compared to the pristine membrane. ZT-4 membrane displayed the highest water fluxand bovine serum albumin (BSA) rejection of 137 ± 1.8 L m–2 h–1 and 94 ± 1%, respectively. The cell viability results revealed that the zwitterion PES membrane had excellent biocompatibility with peripheral blood mononuclear cells. The present work offers a convenient strategy to improve the hydrophilicity, antifouling property, and hemocompatibility of modified TiO2-PES zwitterion membranes for their biomedical and blood-contacting applications such as hemodialysis.

The strategy of modulation blood responses by surface modification with different functional groups on polyester film.

A main problem in the design of blood-contacting biomaterials has been the deficiency of a systematic understanding of blood-biomaterial interactions and the strategy to modulate blood responses. In this work, different functional groups including carboxyl (COOH), hydroxyl (OH) and zwitterionic sulfobetaine group (⊕N((CH3 )2 )(CH2 )3 SO3-○- , SMDB) were grafted on the poly (butylene terephthalate) (PBT) film to study how the functional groups modulate blood responses and in terms of interaction with the coagulation system, the complement system, and platelets. The results showed protein absorption and platelet adhesion was stronger on the PBT bearing COOH group than PBT films bearing OH and zwitterionic sulfobetaine groups (total protein (μg/cm2 ): 32.92 ± 5.89 vs. 22.02 ± 1.44 vs. 19.09 ± 1.59; platelet adhesion (/mm2 ): 1,626.7 ± 120.1 vs. 1,395.6 ± 363.3 vs. 1,102.2 ± 373.7), which had a rougher and negatively charged surface, and the coagulation system was inhibited by binding fibrinogen (Fg) and coagulation factors. Meanwhile, PBT-PSMDB showed anticoagulant property and induced platelet activation. As a result, complement formation on these two films were less than PBT bearing OH groups by inhibiting the coagulation system (C3a (ng/ml): 3,745.4 ± 143.9 vs. 3,290.9 ± 249.7 vs. 4,887.9 ± 88.9; C5a (ng/ml): 22.1 ± 2.6 vs. 22.3 ± 1.8 vs. 27.9 ± 2.0). On the other hand, PBT bearing OH groups did not facilitate remarkable platelet adhesion and activation, and had no influence on platelet aggregation, hypotonic shock response, and coagulation system. The above results showed that the blood responses were highly interlinked, and could be modulated by grafting with different functional groups on the biomaterial surfaces. These findings may help identify a strategy to design materials with better hemocompatibility for blood contact, filtration, and purification applications.

Effect of Recombinant Human Perlecan Domain V Tethering Method on Protein Orientation and Blood Contacting Activity on Polyvinyl Chloride.

Surface modification of biomaterials is a promising approach to control biofunctionality while retaining the bulk biomaterial properties. Perlecan is the major proteoglycan in the vascular basement membrane that supports low levels of platelet adhesion but not activation. Thus, perlecan is a promising bioactive for blood-contacting applications. This study furthers the mechanistic understanding of platelet interactions with perlecan by establishing that platelets utilize domains III and V of the core protein for adhesion. Polyvinyl chloride (PVC) is functionalized with recombinant human perlecan domain V (rDV) to explore the effect of the tethering method on proteoglycan orientation and bioactivity. Tethering of rDV to PVC is achieved via either physisorption or covalent attachment via plasma immersion ion implantation (PIII) treatment. Both methods of rDV tethering reduce platelet adhesion and activation compared to the pristine PVC, however, the mechanisms are unique for each tethering method. Physisorption of rDV on PVC orientates the molecule to hinder access to the integrin-binding region, which inhibits platelet adhesion. In contrast, PIII treatment orientates rDV to allow access to the integrin-binding region, which is rendered antiadhesive to platelets via the glycosaminoglycan (GAG) chain. These effects demonstrate the potential of rDV biofunctionalization to modulate platelet interactions for blood contacting applications.