Epoxylated Zwitterionic Triblock Copolymers Grafted onto Metallic Surfaces for General Biofouling Mitigation.

Titanium and stainless steel materials are widely used in numerous devices or in custom parts for their excellent mechanical properties. However, their lack of biocompatibility seriously limits their usage in the biomedical field. This study focuses on the grafting of triblock copolymers on titanium and stainless steel metal susbtrates for improving their general biofouling resistance. The series of copolymers that we designed is composed of two blocks of zwitterionic sulfobetaine (SBMA) monomers and one block of glycidyl methacrylate (GMA). The number of repeat units forming each block, n, was finely tuned and controlled to 25, 50, 75, or 100, permitting regulation of the grafting thickness, the morphology, and the dependent properties such as the surface hydrophilicity and biofouling resistance. It was shown that the copolymer possessing n = 50 repeat units in each block, corresponding to a molecular weight of about 15.2 kDa, led to the best nonfouling properties, assessed using plasma proteins, blood cells, fibroblasts cells, and various bacteria. This was explained by an optimized grafting degree and chain organization of the copolymer. Lower value (n = 25) and higher values (n = 75, 100) led to low surface coverage and the formation of aggregates, respectively. The best copolymer was grafted onto scalpels (steel) and dental roots (titanium), and antifouling properties demonstrated using Escherichia coli and HT1080 cells. Results of this work show that this unique triblock copolymer holds promise as a potential material for surface modification of biomedical metallic devices, provided a fine-tuning of the blocks organization and length.

Hemocompatibility of polyampholyte copolymers with well-defined charge bias in human blood.

In this work, the hemocompatibility of polyampholyte copolymers from the mixed-charge copolymerization of negatively charged 3-sulfopropyl methacrylate (SA) and positively charged [2-(methacryloyloxy)ethyl] trimethylammonium (TMA) was studied. Charge-bias variation of the prepared poly(SA-co-TMA) copolymers can be controlled using the regulated SA and TMA monomer ratio via homogeneous free radical copolymerization. A systematic study of how charge-bias variations in poly(SA-co-TMA) copolymers affect the hemocompatibility in human blood plasma was reported. The hydrodynamic size of prepared polymers and copolymers is determined to illustrate the correlations between intermolecular cationic/anionic associations and the blood compatibility of polySA, poly(SA-co-TMA), and polyTMA suspensions in human blood plasma. It was found that the protein resistance and hydration capability of prepared copolymers can be effectively controlled by regulating the charge balance of the SA/TMA compositions in poly(SA-co-TMA). The results suggest that polyampholyte copolymers of poly(SA-co-TMA) with overall charge neutrality have a high hydration capability and the best antifouling, anticoagulant, and antihemolytic activities as well as zwitterionic sulfobetaine-based homopolymers when in contact with blood plasma at human body temperature.

Hemocompatibility of poly(vinylidene fluoride) membrane grafted with network-like and brush-like antifouling layer controlled via plasma-induced surface PEGylation.

In this work, the hemocompatibility of PEGylated poly(vinylidene fluoride) (PVDF) microporous membranes with varying grafting coverage and structures via plasma-induced surface PEGylation was studied. Network-like and brush-like PEGylated layers on PVDF membrane surfaces were achieved by low-pressure and atmospheric plasma treatment. The chemical composition, physical morphology, grafting structure, surface hydrophilicity, and hydration capability of prepared membranes were determined to illustrate the correlations between grafting qualities and hemocompatibility of PEGylated PVDF membranes in contact with human blood. Plasma protein adsorption onto different PEGylated PVDF membranes from single-protein solutions and the complex medium of 100% human plasma were measured by enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies. Hemocompatibility of the PEGylated membranes was evaluated by the antifouling property of platelet adhesion observed by scanning electron microscopy (SEM) and the anticoagulant activity of the blood coagulant determined by testing plasma-clotting time. The control of grafting structures of PEGylated layers highly regulates the PVDF membrane to resist the adsorption of plasma proteins, the adhesion of platelets, and the coagulation of human plasma. It was found that PVDF membranes grafted with brush-like PEGylated layers presented higher hydration capability with binding water molecules than with network-like PEGylated layers to improve the hemocompatible character of plasma protein and blood platelet resistance in human blood. This work suggests that the hemocompatible nature of grafted PEGylated polymers by controlling grafting structures gives them great potential in the molecular design of antithrombogenic membranes for use in human blood.

Superior Bioinert Capability of Zwitterionic Poly(4-vinylpyridine propylsulfobetaine) Withstanding Clinical Sterilization for Extended Medical Applications.

The field of bioinert materials is relatively mature, as unique molecular designs for antifouling have been regularly presented over the past 30 years. However, the effect of steam sterilization, a common procedure in hospitals for sterilizing biomedical devices in clinical uses, on the stability of antifouling and hemocompatible biomaterials remains unexplored. The only available set of data indicates that poly(sulfobetaine methacrylate) (SBMA) is unstable and loses its antifouling properties when exposed to hot humid air, depriving it of its attractiveness. Here, we present zwitterionic biomaterial gels of poly(4-vinylpyridine propylsulfobetaine) (4VPPS) and explore their propensity to biofouling before and after a 1 h steam sterilization at 121 °C. After incubation with erythrocytes, leukocytes, thrombocytes, whole blood, or various bacteria ( Escherichia coli, Stenotrophomonas maltophilia), the antifouling properties of unsterilized 4VPPS gels are comparable to those of SBMA gels. Importantly, they are maintained after steam sterilization, unlike those of SBMA gels, which shows that the structure of 4VPPS and the interactions with water remain unaffected by the humid heat treatment. The antifouling properties of gels coated on materials mimicking surfaces used in biomedical devices including stainless steel (surgical knife), silicon (biochips), or titanium (electrocautery pen) are also maintained after similar sterilization. In addition, repeated sterilizations do not affect the antifouling properties of 4VPPS. Therefore, these results provide a substantial advance over the current knowledge on antifouling materials for repeated usage in actual conditions that often involve, in a biomedical environment, steam sterilization.

Turning Expanded Poly(tetrafluoroethylene) Membranes into Potential Skin Wound Dressings by Grafting a Bioinert Epoxylated PEGMA Copolymer.

Despite a set of properties ideal to the design of wound dressings, bioinert membranes are seldom applied as wound-healing systems. This work presents a unique series of random copolymers of glycidyl methacrylate (GMA) and poly(ethylene glycol) methacrylate (PEGMA), namely GMA-r-PEGMA, used to surface-modify by grafting onto method polytetrafluorethylene membranes, with the aim of developing wound dressings for quick and efficient wound closure. It is shown that the membrane modified with G50P50 copolymer combines high surface hydrophilicity, high porosity, protein resistance, bacterial resistance, and hemocompatibility, essential properties to wound dressings. Fibrinogen adsorption was measured to be 11.4 ± 3.9% (compared with virgin membrane) correlating with a low water contact angle (14°), whereas the attachment of fluorescent Escherichia coli after 24 h, erythrocytes, leukocytes, thrombocytes, and cells from whole blood was reduced by 85-90%, compared with the virgin membrane. G50P50 membrane was tested as a wound dressing, which outperformed hydrophilic gels of PEGMA in terms of wound-closure kinetic and a commercial dressing in terms of homogeneity of the granulation layer. The facile surface-modification of ePTFE membrane using unique GMA-r-PEGMA copolymer leads to an antibiofouling porous material with improved hemocompatibility combining numerous essential properties of wound dressings and contributing toward the development of the ideal bandage.

Zwitterionic fibrous polypropylene assembled with amphiphatic carboxybetaine copolymers for hemocompatible blood filtration.

UNLABELLED: The present study serves three main functions. First, it presents a novel random copolymer, made of octadecyl acrylate hydrophobic blocks and 2-(dimethylamino)ethyl methacrylate hydrophilic groups, and it zwitterionic form. Second, random copolymer and zwitterionic random copolymer, OmDn and Z-OmDn, are used to modify polypropylene membranes by evaporation coating. Our investigations unveil that this method leads to sufficiently stable self-assembling provided a minimum number of hydrophobic repeat units of 77, which also corresponds to a hydrophobic degree of 74%. Third, antifouling and hemocompatible properties of membranes are thoroughly investigated using all types of blood cells separately, as well as challenging membranes against whole blood in static and dynamic conditions. Membranes modified with zwitterionic copolymer containing 26% of zwitterionic groups are shown to be highly antifouling and hemocompatible, for a coating density as low as 0.2mg/cm(2). Their application in a specially designed blood filtration module enabled to almost totally inhibit blood cells interactions with membrane material, as well as to importantly reduce platelet activation in the permeate (2.5-fold reduction). STATEMENT OF SIGNIFICANCE: The design of new zwitterionic copolymer material is proposed and demonstrated in this study. It was showed that hydrophobicoctadecyl acrylate segments can be introduced in the zwitterioniccarboxybetaine polymer chain with a well-controlled random sequence. Stable, efficient, and effective surface zwitterionization of hydrophobic polypropylene are obtained via grafting onto approach by evaporation-induced self-assembling coating. In the perspective of potential application, hemocompatible blood filtration was demonstrated with the excellent results of non-activated platelets obtained. DESIGN: New zwitterionicmaterial, amphiphatic carboxybetaine copolymers. DEVELOPMENT: Evaporation-induced self-assembling grafting. APPLICATION: Hemocompatible blood filtration.

Hemocompatibility of pseudozwitterionic polymer brushes with a systematic well-defined charge-bias control.

In this study, a pseudozwitterionic surface bearing positively and negatively mixed charged moieties was developed as a potential hemocompatible material for biomedical applications. In this work, hemocompatility of pseudozwitterionic surface prepared from copolymerization of negatively charged 3-sulfopropyl methacrylate (SA) and positively charged [2-(methacryloyloxy)ethyl] trimethylammonium (TMA) was delineated. Mixed charge distribution in the prepared poly(TMA-co-SA)-grafted surface can be controlled by regulating TMA and SA monomer ratios via surface-initiated atom transfer radical polymerization. The effects of grafting composition and charge bias variations on blood compatibility of poly(TMA-co-SA)-grafted surface were reported. The protein adsorption on different poly(TMA-co-SA)-grafted surfaces from human plasma protein (fibrinogen, HSA, and γ-globulin) solutions was evaluated using an enzyme-linked immunosorbent assay. Blood platelet adhesion and time measurements on plasma clotting were conducted to determine the platelet activation on the grafted surface. It was found that the protein resistance and anti-blood cell adhesion of prepared surface can be precisely controlled by controlling the charge balance of TMA/SA compositions. In addition, different charge bias variations on the poly(TMA-co-SA)-grafted surface would induce electrostatic interactions between plasma proteins and prepared surfaces which lead to adsorptions of interfacial protein and blood cells, plasma clotting, and blood cell hemolysis. Results from this study suggest that the hemocompatility of mixed charged poly(TMA-co-SA)-grafted surface depends on the charge bias level. This provides a great potential for designing biomaterial with unique surface chemical structure which could be used in contact with human blood.

Introducing mixed-charge copolymers as wound dressing biomaterials.

Herein, a pseudozwitterionic structure bearing moieties with mixed positive and negative charges is introduced to develop a potential biomaterial for wound dressing applications. New mixed-charge matrices were prepared by copolymerization of the negatively charged 3-sulfopropyl methacrylate (SA) and positively charged [2-(methacryloyloxy)ethyl] trimethylammonium (TMA) onto expanded polytetrafluoroethylene (ePTFE) membranes. The charge balance was effectively regulated through the control of the initial SA/TMA ratio. The focus was then laid on the assessment of a variety of essential properties of efficient wound dressings including, hydration property, resistance to fibrinogen adsorption, hemocompatibility, as well as resistance to fibroblast attachment and bacteria colonization. It was found that the pseudozwitterionic membranes, compared to those with charge bias in the poly(SA-co-TMA) structure, exhibited the best combination of major properties. Therefore, they were further tested for wound healing. Histological examination of mouse wound treated with the pseudozwitterionic membranes exhibited complete re-epithelialization and total formation of new connective tissues after 14 days, even leading to faster healing than using commercial dressing. Results presented in this work suggest that the mixed-charge copolymers with a perfect balance of positive and negative moieties represent the newest generation of biomaterials for wound dressings.

Surface zwitterionization of expanded poly(tetrafluoroethylene) membranes via atmospheric plasma-induced polymerization for enhanced skin wound healing.

Development of bioinert membranes to prevent blood clotting, tissue adhesion, and bacterial attachment is important for the wound healing process. In this work, two wound-contacting membranes of expanded poly(tetrafluoroethylene) (ePTFE) grafted with zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and hydrophilic poly(ethylene glycol) methacrylate (PEGMA) via atmospheric plasma-induced surface copolymerization were studied. The surface grafting chemical structure, hydrophilicity, and hydration capability of the membranes were determined to illustrate the correlations between bioadhesive properties and wound recovery of PEGylated and zwitterionic ePTFE membranes. Bioadhesive properties of the membranes were evaluated by the plasma protein adsorption, platelet activation, blood cell hemolysis, tissue cell adhesion, and bacterial attachment. It was found that the zwitterionic PSBMA-grafted ePTFE membrane presented high hydration capability and exhibited the best nonbioadhesive character in contact with protein solution, human blood, tissue cells, and bacterial medium. This work shows that zwitterionic membrane dressing provides a moist environment, essential for "deep" skin wound healing observed from the animal rat model in vivo and permits a complete recovery after 14 days, with histology of repaired skin similar to that of normal skin tissue. This work suggests that the bioinert nature of grafted PSBMA polymers obtained by controlling grafting structures gives them great potential in the molecular design of antibioadhesive membranes for use in skin tissue regeneration.