Antifouling Properties of Amine-Oxide-Containing Zwitterionic Polymers.

Biofouling due to nonspecific proteins or cells on the material surfaces is a major challenge in a range of applications such as biosensors, medical devices, and implants. Even though poly(ethylene glycol) (PEG) has become the most widely used stealth material in medical and pharmaceutical products, the number of reported cases of PEG-triggered rare allergic responses continues to increase in the past decades. Herein, a new type of antifouling material poly(amine oxide) (PAO) has been evaluated as an alternative to overcome nonspecific foulant adsorption and impart comparable biocompatibility. Alkyl-substituted PAO containing diethyl, dibutyl, and dihexyl substituents are prepared, and their solution properties are studied. Photoreactive copolymers containing benzophenone as the photo-cross-linker are prepared by reversible addition-fragmentation chain-transfer polymerization and fully characterized by gel permeation chromatography and dynamic light scattering. Then, these water-soluble polymers are anchored onto a silicon wafer with the aid of UV irradiation. By evaluating the fouling resistance properties of these modified surfaces against various types of foulants, protein adsorption and bacterial attachment assays show that the cross-linked PAO-modified surface can efficiently inhibit biofouling. Furthermore, human blood cell adhesion experiments demonstrate that our PAO polymer could be used as a novel surface modifier for biomedical devices.

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.

Convergent charge interval spacing of zwitterionic 4-vinylpyridine carboxybetaine structures for superior blood-inert regulation in amphiphilic phases.

Antifouling materials are indispensable in the biomedical field, but their high hydrophilicity and surface free energy provoke contamination on surfaces under atmospheric conditions, thus limiting their applicability in medical devices. This study proposes a new zwitterionic structure, 4-vinylpyridine carboxybetaine (4VPCB), that results in lower surface free energy and increases biological inertness. In the design of 4VPCB, one to three carbon atoms are inserted between the positive charge and negative charge (carbon space length, CSL) of the pyridyl-containing side chain to adjust hydration with water molecules. The pyridine in the 4VPCB structure provides the hydrophobicity of the zwitterionic functional group, and thus it can have a lower free energy in the gas phase but maintain higher hydrophilicity in the liquid phase environment. Surface plasmon resonance and confocal microscopy were used to analyze the antiprotein adsorption and anti-blood cell adhesion properties of the P4VPCB brush surface. The results showed that the CSL in the P4VPCB structure affected the biological inertness of the surface. The protein adsorption on the surface of P4VPCB2 (CSL= 2) is lower than that on the surfaces of P4VPCB1 (CSL = 1) and P4VPCB3 (CSL = 3), and the optimal resistance to protein adsorption can be reduced to 7.5 ng cm-2. The surface of P4VPCB2 can also exhibit excellent blood-inert function in the adhesion test with various human blood cells, offering a potential possibility for the future design of a new generation of blood-inert medical materials.

Temperature-triggered attachment and detachment of general human bio-foulants on zwitterionic polydimethylsiloxane.

Biofouling has long been a problem for biomaterials, so being able to control the fouling on the surface of a biomaterial would be ideal. In this study a copolymer system was designed comprising three moieties: an epoxy containing group, glycidyl methacrylate (GMA); a thermoresponsive segment, N-isopropylacrylamide (NIPAAm); and an antifouling zwitterionic unit, sulfobetaine methacrylate (SBMA). The copolymers (pGSN), synthesized via free radical polymerization with these 3 moieties, were then grafted onto polydimethylsiloxane (PDMS). The presence of a critical temperature for both the copolymers and the coated PDMS was evidenced by particle size and contact angle measurements. The coated PDMS exhibited controllable temperature-dependent antifouling behaviors and stimuli-responsive phase characteristics in the presence of salts. The interactions of the coated PDMS with biomolecules were tested via attachment of fibrinogen protein, platelets, human whole blood, and tumor cells (HT1080). The attachment and detachment of these biomolecules were studied at different temperatures. Exposed hydrophobic domains of thermoresponsive NIPAAm-rich pGSN containing NIPAAm at 56 mol% generally allows molecular and cellular attachment on the PDMS surface at 37 °C. On the other hand, the coated PDMS with a relatively high content of SBMA (>41 mol%) in the copolymer started to exhibit fouling resistance and lower the thermoresponsive properties. Interestingly, the incorporation of zwitterionic SBMA units into the copolymers was found to accelerate the hydration of the PDMS surfaces and resulted in biomolecular and cellular detachment at 25 °C, which is comparable to the detachment at 4 °C. This modified surface behavior is found to be consistent through all biofouling tests.

Bio-inert interfaces via biomimetic anchoring of a zwitterionic copolymer on versatile substrates.

Bio-inert biomaterial design is vital for fields like biosensors, medical implants, and drug delivery systems. Bio-inert materials are generally hydrophilic and electrical neutral. One limitation faced in the design of bio-inert materials is that most of the modifiers used are specific to their substrate. In this work, we synthesized a novel zwitterionic copolymer containing a catechol group, a non-substrate dependent biomimetic anchoring segment, that can form a stable coating on various materials. No previous study was conducted using a grafting-to approach and determined the critical amount of catechol groups needed to effectively modify a material. The synthesized copolymers of sulfobetaine acrylamide (SBAA) and dopamine methacrylamide (DMA) in this work contains varying numbers of catechol groups, in which the critical number of catechol groups that had effectively modified substrates to have the bio-inert property was determined. The bio-inert property and capability to do coating on versatile substrates were evaluated in contact with human blood by coating different material groups such as ceramic, metallic, and polymeric groups. The novel structure and the simple grafting-to approach provides bio-inert property on various materials, giving them non-specific adsorption and attachment of biomolecules such as plasma proteins, erythrocytes, thrombocytes, bacteria, and tissue cells (85-95% reduction).

Zwitterionic surface grafting of epoxylated sulfobetaine copolymers for the development of stealth biomaterial interfaces.

UNLABELLED: Most biomaterials have a lack of a simple, efficient and robust antifouling modification approach that limits their potential for biomedical applications. The challenge is to develop a universal surface grafting solution to meet the antifouling requirement. In this work, a new formulation of zwitterionic sulfobetaine-based copolymer, ploy(glycidyl methacrylate-co-sulfobetaine methacrylate) (poly(GMA-co-SBMA)), is designed as a chemical for grafting onto material and is introduced for the surface zwitterionization of versatile biomaterials, including ceramic, metal, and plastics. The grafting principle used to stabilize the poly(GMA-co-SBMA) on the target surfaces is based the base-induced ring opening reaction between epoxied and hydroxyl groups. A universal surface modification procedure was developed and performed from an optimized sequence of ultra-violet ozone pretreatment and trimethylamine-catalyzed zwitterionization on a selective case of versatile surfaces including silicon wafer, ceramic glass, titanium, steel, and polystyrene. The prepared poly(GMA-co-SBMA) with an optimum PGMA/PSBMA ratio of 0.23 and a molecular weight of 25kDa exhibited the best resistance to fibrinogen adsorption with over 90% reduction as well as blood cell activation, tissue cell adhesion and bacterial attachment on the zwitterionic copolymer grafted surfaces. The developed antifouling grafting introduces a universal modification method to generate zwitterionic interfaces on versatile biomaterial substrates, providing great potential for application in medical device coating. STATEMENT OF SIGNIFICANCE: A simple, efficient and robust antifouling modification approach is critical for many scientific interests and industrial applications. In current stage, the existing available zwitterionic modifications suffer from the lack of universal surface grafting solution to achieve the antifouling requirement on versatile biomaterial substrates. In this study, we synthesized and characterized a new zwitterionic sulfobetaine-based copolymer, ploy(glycidyl methacrylate-co-sulfobetaine methacrylate) (poly(GMA-co-SBMA)), which is designed as chemical grafting onto material and introduced for the surface zwitterionization of versatile biomaterials, including ceramic, metal, and plastics. This research have a promising opportunity for the application of stealth biomaterial interfaces on the next generation of medical devices.

Ultra-low fouling and high antibody loading zwitterionic hydrogel coatings for sensing and detection in complex media.

UNLABELLED: For surface-based diagnostic devices to achieve reliable biomarker detection in complex media such as blood, preventing nonspecific protein adsorption and incorporating high loading of biorecognition elements are paramount. In this work, a novel method to produce nonfouling zwitterionic hydrogel coatings was developed to achieve these goals. Poly(carboxybetaine acrylamide) (pCBAA) hydrogel thin films (CBHTFs) prepared with a carboxybetaine diacrylamide crosslinker (CBAAX) were coated on gold and silicon dioxide surfaces via a simple spin coating process. The thickness of CBHTFs could be precisely controlled between 15 and 150nm by varying the crosslinker concentration, and the films demonstrated excellent long-term stability. Protein adsorption from undiluted human blood serum onto the CBHTFs was measured with surface plasmon resonance (SPR). Hydrogel thin films greater than 20nm exhibited ultra-low fouling (<5ng/cm(2)). In addition, the CBHTFs were capable of high antibody functionalization for specific biomarker detection without compromising their nonfouling performance. This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors. STATEMENT OF SIGNIFICANCE: In this work, we developed an approach to realize ultra-low fouling and high ligand loading with a highly-crosslinked, purely zwitterionic, carboxybetaine thin film hydrogel (CBHTF) coating platform. The CBHTF on a hydrophilic surface demonstrated long-term stability. By varying the crosslinker content in the spin-coated hydrogel solution, the thickness of CBHTFs could be precisely controlled. Optimized CBHTFs exhibited ultra-low nonspecific protein adsorption below 5ng/cm(2) measured by a surface plasmon resonance (SPR) sensor, and their 3D architecture allowed antibody loading to reach 693ng/cm(2). This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors.

Applying thermosettable zwitterionic copolymers as general fouling-resistant and thermal-tolerant biomaterial interfaces.

We introduced a thermosettable zwitterionic copolymer to design a high temperature tolerance biomaterial as a general antifouling polymer interface. The original synthetic fouling-resistant copolymer, poly(vinylpyrrolidone)-co-poly(sulfobetaine methacrylate) (poly(VP-co-SBMA)), is both thermal-tolerant and fouling-resistant, and the antifouling stability of copolymer coated interfaces can be effectively controlled by regulating the VP/SBMA composition ratio. We studied poly(VP-co-SBMA) copolymer gels and networks with a focus on their general resistance to protein, cell, and bacterial bioadhesion, as influenced by the thermosetting process. Interestingly, we found that the shape of the poly(VP-co-SBMA) copolymer material can be set at a high annealing temperature of 200 °C while maintaining good antifouling properties. However, while the zwitterionic PSBMA polymer gels were bioinert as expected, control of the fouling resistance of the PSBMA polymer networks was lost in the high temperature annealing process. A poly(VP-co-SBMA) copolymer network composed of PSBMA segments at 32 mol % showed reduced fibrinogen adsorption, tissue cell adhesion, and bacterial attachment, but a relatively higher PSBMA content of 61 mol % was required to optimize resistance to platelet adhesion and erythrocyte attachment to confer hemocompatibility to human blood. We suggest that poly(VP-co-SBMA) copolymers capable of retaining stable fouling resistance after high temperature shaping have a potential application as thermosettable materials in a bioinert interface for medical devices, such as the thermosettable coating on a stainless steel blood-compatible metal stent investigated in this study.