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Interactions between Acrylate/Methacrylate Biomaterials and Organic Foulants Evaluated

Interactions between Acrylate/Methacrylate Biomaterials and Organic Foulants Evaluated by Molecular Dynamics Simulations of Simplified Binary Mixtures


Improving hydrophilicity is a key factor for enhancing the biocompatibility of polymer surfaces. Nevertheless, previous studies have reported that poly(2-methoxyethyl acrylate) (PMEA) surfaces demonstrate markedly better biocompatibility than more hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) surfaces. In this work, the origins of the excellent biocompatibility of the PMEA surface are investigated using molecular dynamics (MD) simulations of simplified binary mixtures of acrylate/methacrylate trimers and organic solvents, with n-nonane, 1,5-pentanediol, or 1-octanol serving as the probe organic foulants. The interactions between the acrylate/methacrylate trimers and solvent molecules were evaluated by calculating the radial distribution function (RDF), with the resulting curves indicating that the 2-methoxyethyl acrylate (MEA) trimer has a lower affinity for n-nonane molecules than the 2-hydroxyethyl methacrylate (HEMA) trimer. This result agrees with the experimental consensus that the biocompatibility of PMEA surfaces is better than that of PHEMA surfaces, supporting the hypothesis that the affinity between an acrylate/methacrylate trimer and a foulant molecule in a simplified binary mixture is a significant factor in determining a surface‘s antifouling properties. The RDF curves obtained for the other two solvent systems exhibited behavior that further highlighted the advantages of the PMEA surfaces as biocompatible polymers. In addition, the validity of employing the second virial coefficient (B2) as a predictor of antifouling properties was explored. The order of the B2 values of different binary mixtures indicated that the MEA trimers have the lowest affinities with n-nonane molecules, which confirms that although PMEA is more hydrophobic than PHEMA, it exhibits better biocompatibility. This analysis demonstrates that the MEA’s weaker miscibility with nonpolar foulants contributes to the excellent biocompatibility of PMEA. Thus, B2 is a promising criterion for assessing the miscibility between acrylate/methacrylate materials and nonpolar organic foulants, which indicates the potential for predicting the antifouling properties of acrylate/methacrylate polymer materials by evaluating the value of B2.


Plasma proteins may be adsorbed on the surface of medical devices when they are used in direct contact with human blood. Platelets can subsequently adhere to the adsorbed proteins, inducing biological defense reactions such as thrombus formation.Therefore, the surface of a medical device must be appropriately biocompatible to suppress protein adsorption. Surface modification with zwitterionic materials is the typical strategy for improving a material’s biocompatibility.Poly(2-methoxyethyl acrylate) (PMEA) is another promising biocompatibility modifier. In a previous study,it was shown that although PMEA and poly(2-hydroxyethyl methacrylate) (PHEMA) suppressed protein adsorption similarly well, PMEA markedly inhibited platelet adhesion. Clarifying the reason why PMEA surfaces demonstrate better antifouling properties than the more hydrophilic PHEMA surfaces has been a significant challenge. In previous studies, the excellent antifouling property of PMEA was attributed to the presence of “intermediate water (IW)” (also called loosely bound water), which was hypothesized to prevent protein adsorption on the PMEA surface. These studies suggest that the microscopic behavior of water molecules around the polymer surface is key to enhancing a material’s antifouling properties. Investigating the origins of the different biocompatibilities of PMEA and PHEMA will provide a strategy for controlling the antifouling/fouling properties of various polymer surfaces.


Snapshots of binary mixtures of n-nonane and (a) MEA, (b) MePVE, (c) MEMA, (d) HEMA, (e) HEA, and (f) BA trimers at 30 ns in real time from simulation. Color code: green, trimer; red, n-nonane.


Molecular dynamics (MD) simulations have been used to evaluate the dynamic and static properties of water molecules in the vicinity of polymer side chains. These studies have focused specifically on hydration structures and the microscopic behavior of water molecules in this region. Kuo et al.conducted MD simulations to investigate the water structures of hydrated PMEA, the results of which indicated that bound water in polymers with better biocompatibility possesses higher mobility. Another study, where MD simulations were performed to identify the structure of IW in hydrated PMEA and its analogs, suggested that IW molecules enhance the flexibility of the polymer side chains. MD simulations investigating the dynamic properties of water molecules and side chains of hydrated PMEA and its analogs indicated that polymer materials with a robust hydration layer showed better biocompatibility.


Snapshots of binary mixtures of 1,5-pentanediol and (a) MEA, (b) MePVE, (c) MEMA, (d) HEMA, (e) HEA, and (f) BA trimers at 30 ns in real time from simulation. Color code: green, trimer; blue, 1,5-pentanediol.


The thermodynamic properties of PMEA and PHEMA have also been explored. The free energy profiles of these materials were obtained using MD calculations to evaluate their protein resistances.Analysis of these profiles indicated that the affinities between repeating units and amino acid residues are significant factors that determine protein adsorption properties. In other studies, they used organic solvents such as n-hexane and 1-octanol as simplified probe foulants to assess the microscopic interactions between the constituent moieties of polymer biomaterials and foulant molecules. They suggested that important factors for enhancing a material’s antifouling properties are the balance between organic solvation and hydration around the polar groups of side chains and the molecular mobility of the side chains of the polymer material.


Snapshots of binary mixtures of 1-octanol and (a) MEA, (b) MePVE, (c) MEMA, (d) HEMA, (e) HEA, and (f) BA trimers at 30 ns in real time from simulation. Color code: green, trimer; gray, 1-octanol.


Nevertheless, the origins of the different biocompatibilities of PMEA and PHEMA remain obscure. Detailed evaluations of the interactions between organic foulant molecules and polymer side chains at the microscopic level can contribute to unveiling these origins. In this study, they aim to determine the origins of PMEA’s excellent biocompatibility by estimating the structural properties of molecules around the side chains of acrylate/methacrylate trimers in pure organic solvents. Three types of organic solvent molecules were used as the probe foulants: a nonpolar hydrophobic molecule (n-nonane), a solvent molecule terminated by polar hydroxyl groups (1,5-pentanediol), and a solvent molecule terminated by a polar hydroxyl group and a nonpolar methyl group (1-octanol). Herein, they report on the investigation conducted and discuss the influence of the hydrophilicity of acrylate/methacrylate polymer surfaces, including PMEA and PHEMA, on their antifouling properties. They also explore the ability to predict the biocompatibility of acrylate/methacrylate polymer materials by evaluating the aggregation/dispersion properties of the six trimer/solvent binary mixtures by calculating the second virial coefficient (B2), which is experimentally measured in static/dynamic light scattering. In a previous study,by evaluating B2, the intermolecular interactions of a surface-grafted and unbound free polyampholyte were estimated in aqueous solutions. B2 was also used to evaluate the conformational structure and the interchain aggregation behavior of conjugated polymers in solutions.To the best of our knowledge, no other studies have investigated the correlation between the aggregation/dispersion behavior of a material/foulant mixture and the biocompatibility of the polymer surface. Investigation of these correlations will contribute to the efficient molecular design of polymer surfaces.

  1. Interactions between Acrylate/Methacrylate Biomaterials and Organic Foulants Evaluated by Molecular Dynamics Simulations of Simplified Binary Mixtures Ryo Nagumo, Takumi Matsuoka, and Shuichi Iwata ACS Biomaterials Science & Engineering 2021 7 (8), 3709-3717 DOI: 10.1021/acsbiomaterials.1c00609