Light-Activated, Bioadhesive, Poly(2-hydroxyethyl methacrylate) Brush Coatings

Rapid adhesion between tissue and synthetic materials is relevant to accelerate wound healing and to facilitate the integration of implantable medical devices. Most frequently, tissue adhesives are applied as a gel or a liquid formulation. This manuscript presents an alternative approach to mediate adhesion between synthetic surfaces and tissue. The strategy presented here is based on the modification of the surface of interest with a thin polymer film that can be transformed on-demand, using UV-light as a trigger, from a nonadhesive into a reactive and tissue adhesive state. As a first proof-of-concept, the feasibility of two photoreactive, thin polymer film platforms has been explored. Both of these films, colloquially referred to as polymer brushes, have been prepared using surface-initiated atom transfer radical polymerization (SI-ATRP) of 2-hydroxyethyl methacrylate (HEMA). In the first part of this study, it is shown that direct UV-light irradiation of PHEMA brushes generates tissue-reactive aldehyde groups and facilitates adhesion to meniscus tissue. While this strategy is very straightforward from an experimental point of view, a main drawback is that the generation of the tissue reactive aldehyde groups uses the 250 nm wavelength region of the UV spectrum, which simultaneously leads to extensive photodegradation of the polymer brush. The second part of this report outlines the synthesis of PHEMA brushes that are modified with 4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzoic acid (TFMDA) moieties. UV-irradiation of the TFMDA containing brushes transforms the diazirine moieties into reactive carbenes that can insert into C-H, N-H, and O-H bonds and mediate the formation of covalent bonds between the brush surface and meniscus tissue. The advantage of the TFMDA-modified polymer brushes is that these can be activated with 365 nm wavelength UV light, which does not cause photodegradation of the polymer films. While the work presented in this manuscript has used silicon wafers and fused silica substrates as a first proof-of-concept, the versatility of SI-ATRP should enable the application of this strategy to a broad range of biomedically relevant surfaces.

Mechanochemically Responsive Surfaces and Soft Tissue Adhesive Interfaces Generated via Controlled Radical Polymerization

Nariye Cavusoglu Ataman

Thin coatings applied to surfaces dramatically improve the properties of materials. Thus, they have found application in a broad variety of areas including biomedicine, nanotechnology, bioelectronics and optics, amongst others. Polymer brushes prepared via surface-initiated controlled radical polymerization (SI-CRP) techniques represent a versatile class of thin polymer coatings that provide manifold opportunities to engineer surface and interface properties. Densely grafted polymer brushes prepared via SI-CRP possess several attractive material properties such as low friction coefficients and the ability to prevent biofouling, which are related to the stretched conformation of the surface tethered polymer chains. Those distinctive characteristics of polymer brushes make them highly appealing to engineer the properties of functional interfaces. A first aim of this Thesis is to investigate the mechanochemistry of hydrophilic polymer brushes prepared via surface-initiated atom transfer radical polymerization (SI-ATRP) from silica substrates. The second aim of the Thesis is to explore poly(2-hydroxyethyl methacrylate) (PHEMA) based polymer brushes as soft-tissue adhesives in wet tissue environment. This Thesis is divided into four chapters, which are briefly summarized below. Chapter 1 provides a summary of recent literature that has reported detachment or degrafting of densely grafted hydrophilic polymer brushes from substrates upon exposure to aqueous media. The collective results from these reports suggest that swelling-induced stretching of hydrophilic polymer brushes lead to mechanochemical activation of the bonds near the brush-substrate interface and subsequently facilitates hydrolytic chain cleavage. Chapter 2 aims to shed light on the influence of two fundamental structural polymer brush parameters on the degrafting of surface-tethered, densely grafted polymer chains, viz. (i) the chemical composition of the ATRP initiator that is used to grow the polymer brushes and (ii) the effect of surface curvature. To this end, a series of poly(poly(ethylene glycol) methacrylate) (PPEGMA) and poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMEMA) brushes were grafted from both flat silica substrates as well as silica nanoparticles. Subsequently, the degrafting of the surface-tethered polymer chains was investigated in cell culture medium and phosphate buffered saline (PBS) using various techniques. The aim of the final two Chapters of this Thesis is less on exploring the chain conformation of polymer chains grafted by SI-CRP, but more to use the ability of SI-CRP to prepare thin polymer films that present a high surface concentration of functional groups to mediate soft tissue adhesion. Chapter 3 describes the preparation of photo-active poly(2-hydroxyethyl methacrylate) (PHEMA) brushes as soft tissue bioadhesives. Tissue adhesion in this Chapter is induced as UV-irradiation of PHEMA brushes converts the initially bio-inert side chain hydroxyl groups of these brushes into (putatively) aldehyde groups, which can react with amine groups present in the tissue. The prepared PHEMA brush coated substrates are biocompatible, which avoids fibrous capsule formation and presents functionalities that can be transformed, on-demand, from a non-reactive, non-adhesive state to a reactive, adhesive state in wet tissue environment. While the photoactivation of the PHEMA side chain functional groups is very efficient, it is not very well defined from a chemistry point of view. Chapter 4 therefore, explores an alternative photoactivation chemistry, which is based on the use of the diazirine motif. These diazirine motifs were incorporated in poly(2-hydroxyethyl methacrylate-co-poly(ethylene glycol) methyl ether methacrylate) (P(HEMA-co-PEGMEMA)) copolymer brushes via post-polymerization modification. These diazirine modified brushes are attractive as they may not only be activated by UV-light but also by electrochemical means.

EPFL2016

Interactive Surfaces Based on Polymer Brushes

Dusko Paripovic

While the bulk structure of a material determines its mechanical properties, its surface plays a key role when interactions with the environment are important. Nowadays materials in bio- and nanotechnology are required to possess very complex functionalities and to interact specifically to the stimuli they receive from their surroundings. Thus, their surface modifications are becoming very demanding. In recent years surface initiated controlled radical polymerization techniques have emerged as very versatile strategies that provide a powerful toolbox to tackle the challenges that are set to material scientists. The attractiveness of these methods lies in the possibility to create well defined surface arrangements of polymer chains, which we refer to as polymer brushes, with precise control over thickness, composition and architecture. In addition, these techniques can be applied to very challenging substrates with respect to the chemical composition and geometry, which also includes porous materials. This Thesis, therefore, exploits the possibilities that surface-initiated controlled radical polymerization techniques offer to finely tune interfacial properties of materials and render them capable to interact with chemical and biological species in a desired way. Its paramount aim is to demonstrate how the functionalities and geometry of a polymer brush matrix can be employed to influence inorganic film deposition using synthetic, biomimetic and purely biological mechanism or enhance polymer brushed stability in aqueous media. This Thesis is divided into five distinct chapters, which will be briefly summarized in following paragraphs. Chapter 1 describes the preparation of polymer brushes and strategies that are used to control their chemical composition and architecture. Additionally, it will give an overview on the use of brushes as cell adhesive surfaces as well as templates for the production of nanoparticles and thin inorganic films. Chapter 2 explores a new strategy to guide the chemical solution deposition of thin, microstructured metal films. The proposed strategy is based on the use of poly(2-(methacryloyloxy)ethyl ammonium chloride) (PMETAC) brushes grown via surface-initiated atom transfer radical polymerization as a template. Thin films are prepared by first loading the PMETAC brushes with an appropriate precursor, followed by its reduction by NaBH4 and finally an oxygen plasma treatment to remove the stabilizing polymer brush matrix and generate the desired thin metallic film. Of particular interest is the question whether the thickness and lateral dimensions of the deposited metallic films can be controlled by micropatterning the polymer brush template and varying the brush thickness. In addition, this concept will be extended to the preparation of bimetallic (gold/palladium) films using a single polymer brush matrix. A similar strategy is explored in Chapter 3 to control the deposition of thin calcium carbonate films using a biomimetic process. The process is characterized by the stabilization of amorphous calcium carbonate, the geometry and localication of which can be controlled by the poly(methacrylic acid) brush template. A special focus of this Chapter is to examine the influence of the polymer brush thickness on the mineral deposition and to determine to which extent is the mineral phase is integrated into the polymer brush film. The aim of Chapter 4 is to develop a general approach for the modification of implantable materials with a polymer brush based coating that promotes bone formation. The proposed coatings are prepared via surface-initiated copolymerization of 2-hydoxyethyl methacrylate and 2-(methacryloyl)ethyl phosphate, which results in a thin hydrogel layer that mimics the negatively charged matrix macromolecules involved in natural bone formation. To further emulate the properties of the natural bone extracellular matrix, the coatings will be functionalized with the cell adhesive GGGRGDS peptide. The ability of the proposed coatings to induce bone formation is investigated in in vitro experiments on MC3T3-E1 pre-osteoblasts and evaluated using an ALP and alizarin red assays. Finally, Chapter 5 focuses on studying the parameters that could prevent the hydrolytic cleavage of Si-O bond, which tethers the polymer brushes grafted from SiOx in aqueous media. In the first part of the study, the length of the organosilane initiator's alkyl spacer will be varied, in order to evaluate to which extent it can insulate the site that anchors the hydrophilic polymer brush to the substrate. In the second part, a short, hydrophobic block will be introduced between the silicon oxide substrate and the hydrophilic polymer in order to more efficiently protect the underlying Si-O bond from the surrounding aqueous media and prevent the chain detachment.

EPFL2011

Synthesis of Responsive Polymer Brushes for Sensing Applications

Nicolas Bertrand Schüwer

During the past decades the field of sensors has been subject to much attention due to an increased demand for (bio)sensors and environmental monitoring. The efforts have been concentrated to create sensors which are reliable, highly sensitive and selective, small and fast responding. Surface modification by polymer coating has been proven an excellent method to introduce selectivity on actuators. Among the various techniques that allow the formation of polymer thin film, polymer brushes have gained attention along the past decades due to their unique structure and the possibility offered by controlled/"living" surface-initiated radical polymerization technique to generate polymer thin film with precisely controlled thickness, composition and architecture. Polymer brushes have found numerous applications including nonbiofouling surfaces and cell adhesive surfaces, protein binding and immobilization, chromatography supports, membrane functionalization, responsive surface, antibacterial coatings or low friction surfaces. Despite their interesting properties and the numerous reports describing the potential of polymer brush as responsive surface, their use for "real" sensing applications has receive little or no attention so far. This Thesis describes how polymer brushes can be employed as selective surface modification for sensing application. We aimed at synthesizing polymer thin film able to detect analytes of interest, with a particular focus on low detection limit and high selectivity. After a short introduction to the field of polymer brushes (Chapter 1), Chapter 2 presents a review of the work accomplished in the field of responsive polymer brushes with an emphasis on solvent responsive, thermoresponsive, pH- and ion-sensitive polymer brushes. The pH-induced swelling and collapse of surface-tethered, weak polyelectrolyte brushes is of interest not only for the development of responsive surface coatings but also for the pH controlled transport or adsorption. Chapter 3 discusses results of an extensive series of quartz crystal microbalance (QCM) experiments that aimed at further understanding the influence of brush thickness and density on the pH-responsiveness of poly(methacrylic acid) (PMAA) brushes and developing strategies that allow to engineer the pH responsiveness and dynamic response range of PMAA based brushes. It was observed that due to their high grafting density, the apparent pKa of surface-tethered PMAA differs from that of the corresponding free polymer in solution and also covers a broader pH range. The pKa of the PMAA brushes was found to depend both on brush thickness and density; thicker brushes showed a higher pKa value and brushes of higher density started to swell at higher pH. The second part of this section demonstrates the feasibility of the N-hydroxysuccinimide-mediated post-polymerization modification to engineer the pH responsiveness of the PMAA brushes. By using appropriate amine functionalized acids, it was possible to tune both the pH of maximum response as well as the dynamic response range of these PMAA based polyelectrolyte brushes. In Chapter 4, benzo-15-crown-5 functionalized polymer brushes prepared via surface-initiated atom transfer radical polymerization were used as the active layer in a potassium-selective QCM sensor. The polymer brushes allowed the selective detection of potassium ions, even in the presence of a large excess of sodium ions and the sensitivity of the sensor could be tuned by varying the brush thickness. Chapter 5 demonstrates the possibility to use peptide functionalized polymer brush, prepared via surface-initiated atom transfer radical polymerization (SI-ATRP), to probe heavy metal ions via voltammetric based methods. The polymer brush enhanced the mercury (II) ions sensitivity as compared to the bar electrode and allowed the detection of mercury down to the nanomolar concentration range. Furthermore it was demonstrated that the heavy metal recognition is a reversible and reproducible process. Post-polymerization modification reactions are widely employed to prepare functional polymer brushes. Relatively little is known, however, about the distribution of functional groups in such post-modified brushes. Using neutron reflectivity and UV-visible spectroscopy as principal tools, Chapter 6 investigates the p-nitrophenyl chloroformate (NPC) mediated post-polymerization modification of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes, prepared via surface-initiated atom transfer radical polymerization, with D-10 leucine and D-3 serine. The neutron reflectivity experiments indicate that the post-polymerization modification depends both on the brush thickness and density. Whereas, for dense brushes, post-polymerization modification with D-10 leucine is limited to the top ∼ 200 Å of the brush, independently of the brush thickness, the extent of post-modification can be significantly extended by decreasing brush density, or by using the more hydrophilic and sterically less demanding D-3 serine, which reflects the ability of this amino acid to more readily penetrate the brush. UV-vis. experiment revealed that the NPC activation is also non-uniform, but brush thickness and density dependent, which adds to brush thickness, density and the nature of the amino acid as another of a complex set of variables that determine the final distribution of functional groups in post-modified brushes.

EPFL2011

Interactive Surfaces Based on Polymer Brushes

Dusko Paripovic

EPFL2011

Synthesis of Responsive Polymer Brushes for Sensing Applications

Nicolas Bertrand Schüwer

EPFL2011

Mechanochemically Responsive Surfaces and Soft Tissue Adhesive Interfaces Generated via Controlled Radical Polymerization

Nariye Cavusoglu Ataman

EPFL2016