Molecular Approach to Conjugated Polymers with Biomimetic Properties.

The field of bioelectronics involves the fascinating interplay between biology and human-made electronics. Applications such as tissue engineering, biosensing, drug delivery, and wearable electronics require biomimetic materials that can translate the physiological and chemical processes of biological systems, such as organs, tissues. and cells, into electrical signals and vice versa. However, the difference in the physical nature of soft biological elements and rigid electronic materials calls for new conductive or electroactive materials with added biomimetic properties that can bridge the gap. Soft electronics that utilize organic materials, such as conjugated polymers, can bring many important features to bioelectronics. Among the many advantages of conjugated polymers, the ability to modulate the biocompatibility, solubility, functionality, and mechanical properties through side chain engineering can alleviate the issues of mechanical mismatch and provide better interface between the electronics and biological elements. Additionally, conjugated polymers, being both ionically and electrically conductive through reversible doping processes provide means for direct sensing and stimulation of biological processes in cells, tissues, and organs. In this Account, we focus on our recent progress in molecular engineering of conjugated polymers with tunable biomimetic properties, such as biocompatibility, responsiveness, stretchability, self-healing, and adhesion. Our approach is general and versatile, which is based on functionalization of conjugated polymers with long side chains, commonly polymeric or biomolecules. Applications for such materials are wide-ranging, where we have demonstrated conductive, stimuli-responsive antifouling, and cell adhesive biointerfaces that can respond to external stimuli such as temperature, salt concentration, and redox reactions, the processes that in turn modify and reversibly switch the surface properties. Furthermore, utilizing the advantageous chemical, physical, mechanical and functional properties of the grafts, we progressed into grafting of the long side chains onto conjugated polymers in solution, with the vision of synthesizing solution-processable conjugated graft copolymers with biomimetic functionalities. Examples of the developed materials to date include rubbery and adhesive photoluminescent plastics, biomolecule-functionalized electrospun biosensors, thermally and dually responsive photoluminescent conjugated polymers, and tunable self-healing, adhesive, and stretchable strain sensors, advanced functional biocidal polymers, and filtration membranes. As outlined in these examples, the applications of these biomimetic, conjugated polymers are still in the development stage toward truly printable, organic bioelectronic devices. However, in this Account, we advocate that molecular engineering of conjugated polymers is an attractive approach to a versatile class of organic electronics with both ionic and electrical conductivity as well as mechanical properties required for next-generation bioelectronics.

Manipulation of cytokine secretion in human dendritic cells using glycopolymers with picomolar affinity for DC-SIGN.

The human C-type lectin DC-SIGN (CD209) is a significant receptor on the surface of dendritic cells (DCs) - crucial components of host defense that bridge the innate and adaptive immune systems. A range of linear glycopolymers, constructed via controlled radical polymerization techniques have been shown to interact with DC-SIGN with affinities in the physiologically active range. However, these first generation glycopolymers possess limited structural definition and their effects on DCs were not known. Here we report the development of star-shaped mannose glycopolymers with the aim of targeting the clustered domain arrangement of DC-SIGN and these were shown to bind with picomolar affinity. Increased secretion of IL-10 with simultaneous decrease in secreted IL-12p70 occurred in activated DCs incubated with star-shaped glycopolymers - a cytokine secretion pattern characteristic of wound-healing tissue environments. Incorporating stellar architecture into glycopolymer design could be key to developing selective and very high-affinity therapeutic materials with distinct immunomodulatory and tissue repair potential.

One-Pot Synthesis of Charged Amphiphilic Diblock and Triblock Copolymers Via High-Throughput Cu(0)-Mediated Polymerization.

Block copolymers containing functionalized monomers, for example those containing charged groups, can be used for many purposes, one of which is the design of polymeric supramolecular materials based on electrostatic interactions. In this paper the synthesis of diblock copolymers and ABA-triblock copolymers containing poly(n-butyl acrylate) as a first or middle block and poly(2-(dimethylamino)ethyl acrylate), poly(1-ethoxyethyl acrylate) and poly(1-ethoxyethyl-2-carboxyethyl acrylate) as second or outer blocks, resulting in block copolymers that can contain positive or negative charges, is reported. The polymerizations were performed and optimized via one-pot sequential monomer addition reactions via Cu(0)-mediated polymerization using an automated parallel synthesizer. Different initiators, monomer concentrations and polymerization times were tested. While a bromide-containing initiator led to the best results for most monomers, when polymerizing 2-(dimethylamino)ethyl acrylate the use of a chloride-containing initiator was necessary. Due to the slower polymerization using this initiator, a longer polymerization time was needed before addition of the second monomer. Using the optimized conditions, the diblock and triblock copolymers could be synthesized with good control over molecular weight and dispersities around 1.1 were obtained.

One-Pot Automated Synthesis of Quasi Triblock Copolymers for Self-Healing Physically Crosslinked Hydrogels.

The preparation of physically crosslinked hydrogels from quasi ABA-triblock copolymers with a water-soluble middle block and hydrophobic end groups is reported. The hydrophilic monomer N-acryloylmorpholine is copolymerized with hydrophobic isobornyl acrylate via a one-pot sequential monomer addition through reversible addition fragmentation chain-transfer (RAFT) polymerization in an automated parallel synthesizer, allowing systematic variation of polymer chain length and hydrophobic-hydrophilic ratio. Hydrophobic interactions between the outer blocks cause them to phase-separate into larger hydrophobic domains in water, forming physical crosslinks between the polymers. The resulting hydrogels are studied using rheology and their self-healing ability after large strain damage is shown.

Supramolecular polymer networks: hydrogels and bulk materials.

Supramolecular polymer networks are materials crosslinked by reversible supramolecular interactions, such as hydrogen bonding or electrostatic interactions. Supramolecular materials show very interesting and useful properties resulting from their dynamic nature, such as self-healing, stimuli-responsiveness and adaptability. Here we will discuss recent progress in polymer-based supramolecular networks for the formation of hydrogels and bulk materials.

Tuning of Polymeric Nanoparticles by Coassembly of Thermoresponsive Polymers and a Double Hydrophilic Thermoresponsive Block Copolymer.

The coassembly behavior of thermoresponsive statistical copolymers and a double hydrophilic block copolymer having a permanently hydrophilic block and a thermoresponsive block is investigated. By adjusting the hydrophilicity of the thermoresponsive statistical copolymers, hybrid nanoparticles are obtained with various ratios of the two species. Importantly, the size of these nanoparticles can be controlled in between 40 and 250 nm dependent on the TCP and the amount of statistical copolymers in the solution. Simultaneous analysis of static and dynamic light scattering data indicates that the possible structure of nanoparticles varies from hard sphere to less compact architecture and most probably depends on a difference between cloud point temperatures of individual components. This developed coassembly method provides a simple platform for the preparation of defined polymeric nanoparticles.

One-Pot Preparation of Inert Well-Defined Polymers by RAFT Polymerization and In Situ End Group Transformation.

A one-pot procedure that straightforwardly combines reversible addition-fragmentation chain transfer (RAFT) polymerization and end group transformation to remove the RAFT end groups is developed for the synthesis of well-defined poly(meth)acrylates and polyacrylamides with inert end groups. This procedure only requires the addition of an amine at the end of the standard RAFT polymerization procedure, which avoids the separation and purification of the intermediate polymers and, hence, extremely reduces the working time and utilized amount of solvents. Upon addition of the amine, a thiol group is formed by aminolysis of the thiocarbonylthio group, which subsequently undergoes Michael addition with unreacted monomer leading to an inert thioether functionalized polymer.

Degradable ketal-based block copolymer nanoparticles for anticancer drug delivery: a systematic evaluation.

Low solubility of potent (anticancer) drugs is a major driving force for the development of noncytotoxic, stimuli-responsive nanocarriers, including systems based on amphiphilic block copolymers. In this regard, we investigated the potential of block copolymers based on 2-hydroxyethyl acrylate (HEA) and the acid-sensitive ketal-containing monomer (2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (DMDMA) to form responsive drug nanocarriers. Block copolymers were successfully synthesized by sequential reversible addition-fragmentation chain transfer (RAFT) polymerization, in which we combined a hydrophilic poly(HEA)x block with a (responsive) hydrophobic poly(HEAm-co-DMDMAn)y copolymer block. The DMDMA content of the hydrophobic block was systematically varied to investigate the influence of polymer design on physicochemical properties and in vitro biological performance. We found that a DMDMA content higher than 11 mol % is required for self-assembly behavior in aqueous medium. All particles showed colloidal stability in PBS at 37 °C for at least 4 days, with sizes ranging from 23 to 338 nm, proportional to the block copolymer DMDMA content. Under acidic conditions, the nanoparticles decomposed into soluble unimers, of which the decomposition rate was inversely proportional to the block copolymer DMDMA content. Flow cytometry and confocal microscopy showed dose-dependent, active in vitro cellular uptake of the particles loaded with hydrophobic octadecyl rhodamine B chloride (R18). The block copolymers showed no intrinsic in vitro cytotoxicity, while loaded with paclitaxel (PTX), a significant decrease in cell viability was observed comparable or better than the two commercial PTX nanoformulations Abraxane and Genexol-PM at equal PTX dose. This systematic approach evaluated and showed the potential of these block copolymers as nanocarriers for hydrophobic drugs.

RAFT polymerization of 4-vinylphenylboronic acid as the basis for micellar sugar sensors.

Well-defined homo and mPEGylated block (co)polymers of the commercially available unprotected 4-vinylphenylboronic acid (4-VBA) monomer are reported based on reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymerization kinetics are studied in detail for homo and block (co)polymerizations with different chain transfer agents (CTAs) to optimize the preparation of well-defined polymer structures, eventually leading to comparatively low dispersities (D ≤ 1.25). Subsequently, block (co)polymers with methoxy poly(ethylene glycol) mPEG-b-P(4-VBA) are prepared using a mPEG-functionalized CTA. The formed block copolymer mPEG114 -b-P(4-VBA)30 is demonstrated to be pH and glucose responsive as its micellization behavior is dictated by pH as well as the presence of glucose. The glucose-responsive pH window of mPEG114 -b-P(4-VBA)30 is found to be pH 9-10 based on the DLS and TEM measurement.

Poly(2-oxazoline) hydrogel monoliths via thiol-ene coupling.

Copoly(2-oxazoline)s, prepared by the cationic ring-opening polymerization of 2-(dec-9-enyl)-2-oxazoline with either 2-methyl-2-oxazoline or 2-ethyl-2-oxazoline, are crosslinked with small dithiol molecules under UV irradiation to form homogeneous networks. In situ monitoring of the crosslinking reaction by photo-rheology reveals the formation of soft gels within minutes. The degree of swelling in water is tunable based on the hydrophilicity of the starting macromers and the proportion of alkene side arms present. Furthermore, degradable hydrogels are prepared based on incorporation of a hydrolytically cleavable dithiol crosslinker. The rapid synthesis of the macromers and mild crosslinking conditions make these materials ideal for future biomaterial applications.

Controlled Alternate Layer-by-Layer Assembly of Lectins and Glycopolymers Using QCM-D.

Layer-by-layer (LBL) assembly of concanavalin A (Con A), peanut agglutinin (PNA) plant lectins, and well-defined synthetic glycopolymers via their biological affinities have been prepared using a quartz crystal microbalance with dissipation monitoring (QCM-D). We demonstrate the use of mannose/galactose glycopolymers as lectin binders due to their selective binding to Con A/PNA, respectively. A detailed analysis of the adsorption processes and the adsorbed layer are provided and tuning the composition of multilayers using a series of well-defined glycopolymers differing only in the pendant sugar ratio is discussed.

Salt-induced disintegration of lysozyme-containing polyelectrolyte complex micelles.

The salt-induced disintegration of lysozyme-filled polyelectrolyte complex micelles, consisting of positively charged homopolymers (PDMAEMA150), negatively charged diblock copolymers (PAA42-PAAm417), and lysozyme, has been studied with dynamic light scattering (DLS) and small-angle neutron scattering (SANS). These measurements show that, from 0 to 0.2 M NaCl, both the hydrodynamic radius (Rh) and the core radius (Rcore) decrease with increasing salt concentration. This suggests that the micellar structures rearrange. Moreover, from approximately 0.2 to 0.4 M NaCl the light-scattering intensity is constant. In this salt interval, the hydrodynamic radius increases, has a maximum at 0.3 M NaCl, and subsequently decreases. This behavior is observed in both a lysozyme-containing system and a system without lysozyme. The SANS measurements on the lysozyme-filled micelles do not show increased intensity or a larger core radius at 0.3 M NaCl. This indicates that from 0.2 to 0.4 M NaCl another structure is formed, consisting of just the diblock copolymer and the homopolymer, because at 0.12 M NaCl the lysozyme-PAA42-PAAm417 complex has disintegrated. One may expect that the driving force for the formation of the complex in this salt range is other than electrostatic.