Baylis–Hillman Reaction as a Versatile Platform for the Synthesis of Diverse Functionalized Polymers by Chain and Step Polymerization

The Baylis–Hillman reaction, which is a carbon–carbon bond forming reaction between an aldehyde and an activated alkene, was utilized to prepare densely functionalized monomers suitable for chain and step polymerization. By reacting formaldehyde with various alkyl acrylates, a series of alkyl α-hydroxymethyl acrylate monomers were synthesized. These monomers efficiently underwent RAFT polymerization to provide α-hydroxymethyl-substituted polyacrylates with well controlled molecular weight and low polydispersity. The resulting homopolymers were also efficient macro-chain transfer agents for further RAFT polymerization. The Baylis–Hillman reaction was also utilized to synthesize alkene functionalized diols which underwent step-growth polymerization to provide polyesters and poly­(ester urethane)­s. Furthermore, it was demonstrated that the alkene group can be quantitatively functionalized by thiol–ene click chemistry to provide a series of polymers with diverse physical properties

Pendant Amines in the Hard or Soft Segments of PCL-Polyurethanes Have Contrasting Effects on the Mechanical and Surface Properties

Thermoplastic segmented polyurethanes (TPUs) are used in numerous applications due to their versatile mechanical and morphological properties. Various factors, such as the identity, symmetry, molecular weight of the soft and hard segments, and types of chain extenders, influence the properties of segmented polyurethanes. In this study, we systematically varied the location of pendant cationic amines in polycaprolactone-based polyurethanes, positioning them in either the hard or soft segment, where all other parameters are held constant. This study was aimed at understanding the effect of the cationic amine location on the mechanical, morphological, and surface properties of such polyurethanes with the expectation that such studies will provide the framework to broaden the properties of segmented polyurethanes. The results from differential scanning calorimetry, dynamic mechanical analysis, X-ray scattering, and infrared spectroscopy demonstrated that the location of the functional group significantly affects polyurethane microphase separation, morphology, and interactions between soft and hard segments. When the cationic amine is in the soft segment, the glass transition temperature, storage modulus, and H-bonding increase due to more interface interactions between the soft and hard phases while maintaining a nondisrupted hard segment. Due to its asymmetric structure, incorporating the cationic amine in the hard segment disrupts its crystallinity and increases the hard segment polarity. These factors contribute to improved microphase separation, reduced interphase H-bonding, and reduced toughness. These cationic amine-modified TPUs still maintain their low Young’s modulus (∼10 MPa) while exhibiting a more hydrophilic surface. In addition, the cationic amines demonstrate bactericidal properties due to a contact-killing mechanism

Nontoxic Cationic Coumarin Polyester Coatings Prevent Pseudomonas aeruginosa Biofilm Formation

The rapid increase in bacterial infections and antimicrobial resistance is a growing public health concern. Infections arising from bacterial contamination of surgical tools, medical implants, catheters, and hospital surfaces can potentially be addressed by antimicrobial polymeric coatings. The challenge in developing such polymers for in vivo use is the ability to achieve high antimicrobial efficacy while at the same time being nontoxic to human cells. Although several classes of antimicrobial polymers have been developed, many of them cannot be used in the clinical setting due to their nonselective toxicity toward bacteria and mammalian cells. Here, we demonstrate that coumarin polyesters with cationic pendant groups are very effective against Gram negative Pseudomonas aeruginosa. Coumarin polyesters with pendant cationic amine groups were coated onto glass coverslips and tested for their antimicrobial activity against P. aeruginosa colonization of the surface. The results demonstrate that the cationic coumarin polyester kills the surface attached bacterial cells preventing biofilm formation but does not show any hemolytic activity or discernible toxicity toward mammalian cells. The antimicrobial polyesters described in this work have several advantages desired in antimicrobial coatings such as high antimicrobial activity, low toxicity toward mammalian cells, visualization and ease of synthesis and fabrication, all of which are necessary for translation to the clinic

Kinetics of UV Irradiation Induced Chain Scission and Cross-Linking of Coumarin-Containing Polyester Ultrathin Films

Photoresponsive thin films are commonly encountered as high performance coatings as well as critical component, photoresists, for microelectronics manufacture. Despite intensive investigations into the dynamics of thin glassy polymer films, studies involving reactions of thin films have typically been limited by difficulties in decoupling segregation of reacting components or catalysts due to the interfaces. Here, thin films of coumarin polyesters overcome this limitation where the polyester undergoes predominately cross-linking upon irradiation at 350 nm, while chain scission occurs with exposure to 254 nm light. Spectroscopic ellipsometry is utilized to track these reactions as a function of exposure time to elucidate the associated reaction kinetics for films as thin as 15 nm. The cross-linking appears to follow a second order kinetic rate law, while oxidation of the coumarin that accompanies the chain scission and enables this reaction to be tracked spectroscopically appears to be a first order reaction in coumarin concentration. Because of the asymmetry in the coumarin diol monomer and the associated differences in local structure that result during formation of the polyester, two populations of coumarin are required to fit the reaction kinetics; 10–20% of the coumarin is significantly more reactive, but these groups appear to undergo chain scission/oxidation at both wavelengths. These reaction rate constants are nearly independent (within 1 order of magnitude) of film thickness down to 15 nm. There is maximum rate at a finite thickness for the 254 nm exposure, which we attribute to constructive interference of the UV radiation within the polymer film, rather than typical confinement effects; no thickness dependence in reaction rates is observed for the 350 nm exposure. The utilization of a single polymer with two distinct reactions enables unambiguous investigation of thickness effects on reactions

Bactericidal Peptidomimetic Polyurethanes with Remarkable Selectivity against <i>Escherichia coli</i>

The increasing incidence of drug-resistant strains of bacteria necessitates the development of new classes of antimicrobials. Host defense peptides, also known as antimicrobial peptides, are promising in this regard but have several drawbacks. Herein, we show that peptidomimetic polyurethanes with pendant functional groups that mimic lysine and valine amino acid residues have high antibacterial activity against Gram negative <i>Escherichia coli</i>, yet are less effective against Gram positive <i>Staphylococcus aureus</i>. All the polyurethanes designed in this study display high bactericidal activity against <i>E. coli</i>, whereas the polyurethanes with high concentrations of lysine mimicking functional groups display minimal cytotoxicity toward mammalian cells. Control experiments with pexiganan, an analogue of the host defense peptide magainin, showed that the polyurethanes described here have high bactericidal activity, while having comparable hemocompatibility and lower mammalian cell toxicity. Overall, the results point to an encouraging new class of peptidomimetic synthetic polymers with selective bactericidal activity to <i>E. coli</i> and low mammalian cell toxicity

A Library of Thermoresponsive, Coacervate-Forming Biodegradable Polyesters

We report on a new class of thermoresponsive biodegradable polyesters (TR-PE) inspired by polyacrylamides and elastin-like proteins (ELPs). The polyesters display reversible phase transition with tunable cloud point temperatures (<i>T</i>_cp) in aqueous solution as evidenced by UV–vis spectroscopy, ¹H NMR, and DLS measurements. These polyesters form coacervate droplets above their lower critical solution temperature (LCST). The <i>T</i>_cp of the polyesters is influenced by the solutes such as urea, SDS, and NaCl. The <i>T</i>_cp of the copolymers shows a linear correlation with the composition of the polyesters indicating the ability to tune the phase change temperature. We also show that such thermoresponsive coacervates are capable of encapsulating small molecules such as Nile Red. Furthermore, the polyesters are hydrolytically degradable

Reorganization of an Amphiphilic Glassy Polymer Surface in Contact with Water Probed by Contact Angle and Sum Frequency Generation Spectroscopy

We address the question of how a surface of a glassy polymer reorganizes after coming in contact with water. Because contact angle hysteresis measurements are also affected by surface roughness and chemical heterogeneity, we have used surface-sensitive sum frequency generation spectroscopy (SFG) in conjunction with water contact angles to answer this question. To increase the magnitude of the surface reorganization, we have designed an amphiphilic polymer, poly­(α-hydroxymethyl-<i>n</i>-butyl acrylate) (PHNB), to study the changes in the structure of polar hydroxy groups and nonpolar (methyl and methylene) groups at the interface. The SFG and the water contact angles show that reorganization does occur for PHNB below <i>T</i>_g. However, complete reorganization requires heating the sample above the bulk <i>T</i>_g. These heating experiments were conducted by first heating the sample in the presence of water and then followed by cooling the sample to room temperature in the presence of water to lock the changes in the surface structure (we refer to this treatment as water annealing). The polar contribution to the total surface energy of PHNB, determined by Owens–Wendt–Rabel–Kaelble (OWRK) method at room temperature, increases after water annealing above <i>T</i>_g. This is consistent with our SFG results that show an increase in concentration of polar hydroxy groups at room temperature after water annealing the PHNB film above <i>T</i>_g. For PHNB, the contact angle hysteresis is higher for samples that are water annealed above <i>T</i>_g. This is consistent with the surface energy and SFG results. For a low-<i>T</i>_g polymer, poly­(<i>n</i>-butyl acrylate), which has the same nonpolar side group but lacks the hydroxyl group, surface reorganization takes place immediately after contact with water, and these changes are reversible

Multiphasic Coacervates Assembled by Hydrogen Bonding and Hydrophobic Interactions

Coacervation has emerged as a prevalent mechanism to compartmentalize biomolecules in living cells. Synthetic coacervates help in understanding the assembly process and mimic the functions of biological coacervates as simplified artificial systems. Though the molecular mechanism and mesoscopic properties of coacervates formed from charged coacervates have been well investigated, the details of the assembly and stabilization of nonionic coacervates remain largely unknown. Here, we describe a library of coacervate-forming polyesteramides and show that the water-tertiary amide bridging hydrogen bonds and hydrophobic interactions stabilize these nonionic, single-component coacervates. Analogous to intracellular biological coacervates, these coacervates exhibit “liquid-like” features with low viscosity and low interfacial energy, and form coacervates with as few as five repeating units. By controlling the temperature and engineering the molar ratio between hydrophobic interaction sites and bridging hydrogen bonding sites, we demonstrate the tuneability of the viscosity and interfacial tension of polyesteramide-based coacervates. Taking advantage of the differences in the mesoscopic properties of these nonionic coacervates, we engineered multiphasic coacervates with core–shell architectures similar to those of intracellular biological coacervates, such as nucleoli and stress granule-p-body complexes. The multiphasic structures produced from these synthetic nonionic polyesteramide coacervates may serve as a valuable tool for investigating physicochemical principles deployed by living cells to spatiotemporally control cargo partitioning, biochemical reaction rates, and interorganellar signal transport

A Solvent and Initiator Free, Low-Modulus, Degradable Polyester Platform with Modular Functionality for Ambient-Temperature 3D Printing

3D printing has enabled the design of biomaterials into intricate and customized scaffolds. However, current 3D printed biomaterial scaffolds have potential drawbacks due to residual monomers, free-radical initiators, solvents, or printing at elevated temperatures. This work describes a solvent, initiator, and monomer-free degradable polyester platform for room temperature 3D printing. Linoleic acid side chains derived from soybean oil lowers the <i>T</i>_g and prevents packing and entanglement, ensuring that <i>G</i>″ > <i>G</i>′ during room temperature printing. Upon printing, cross-linking of pendant functionalized coumarin moieties fixes the viscous filaments to elastomeric solids. Furthermore, the modular design of the polyester platform enables conjugation of ligands, as demonstrated by the conjugation of FITC to surface amines on the 3D printed scaffolds. This low modulus, printable polyester platform addresses several design challenges in 3D printing of functional biomaterials and could potentially be useful in many tissue engineering applications

Multiphasic Coacervates Assembled by Hydrogen Bonding and Hydrophobic Interactions

Coacervation has emerged as a prevalent mechanism to compartmentalize biomolecules in living cells. Synthetic coacervates help in understanding the assembly process and mimic the functions of biological coacervates as simplified artificial systems. Though the molecular mechanism and mesoscopic properties of coacervates formed from charged coacervates have been well investigated, the details of the assembly and stabilization of nonionic coacervates remain largely unknown. Here, we describe a library of coacervate-forming polyesteramides and show that the water-tertiary amide bridging hydrogen bonds and hydrophobic interactions stabilize these nonionic, single-component coacervates. Analogous to intracellular biological coacervates, these coacervates exhibit “liquid-like” features with low viscosity and low interfacial energy, and form coacervates with as few as five repeating units. By controlling the temperature and engineering the molar ratio between hydrophobic interaction sites and bridging hydrogen bonding sites, we demonstrate the tuneability of the viscosity and interfacial tension of polyesteramide-based coacervates. Taking advantage of the differences in the mesoscopic properties of these nonionic coacervates, we engineered multiphasic coacervates with core–shell architectures similar to those of intracellular biological coacervates, such as nucleoli and stress granule-p-body complexes. The multiphasic structures produced from these synthetic nonionic polyesteramide coacervates may serve as a valuable tool for investigating physicochemical principles deployed by living cells to spatiotemporally control cargo partitioning, biochemical reaction rates, and interorganellar signal transport