Grafting Density Governs the Thermoresponsive Behavior of P(OEGMA-co-RMA) Statistical Copolymers.

Thermoresponsive copolymers that exhibit a lower critical solution temperature (LCST) have been exploited to prepare stimuli-responsive materials for a broad range of applications. It is well understood that the LCST of such copolymers can be controlled by tuning molecular weight or through copolymerization of two known thermoresponsive monomers. However, no general methodology has been established to relate polymer properties to their temperature response in solution. Herein, we sought to develop a predictive relationship between polymer hydrophobicity and cloud point temperature (T CP). A series of statistical copolymers were synthesized based on hydrophilic oligoethylene glycol monomethyl ether methacrylate (OEGMA) and hydrophobic alkyl methacrylate monomers and their hydrophobicity was compared using surface area-normalized partition coefficients (log P oct/SA). However, while some insight was gained by comparing T CP and hydrophobicity values, further statistical analysis on both experimental and literature data showed that the molar percentage of comonomer (i.e., grafting density) was the strongest influencer of T CP, regardless of the comonomer used. The lack of dependence of T CP on comonomer chemistry implies that a broad range of functional, thermoresponsive materials can be prepared based on OEGMA by simply tuning grafting density.

The Importance of Cooperativity in Polymer Blending: Toward Controlling the Thermoresponsive Behavior of Blended Block Copolymer Micelles.

Understanding, predicting, and controlling the self-assembly behavior of stimuli-responsive block copolymers remains a pertinent challenge. As such, the copolymer blending protocol provides an accessible methodology for obtaining a range of intermediate polymeric nanostructures simply by blending two or more block copolymers in the desired molar ratio to target specific stimuli-responsiveness. Herein, thermoresponsive diblock copolymers are blended in various combinations to investigate whether the resultant cloud point temperature can be modulated by simple manipulation of the molar ratio. Thermoresponsive amphiphilic diblock copolymers composed of statistical poly(n-butyl acrylate-co-N,N-dimethylacrylamide) core-forming blocks and four different thermoresponsive corona-forming blocks, namely poly(diethylene glycol monomethyl ether methacrylate) (p(DEGMA)), poly(N-isopropylacrylamide), poly(N,N-diethylacrylamide), and poly(oligo(ethylene glycol) monomethyl ether methacrylate) (p(OEGMA)) are selected for evaluation. Using variable temperature turbidimetry, the thermoresponsive behavior of blended diblock copolymer self-assemblies is assessed and compared to the thermoresponsive behavior of the constituent pure diblock copolymer micelles to determine whether comicellization is achieved and more significantly, whether the two blended corona-forming thermoresponsive blocks exhibit cooperative behavior. Interestingly, blended diblock copolymer micelles composed of p(DEGMA)/p(OEGMA) mixed coronae display cooperative behavior, highlighting the potential of copolymer blending for the preparation of stimuli-responsive nanomaterials in applications such as oil recovery, drug delivery, biosensing, and catalysis.

Correction to "Grafting Density Governs the Thermoresponsive Behavior of P(OEGMA-co-RMA) Statistical Copolymers".

[This corrects the article DOI: 10.1021/acsmacrolett.0c00461.].

Polymerization-Induced Polymersome Fusion.

The dynamic interactions of membranes, particularly their fusion and fission, are critical for the transmission of chemical information between cells. Fusion is primarily driven by membrane tension built up through membrane deformation. For artificial polymersomes, fusion is commonly induced via the external application of a force field. Herein, fusion-promoted development of anisotropic tubular polymersomes (tubesomes) was achieved in the absence of an external force by exploiting the unique features of aqueous ring-opening metathesis polymerization-induced self-assembly (ROMPISA). The out-of-equilibrium tubesome morphology was found to arise spontaneously during polymerization, and the composition of each tubesome sample (purity and length distribution) could be manipulated simply by targeting different core-block degrees of polymerization (DPs). The evolution of tubesomes was shown to occur via fusion of "monomeric" spherical polymersomes, evidenced most notably by a step-growth-like relationship between the fraction of tubular to spherical nano-objects and the average number of fused particles per tubesome (analogous to monomer conversion and DP, respectively). Fusion was also confirmed by Förster resonance energy transfer (FRET) studies to show membrane blending and confocal microscopy imaging to show mixing of the polymersome lumens. We term this unique phenomenon polymerization-induced polymersome fusion, which operates via the buildup of membrane tension exerted by the growing polymer chains. Given the growing body of evidence demonstrating the importance of nanoparticle shape on biological activity, our methodology provides a facile route to reproducibly obtain samples containing mixtures of spherical and tubular polymersomes, or pure samples of tubesomes, of programmed length. Moreover, the capability to mix the interior aqueous compartments of polymersomes during polymerization-induced fusion also presents opportunities for its application in catalysis, small molecule trafficking, and drug delivery.

Tuning the membrane permeability of polymersome nanoreactors developed by aqueous emulsion polymerization-induced self-assembly.

Polymeric vesicles (or polymersomes) are hollow bilayer structures consisting of an inner aqueous compartment enclosed by a hydrophobic membrane. Vesicular constructs are ubiquitous in nature and perform a variety of functions by compartmentalizing molecules into disparate environments. For polymer chemists, the synthesis of vesicles can be readily accomplished using polymerization-induced self-assembly (PISA), whereby pure vesicle morphologies can be easily accessed by tuning initial reaction parameters. Research into polymersomes is motivated primarily by the fact that hydrophilic cargo such as drug molecules, DNA, or enzymes can be encapsulated and protected from the often harsh conditions of the surrounding environment. A key factor governing the capability of vesicles to retain and protect their cargo is the permeability of their hydrophobic membrane. Herein, we demonstrate that membrane permeability of enzyme-loaded epoxy-functionalized polymersomes synthesized by aqueous emulsion PISA can be modulated via epoxide ring-opening with various diamine cross-linkers and hydrophobic primary amines. In general, membrane cross-linking or amine conjugation resulted in increased polymersome membrane thickness. Membrane modification was also found to decrease permeability in all cases, as measured by enzymatically-catalysed oxidation of an externally administered substrate. Functionalization with hydrophobic amines resulted in the largest reduction in enzyme activity, suggesting significant blocking of substrate diffusion into the central aqueous compartment. This procedurally facile strategy yields meaningful insight into how the chemical structure of the membrane influences permeability and thus could be generally applied to the formulation of polymeric vesicles for therapeutic applications.

Predicting Monomers for Use in Aqueous Ring-Opening Metathesis Polymerization-Induced Self-Assembly.

Aqueous polymerization-induced self-assembly (PISA) is a well-established methodology enabling in situ synthesis of polymeric nanoparticles of controllable morphology. Notably, PISA via ring-opening metathesis polymerization (ROMPISA) is an emerging technology for block copolymer self-assembly, mainly due to its high versatility and robustness. However, a limited number of monomers suitable for core-forming blocks in aqueous ROMPISA have been reported to date. In this work, we identified seven monomers for use as either corona- or core-forming blocks during aqueous ROMPISA by in silico calculation of relative hydrophobicity for corresponding oligomeric models. The predicted monomers were validated experimentally by conducting ROMPISA using our previously reported two-step approach. In addition to predictive data, our computational model was exploited to identify trends between polymer hydrophobicity and the morphology of the self-assembled nano-objects they formed. We expect that this methodology will greatly expand the scope of aqueous ROMPISA, as monomers can be easily identified based on the structure-property relationships observed herein.

Predicting Monomers for Use in Polymerization-Induced Self-Assembly.

We report an in silico method to predict monomers suitable for use in polymerization-induced self-assembly (PISA). By calculating the dependence of LogPoct /surface area (SA) on the length of the growing polymer chain, the change in hydrophobicity during polymerization was determined. This allowed for evaluation of the capability of a monomer to polymerize to form self-assembled structures during chain extension. Using this method, we identified five new monomers for use in aqueous PISA via reversible addition-fragmentation chain transfer (RAFT) polymerization, and confirmed that these all successfully underwent PISA to produce nanostructures of various morphologies. The results obtained using this method correlated well with and predicted the differences in morphology obtained from the PISA of block copolymers of similar molecular weight but different chemical structures. Thus, we propose this method can be utilized for the discovery of new monomers for PISA and also the prediction of their self-assembly behavior.

Structural Determinants of the Stability of Enzyme-Responsive Polyion Complex Nanoparticles Targeting Pseudomonas aeruginosa's Elastase.

Here, we report how the stability of polyion complex (PIC) particles containing Pseudomonas aeruginosa's elastase (LasB) degradable peptides and antimicrobial poly(ethylene imine) is significantly improved by careful design of the peptide component. Three LasB-degradable peptides are reported herein, all of them carrying the LasB-degradable sequence -GLA- and for which the number of anionic amino acids and cysteine units per peptide were systematically varied. Our results suggest that while net charge and potential to cross-link via disulfide bond formation do not have a predictable effect on the ability of LasB to degrade these peptides, a significant effect of these two parameters on particle preparation and stability is observed. A range of techniques has been used to characterize these new materials and demonstrates that increasing the charge and cross-linking potential of the peptides results in PIC particles with better stability in physiological conditions and upon storage. These results highlight the importance of molecular design for the preparation of PIC particles and should underpin the future development of these materials for responsive drug delivery.

Precision Epitaxy for Aqueous 1D and 2D Poly(ε-caprolactone) Assemblies.

The fabrication of monodisperse nanostructures of highly controlled size and morphology with spatially distinct functional regions is a current area of high interest in materials science. Achieving this control directly in a biologically relevant solvent, without affecting cell viability, opens the door to a wide range of biomedical applications, yet this remains a significant challenge. Herein, we report the preparation of biocompatible and biodegradable poly(ε-caprolactone) 1D (cylindrical) and 2D (platelet) micelles in water and alcoholic solvents via crystallization-driven self-assembly. Using epitaxial growth in an alcoholic solvent, we show exquisite control over the dimensions and dispersity of these nanostructures, allowing access to uniform morphologies and predictable dimensions based on the unimer-to-seed ratio. Furthermore, for the first time, we report epitaxial growth in aqueous solvent, achieving precise control over 1D nanostructures in water, an essential feature for any relevant biological application. Exploiting this further, a strong, biocompatible and fluorescent hydrogel was obtained as a result of living epitaxial growth in aqueous solvent and cell culture medium. MC3T3 and A549 cells were successfully encapsulated, demonstrating high viability (>95% after 4 days) in these novel hydrogel materials.

Reversibly Manipulating the Surface Chemistry of Polymeric Nanostructures via a "Grafting To" Approach Mediated by Nucleobase Interactions.

"Grafting to" polymeric nanostructures or surfaces is a simple and versatile approach to achieve functionalization. Herein, we describe the formation of mixed polymer-grafted nanoparticles through a supramolecular "grafting to" method that exploits multiple hydrogen-bonding interactions between the thymine (T)-containing cores of preformed micelles and the complementary nucleobase adenine (A) of added diblock copolymers. To demonstrate this new "grafting to" approach, mixed-corona polymeric nanoparticles with different sizes were prepared by the addition of a series of complementary diblock copolymers containing thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) to a preformed micelle with a different coronal forming block, poly(4-acryloylmorpholine) (PNAM). PNIPAM chains were distributed throughout the corona and facilitated a fast and fully reversible size change of the resulting mixed-corona micelles upon heating. Through the introduction of an environmentally sensitive fluorophore, the reversible changes in nanoparticle size and coronal composition could be easily probed. Furthermore, preparation of mixed-corona micelles also enabled ligands, such as d-mannose, to be concealed and displayed on the micelle surface. This supramolecular "grafting to" approach provides a straightforward route to fabricate highly functionalized mixed polymeric nanostructures or surfaces with potential applications in targeted diagnosis or therapy and responsive surfaces.

Quantification of gingival contour and volume from digital impressions as a novel method for assessing gingival health.

OBJECTIVE: To evaluate the novel assessment of gingival contour volume measurement from digital impressions compared with traditional clinical indices (Modified Gingival Index and Bleeding Index) and oral microflora following a dental prophylaxis. METHODS: Following baseline examinations and full mouth digital impression using the LAVA™ Oral Chairside Scanner (COS), subjects had one maxillary quadrant and the contra-lateral mandibular quadrant randomly allocated to receive a complete dental prophylaxis. Subjects then brushed twice daily at home using a standard toothpaste. After 1, 2, 4, 6 and 12 weeks gingivitis examinations and digital impressions of the maxillary and mandibular arches were taken. RESULTS: Significant improvements in gingivitis for the prophylaxis versus no prophylaxis quadrants were observed up to six weeks using both the traditional gingivitis indices and the assessment of change in gingival contour volume from the digital impressions. CONCLUSION: The assessment of changes in gingival contour volume may be a promising technique for the objective and quantitative clinical evaluation of products or procedures used to treat gingivitis. The effects of a dental prophylaxis were demonstrated by both this novel measure and traditional clinical indices.