Improved Mechanical Strength without Sacrificing Li-Ion Transport in Polymer Electrolytes.

Next-generation batteries demand solid polymer electrolytes (SPEs) with rapid ion transport and robust mechanical properties. However, many SPEs with liquid-like Li+ transport mechanisms suffer a fundamental trade-off between conductivity and strength. Dynamic polymer networks can improve bulk mechanics with minimal impact to segmental relaxation or ionic conductivity. This study demonstrates a system where a single polymer-bound ligand simultaneously dissociates Li+ and forms long-lived Ni2+ networks. The polymer comprises an ethylene oxide backbone and imidazole (Im) ligands, blended with Li+ and Ni2+ salts. Ni2+-Im dynamic cross-links result in the formation of a rubbery plateau resulting in, consequently, storage modulus improvement by a factor of 133× with the introduction of Ni2+ at rNi = 0.08, from 0.014 to 1.907 MPa. Even with Ni2+ loading, the high Li+ conductivity of 3.7 × 10-6 S/cm is retained at 90 °C. This work demonstrates that decoupling of ion transport and bulk mechanics can be readily achieved by the addition of multivalent metal cations to polymers with chelating ligands.

Tailoring Network Topology in Mechanically Robust Hydrogels for 3D Printing and Injection.

Tissue engineering and regenerative medicine are confronted with a persistent challenge: the urgent demand for robust, load-bearing, and biocompatible scaffolds that can effectively endure substantial deformation. Given that inadequate mechanical performance is typically rooted in structural deficiencies─specifically, the absence of energy dissipation mechanisms and network uniformity─a crucial step toward solving this problem is generating synthetic approaches that enable exquisite control over network architecture. This work systematically explores structure-property relationships in poly(ethylene glycol)-based hydrogels constructed utilizing thiol-yne chemistry. We systematically vary polymer concentration, constituent molar mass, and cross-linking protocols to understand the impact of architecture on hydrogel mechanical properties. The network architecture was resolved within the molecular model of Rubinstein-Panyukov to obtain the densities of chemical cross-links and entanglements. We employed both nucleophilic and radical pathways, uncovering notable differences in mechanical response, which highlight a remarkable degree of versatility achievable by tuning readily accessible parameters. Our approach yielded hydrogels with good cell viability and remarkably robust tensile and compression profiles. Finally, the hydrogels are shown to be amenable to advanced processing techniques by demonstrating injection- and extrusion-based 3D printing. Tuning the mechanism and network regularity during the cell-compatible formation of hydrogels is an emerging strategy to control the properties and processability of hydrogel biomaterials by making simple and rational design choices.

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants.

Long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been commercialized for over 30 years in at least 20 FDA-approved products. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic formulations having drug release profiles equivalent to those of the reference listed drugs. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting formulations. This work seeks to better understand how variability in the physicochemical properties of similar PLGAs affects drug release from PLGA solid implants using Ozurdex (dexamethasone intravitreal implant) as the model system. Four 50:50, acid-terminated PLGAs of similar molecular weights were used to prepare four dexamethasone intravitreal implants structurally equivalent to Ozurdex. The PLGAs were extensively characterized by using a variety of analytical techniques prior to implant manufacture using a continuous, hot-melt extrusion process. In vitro release testing of the four structurally equivalent implants was performed in both normal saline and phosphate-buffered saline (PBS), yielding drastically different results between the two methods. In normal saline, no differences in the release profiles were observed. In PBS, the drug release profiles were sensitive to small changes in the residual monomer content, carboxylic acid end group content, and blockiness of the polymers. This finding further underscores the need for a physiologically relevant in vitro release testing method as part of a robust quality control strategy for PLGA-based solid implant formulations.

Manufacturing dexamethasone intravitreal implants: Process control and critical quality attributes.

Over 20 long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been approved by the FDA to date. PLGA is a biodegradable polymer that can extend drug release from these dosage forms for up to six months after administration. Despite the commercial success of several of these formulations, there are still a limited number of products that utilize PLGA, and there are currently no generic counterparts of these products on the market. Significant technical challenges are associated with preparation of chemically and structurally equivalent formulations that yield an equivalent drug release profile to the reference listed drug (RLD) both in vitro and in vivo. In this work, Ozurdex (dexamethasone intravitreal implant) was used as a model system to explore how the manufacturing process of PLGA-based solid implants impacts the quality and performance of the dosage form. Control of implant structural characteristics, including diameter, internal porosity, and surface roughness, was required to maintain accurate unit dose potency. Implants were prepared by a continuous hot-melt extrusion process that was thoroughly characterized to show the importance of precise feeding control to meet dimensional specifications. Five extruder die designs were evaluated using the same hot-melt extrusion process to produce five structurally-distinct implants. The structural differences did not alter the in vitro drug release profile when tested in both normal saline and phosphate-buffered saline (pH 7.4); however, implant porosity was shown to impact the mechanical strength of the implants. This work seeks to provide insight into the manufacturing process of PLGA-based solid implants to support development of future novel and generic drug products.

A guide to modern methods for poly(thio)ether synthesis using Earth-abundant metals.

Polyethers and polythioethers have a long and storied history dating back to the start of polymer science as a distinct field. As such, these materials have been utilized in a wide range of commercial applications and fundamental studies. The breadth of their material properties and the contexts in which they are applied is ultimately owed to their diverse monomer pre-cursors, epoxides and thiiranes, respectively. The facile polymerization of these monomers, both historically and contemporaneously, across academia and industry, has occurred through the use of Earth-abundant metals as catalysts and/or initiators. Despite this, polymerization methods for these monomers are underutilized compared to other monomer classes like cyclic olefins, vinyls, and (meth)acrylates. We feel a focused review that clearly outlines the benefits and shortcomings of extant synthetic methods for poly(thio)ethers along with their proposed mechanisms and quirks will help facilitate the utilization of these methods and by extension the unique polymer materials they create. Therefore, this Feature Article briefly describes the applications of poly(thio)ethers before discussing the feature-set of each poly(thio)ether synthetic method and qualitatively scoring them on relevant metrics (e.g., ease-of-use, molecular weight control, etc.) to help would-be poly(thio)ether-makers find an appropriate synthetic approach. The article is concluded with a look ahead at the future of poly(thio)ether synthesis with Earth-abundant metals.

Drug release mechanisms of high-drug-load, melt-extruded dexamethasone intravitreal implants.

Ozurdex is an FDA-approved sustained-release, biodegradable implant formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for up to 6 months. Hot-melt extrusion is used to prepare the 0.46 mm × 6 mm, rod-shaped implant by embedding the drug in a matrix of poly(lactic-co-glycolic acid) (PLGA) in a 60:40 drug:polymer ratio by weight. In our previous work, the Ozurdex implant was carefully studied and reverse engineered to produce a compositionally and structurally equivalent implant for further analysis. In this work, the reverse-engineered implant was thoroughly characterized throughout the in vitro dissolution process to elucidate the mechanisms of controlled drug release. The implant exhibited a triphasic release profile in 37 °C normal saline with a small burst release (1-2 %), a one-week lag phase with limited release (less than 10 %), and a final phase where the remainder of the dose was released over 3-4 weeks. The limited intermolecular interaction between dexamethasone and PLGA rendered the breakdown of the polymer the dominating mechanism of controlled release. A close relationship between drug release and total implant mass loss was observed. Unique chemical and structural differences were seen between the core of the implant and the implant surface driven by diffusional limitations, autocatalytic hydrolysis, and osmotic effects.

Synthesis of Poly(allyl glycidyl ether)-Derived Polyampholytes and Their Application to the Cryopreservation of Living Cells.

Through the postpolymerization modification of poly(allyl glycidyl ether) (PAGE), a functionalizable polyether with a poly(ethylene oxide) backbone, we engineered a new class of highly tunable polyampholyte materials. These polyampholytes can be synthesized to have several useful properties, including low cytotoxicity and pH-responsive coacervate formation. In this study, we used PAGE-based polyampholytes (PAGE-PAs) for the cryopreservation of mammalian cell suspensions. Typically, dimethyl sulfoxide (DMSO) is the cryoprotectant used for preserving mammalian cells, but DMSO suffers from key drawbacks including toxicity and difficult post-thaw removal that motivates the development of new materials and methods. Toxicity and post-thaw survival were dependent on PAGE-PA composition with the highest immediate post-thaw survival for normal human dermal fibroblasts occurring for the least toxic PAGE-PA at a cation/anion ratio of 35:65. With low toxicity, the PAGE-PA concentration could be increased in order to increase immediate post-thaw survival of the immortalized mouse embryonic fibroblasts (NIH/3T3). While immediate post-thaw viability was achieved using only the PAGE-PAs, long-term cell survival was low, highlighting the challenges involved with the design of cryoprotective polyampholytes. An environment utilizing both PAGE-PAs and DMSO in a cryoprotective solution offered promising post-thaw viabilities exceeding 70%, with long-term metabolic activities comparable to unfrozen cells.

Reverse engineering the Ozurdex dexamethasone intravitreal implant.

Ozurdex is a biodegradable implant formulated for sustained-release delivery of the corticosteroid dexamethasone to the posterior segment of the eye. The small, rod-shaped implant is administered directly to the vitreous using a dedicated applicator, and releases drug for up to 6 months after administration. Sustained release is achieved by embedding dexamethasone in a matrix of 50:50 poly(lactic-co-glycolic acid) (PLGA). In this work, the Ozurdex implant was thoroughly characterized to enable the reverse engineering of a compositionally and structurally equivalent implant. Advanced imaging techniques such as scanning electron microscopy (SEM) and microcomputed tomography (microCT) revealed that the Ozurdex implant exhibits an irregular surface and an internal porosity of 6% due to a large number of discrete voids approximately 3 µm in diameter. Thermal and spectroscopic analyses showed limited interaction between the drug and the polymer, resulting in a two-phase system of dexamethasone crystals embedded within a PLGA matrix. Reverse-engineered implants with properties similar to Ozurdex were prepared using a two-step hot-melt extrusion process. The reverse-engineered implants exhibited a triphasic drug release profile similar to Ozurdex. This work seeks to provide insight into the manufacturing process and characterization of PLGA-based solid implants to support future generic product development.

Machine learning-aided engineering of hydrolases for PET depolymerization.

Plastic waste poses an ecological challenge1-3 and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling4. Poly(ethylene terephthalate) (PET) accounts for 12% of global solid waste5, and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products6-10. Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics11. Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives12 between 30 and 50 °C and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 ºC. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale.

"Benchtop" Biaryl Coupling Using Pd/Cu Cocatalysis: Application to the Synthesis of Conjugated Polymers.

Typically, Suzuki couplings used in polymerizations are performed at raised temperatures in inert atmospheres. As a result, the synthesis of aromatic materials that utilize this chemistry often demands expensive and specialized equipment on an industrial scale. Herein, we describe a bimetallic methodology that exploits the distinct reactivities of palladium and copper to perform high yielding aryl-aryl dimerizations and polymerizations that can be performed on a benchtop under ambient conditions. These couplings are facile and can be performed by simple mixing in the open vessel. To demonstrate the utility of this method in the context of polymer synthesis: polyfluorene, polycarbazole, polysilafluorene, and poly(6,12-dihydro-dithienoindacenodithiophene) were created at ambient temperature and open to air.

Relationship between Ionic Conductivity, Glass Transition Temperature, and Dielectric Constant in Poly(vinyl ether) Lithium Electrolytes.

We report a partial elucidation of the relationship between polymer polarity and ionic conductivity in polymer electrolyte mixtures comprising a homologous series of nine poly(vinyl ether)s (PVEs) and lithium bis(trifluoromethylsulfonyl)imide. Recent simulation studies have suggested that low dielectric polymer hosts with glass transition temperatures far below ambient conditions are expected to have ionic conductivity limited by salt solubility and dissociation. In contrast, high dielectric hosts are expected to have the potential for high ion solubility but slow segmental dynamics due to strong polymer-polymer and polymer-ion interactions. We report results for PVEs in the low polarity regime with dielectric constants of about 1.3 to 9.0. Ionic conductivity measured for the PVE and salt mixtures ranged from about 10-10 to 10-3 S/cm. In agreement with the predictions from computer simulations, the ionic conductivity increased with dielectric constant and plateaued as the dielectric approached 9.0, comparable to the dielectric constant of the widely used poly(ethylene oxide).

Impact of Macromonomer Molar Mass and Feed Composition on Branch Distributions in Model Graft Copolymerizations.

Graft polymers are useful in a versatile range of material applications. Understanding how changes to the grafted architecture, such as the grafting density (z), the side-chain degree of polymerization (Nsc), and the backbone degree of polymerization (Nbb), affect polymer properties is critical for accurately tuning material performance. For graft-through copolymerizations, changes to Nsc and z are controlled by the macromonomer degree of polymerization (NMM) and the initial fraction of the macromonomer in the feed (fMM0), respectively. We show that changes to these parameters can influence the copolymerization reactivity ratios and, in turn, impact the side-chain distribution along a graft polymer backbone. Poly((±)-lactide) macromonomers with NMM values as low as ca. 1 and as high as 72 were copolymerized with a small-molecule dimethyl ester norbornene comonomer over a range of fMM0 values (0.1 ≤ fMM0 ≤ 0.8) using ring-opening metathesis polymerization (ROMP). Monomer conversion was determined using 1H nuclear magnetic resonance spectroscopy, and the data were fit with terminal and nonterminal copolymerization models. The results from this work provide essential information for manipulating Nsc and z while maintaining synthetic control over the side-chain distribution for graft-through copolymerizations.

Mechanism of Polymer-Mediated Cryopreservation Using Poly(methyl glycidyl sulfoxide).

Under the right conditions, some biological systems can maintain high viability after being frozen and thawed, but many others (e.g., organs and many mammalian cells) cannot. To increase the rates of post-thaw viability and widen the library of living cells and tissues that can be stored frozen, an improved understanding of the mode of action of polymeric cryoprotectants is required. Here, we present a polymeric cryoprotectant, poly(methyl glycidyl sulfoxide) (PMGS), that achieved higher post-thaw viability for fibroblast cells than its small-molecule analogue dimethyl sulfoxide. By limiting the amount of water that freezes and facilitating cellular dehydration after ice nucleation, PMGS mitigates the mechanical and osmotic stresses that the freezing of water imparts on cells and facilitates higher-temperature vitrification of the remaining unfrozen volume. The development of PMGS advances a fundamental physical understanding of polymer-mediated cryopreservation, which enables new material design for long-term preservation of complex cellular networks and tissue.

Aerobic radical polymerization mediated by microbial metabolism.

Performing radical polymerizations under ambient conditions is a major challenge because molecular oxygen is an effective radical quencher. Here we show that the facultative electrogen Shewanella oneidensis can control metal-catalysed living radical polymerizations under apparent aerobic conditions by first consuming dissolved oxygen via aerobic respiration, and then directing extracellular electron flux to a metal catalyst. In both open and closed containers, S. oneidensis enabled living radical polymerizations without requiring the preremoval of oxygen. Polymerization activity was closely tied to S. oneidensis anaerobic metabolism through specific extracellular electron transfer proteins and was effective for a variety of monomers using low (parts per million) concentrations of metal catalysts. Finally, polymerizations survived repeated challenges of oxygen exposure and could be initiated using lyophilized or spent (recycled) cells. Overall, our results demonstrate how the unique ability of S. oneidensis to use both oxygen and metals as respiratory electron acceptors can be leveraged to address salient challenges in polymer synthesis.

Spatial Control of the Self-assembled Block Copolymer Domain Orientation and Alignment on Photopatterned Surfaces.

Polarity-switching photopatternable guidelines can be directly used to both orient and direct the self-assembly of block copolymers. We report the orientation and alignment of poly(styrene-block-4-trimethylsilylstyrene) (PS-b-PTMSS) with a domain periodicity, L0, of 44 nm on thin photopatternable grafting surface treatments (pGSTs) and cross-linkable surface treatments (pXSTs), containing acid-labile 4-tert-butoxystyrene monomer units. The surface treatment was exposed using electron beam lithography to create well-defined linear arrays of neutral and preferential regions. Directed self-assembly (DSA) of PS-b-PTMSS with much lower defectivity was observed on pXST than on pGST guidelines. The study of the effect of film thickness on photoacid diffusion by Fourier transform infrared spectroscopy and near-edge X-ray absorption fine structure spectroscopy suggested slower diffusion in thinner films, potentially enabling production of guidelines with sharper interfaces between the unexposed and exposed lines, and thus, the DSA of PS-b-PTMSS on thinner pXST guidelines resulted in better alignment control.

Chemically Triggered Synthesis, Remodeling, and Degradation of Soft Materials.

Polymer topology dictates dynamic and mechanical properties of materials. For most polymers, topology is a static characteristic. In this article, we present a strategy to chemically trigger dynamic topology changes in polymers in response to a specific chemical stimulus. Starting with a dimerized PEG and hydrophobic linear materials, a lightly cross-linked polymer, and a cross-linked hydrogel, transformations into an amphiphilic linear polymer, lightly cross-linked and linear random copolymers, a cross-linked polymer, and three different hydrogel matrices were achieved via two controllable cross-linking reactions: reversible conjugate additions and thiol-disulfide exchange. Significantly, all the polymers, before or after topological changes, can be triggered to degrade into thiol- or amine-terminated small molecules. The controllable transformations of polymeric morphologies and their degradation herald a new generation of smart materials.

Coordination-Assisted Self-Assembled Polypeptide Nanogels to Selectively Combat Bacterial Infection.

In the present scenario, the invention of bacteria-selective antimicrobial agent comprising negligible toxicity and hemolytic effect is a great challenge. To surmount this challenge, here, a series of polypeptide nanogels (PNGs) have been fabricated by a coordination-assisted self-assembly of a mannose-conjugated antimicrobial polypeptide, poly(arginine-r-valine)-mannose (poly(Arg-r-Val)-M2), with Zn2+ ions. The fabricated PNGs are spherical in shape with a unique structural appearance similar to that of Taxus baccata fruits. PNGs, with a unique structural arrangement and threshold surface charge density, selectively interact with the bacterial membrane and exhibit potent antimicrobial activity, as reflected in their lower minimum inhibitory concentration values (varies from 2 to 16 µg/mL). PNGs show a remarkably high binding constant, 6.02 × 105 M-1 (from isothermal titration calorimetry, ITC), with the bacterial membrane which manifests its potent bactericidal effect. PNGs are nontoxic against mammalian and red blood cells as reflected from their higher cell viability and insignificant hemolytic effect. PNGs are taken up by the bacterial membrane and selectively undergo structural deformation (scrutinized by ITC) followed by an exposure of free poly(Arg-r-Val)-M2 molecules. The free poly(Arg-r-Val)-M2 molecules are enforced to lyse the bacterial membrane (visualized by cryo-transmission electron microscopy) followed by the diffusion of the cytoplasmic component out of the membrane which culminates in the final death of the bacterium.

Influence of Host Polarity on Correlating Salt Concentration, Molecular Weight, and Molar Conductivity in Polymer Electrolytes.

We use coarse-grained molecular dynamics simulations to study the effect of salt concentration and host polymer molecular weight on ion transport in polymer electrolytes. We find that increasing salt concentration or molecular weight similarly slows polymer dynamics across a wide range of host polarities, and that the resulting relaxation times display a correlation to the product of the salt concentration and polymer molecular weight. However, we find that molar conductivity only decreases with polymer dynamics at high polarities but is uncorrelated with the latter at low polarities. We attribute such differences to the variation in ionic aggregation between high and low polarity electrolytes. At low polarity, ionic dissociation significantly increases with molecular weight and salt concentration, offsetting the slowdown in polymer dynamics and yielding the observed insensitivity of molar conductivity. However, at high polarity, ions are mostly dissociated, independent of either molecular weight or salt concentration, thereby strongly coupling molar conductivity to polymer dynamics.

Sequence-Dependent Peptide Surface Functionalization of Metal-Organic Frameworks.

We report a noncovalent surface functionalization technique for water-stable metal-organic frameworks using short peptide sequences identified via phage display. Specific frameworks-binding peptides were identified for crystalline Zn(MeIM)2 (MeIM: 2-methylimidazole, ZIF-8), semiamorphous Fe-BTC (BTC: 1,3,5-benzene-tricarboxylate), and Al(OH)(C4H2O4) (MIL-53(Al)-FA, FA: fumaric acid), and their thermodynamic binding affinities and specificities were measured. Electron microscopy, powder X-ray diffraction, and gas adsorption analysis confirmed that the peptide-functionalized frameworks retained similar characteristics compared to their as-synthesized counterparts. Confocal laser-scanning microscopy demonstrated that peptide was localized on the surface of the frameworks, whereas surface area measurements showed no evidence of pore blockage. Finally, we measured the pH-dependent release of fluorescein from peptide-functionalized frameworks and discovered that peptide binding can attenuate fluorescein release by improving framework stability under low pH conditions. Our results demonstrate that phage display can be used as a general method to identify specific peptide sequences with strong binding affinity to water-stable metal-organic frameworks and that these peptides can alter drug release kinetics by affecting framework stability in aqueous environments.