SciCombinator

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Concept: Polymer chemistry

178

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer’s disease. Despite the importance of plaques to Alzheimer’s disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer’s disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer’s disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer’s disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer’s disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer’s disease pathogenesis.

Concepts: Alzheimer's disease, Neuron, Polymer chemistry, Monomer, Acetylcholine, Toxicity, Oligomer, Neurofibrillary tangle

173

Polymersomes, made up of amphiphilic block copolymers, are emerging as a powerful tool in drug delivery and synthetic biology due to their high stability, chemical versatility, and surface modifiability. The full potential of polymersomes, however, has been hindered by a lack of versatile methods for shape control. Here we show that a range of non-spherical polymersome morphologies with anisotropic membranes can be obtained by exploiting hydrophobic directional aromatic interactions between perylene polymer units within the membrane structure. By controlling the extent of solvation/desolvation of the aromatic side chains through changes in solvent quality, we demonstrate facile access to polymersomes that are either ellipsoidal or tubular-shaped. Our results indicate that perylene aromatic interactions have a great potential in the design of non-spherical polymersomes and other structurally complex self-assembled polymer structures.

Concepts: Cell membrane, Structure, Polymer, Copolymer, Polymer chemistry

171

Fibrin polymerization is a necessary part of hemostasis but clots can obstruct blood vessels and cause heart attacks and strokes. The polymerization reactions are specific and controlled, involving strong knob-into-hole interactions to convert soluble fibrinogen into insoluble fibrin. It has long been assumed that clots and thrombi are stable structures until proteolytic digestion. On the contrary, using the technique of fluorescence recovery after photobleaching, we demonstrate here that there is turnover of fibrin in an uncrosslinked clot. A peptide representing the knobs involved in fibrin polymerization can compete for the holes and dissolve a preformed fibrin clot, or increase the fraction of soluble oligomers, with striking rearrangements in clot structure. These results imply that in vivo clots or thrombi are more dynamic structures than previously believed that may be remodeled as a result of local environmental conditions, may account for some embolization, and suggest a target for therapeutic intervention.

Concepts: Protein, Stroke, Coagulation, Polymer chemistry, Fibrin, Hemostasis, Thrombus, Monomer

98

We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures.

Concepts: Polymer, Polymer chemistry, Differential scanning calorimetry, Glass, Glass transition, Shape memory alloy, Polymers, Shape memory polymer

58

Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.

Concepts: Chemical reaction, Polymer chemistry, Cross-link, Cross-linked polyethylene

48

The widespread prevalence of commercial products made from microgels illustrates the immense practical value of harnessing the jamming transition; there are countless ways to use soft, solid materials that fluidize and become solid again with small variations in applied stress. The traditional routes of microgel synthesis produce materials that predominantly swell in aqueous solvents or, less often, in aggressive organic solvents, constraining ways that these exceptionally useful materials can be used. For example, aqueous microgels have been used as the foundation of three-dimensional (3D) bioprinting applications, yet the incompatibility of available microgels with nonpolar liquids, such as oils, limits their use in 3D printing with oil-based materials, such as silicone. We present a method to make micro-organogels swollen in mineral oil, using block copolymer self-assembly. The rheological properties of this micro-organogel material can be tuned, leveraging the jamming transition to facilitate its use in 3D printing of silicone structures. We find that the minimum printed feature size can be controlled by the yield stress of the micro-organogel medium, enabling the fabrication of numerous complex silicone structures, including branched perfusable networks and functional fluid pumps.

Concepts: Polymer, Polymer chemistry, Liquid, Glass transition, Elasticity, Linear elasticity, Oil, Lubricant

41

Nitrogen-based thermoset polymers have many industrial applications (for example, in composites), but are difficult to recycle or rework. We report a simple one-pot, low-temperature polycondensation between paraformaldehyde and 4,4'-oxydianiline (ODA) that forms hemiaminal dynamic covalent networks (HDCNs), which can further cyclize at high temperatures, producing poly(hexahydrotriazine)s (PHTs). Both materials are strong thermosetting polymers, and the PHTs exhibited very high Young’s moduli (up to ~14.0 gigapascals and up to 20 gigapascals when reinforced with surface-treated carbon nanotubes), excellent solvent resistance, and resistance to environmental stress cracking. However, both HDCNs and PHTs could be digested at low pH (<2) to recover the bisaniline monomers. By simply using different diamine monomers, the HDCN- and PHT-forming reactions afford extremely versatile materials platforms. For example, when poly(ethylene glycol) (PEG) diamine monomers were used to form HDCNs, elastic organogels formed that exhibited self-healing properties.

Concepts: Polymer chemistry, Monomer, Plastic, Carbon fiber, Thermoplastic, Polyethylene terephthalate, Thermosetting plastics, Thermosetting polymer

33

Ring-opening polymerization of lactones is a versatile approach to generate well-defined functional polyesters. Typical ring-opening catalysts are subject to a trade-off between rate and selectivity. Here we describe an effective catalytic system combining alkoxides with thioureas that catalyses rapid and selective ring-opening polymerizations. Deprotonation of thioureas by sodium, potassium or imidazolium alkoxides generates a hydrogen-bonded alcohol adduct of the thiourea anion (thioimidate). The ring-opening polymerization of L-lactide mediated by these alcohol-bonded thioimidates yields highly isotactic polylactide with fast kinetics and living polymerization behaviour, as evidenced by narrow molecular weight distributions (Mw/Mn < 1.1), chain extension experiments and minimal transesterifications. Computational studies indicate a bifunctional catalytic mechanism whereby the thioimidate activates the carbonyl of the monomer and the alcohol initiator/chain end to effect the selective ring-opening of lactones and carbonates. The high selectivity of the catalyst towards monomer propagation over transesterification is attributed to a selective activation of monomer over polymer chains.

Concepts: Hydrogen, Catalysis, Polymer, Polymer chemistry, Monomer, Functional groups, Enzyme catalysis, Polymerization

31

Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Concepts: Pharmacology, Polymer, Polymer chemistry, Solubility, Monomer, Solid, Biopharmaceutics Classification System, Polymerization

31

Covalent and supramolecular polymers are two distinct forms of soft matter, composed of long chains of covalently and noncovalently linked structural units, respectively. We report a hybrid system formed by simultaneous covalent and supramolecular polymerizations of monomers. The process yields cylindrical fibers of uniform diameter that contain covalent and supramolecular compartments, a morphology not observed when the two polymers are formed independently. The covalent polymer has a rigid aromatic imine backbone with helicoidal conformation, and its alkylated peptide side chains are structurally identical to the monomer molecules of supramolecular polymers. In the hybrid system, covalent chains grow to higher average molar mass relative to chains formed via the same polymerization in the absence of a supramolecular compartment. The supramolecular compartments can be reversibly removed and re-formed to reconstitute the hybrid structure, suggesting soft materials with novel delivery or repair functions.

Concepts: Electron, Chemical bond, Polymer, Polymer chemistry, Monomer, Soft matter, Polymerization, Delocalized electron