We describe the synthesis, characterization and direct-write 3D printing of triblock copolymer hydrogels that have a tunable response to temperature and shear stress. In aqueous solutions, these polymers utilize the temperature-dependent self-association of poly(alkyl glycidyl ether) 'A' blocks and a central poly(ethylene oxide) segment to create a physically crosslinked three-dimensional network. The temperature response of these hydrogels was dependent upon composition, chain length and concentration of the 'A' block in the copolymer. Rheological experiments confirmed the existence of sol-gel transitions and the shear-thinning behavior of the hydrogels. The temperature- and shear-responsive properties enabled direct-write 3D printing of complex objects with high fidelity. Hydrogel cytocompatibility was also confirmed by incorporating HeLa cells into select hydrogels resulting in high viabilities over 24 h. The tunable temperature response and innate shear-thinning properties of these hydrogels, coupled with encouraging cell viability results, present an attractive opportunity for additive manufacturing and tissue engineering applications. (c) 2018 Society of Chemical Industry

Additive manufacturing, commonly referred to as 3D printing (3DP), has ushered in a new era of advanced manufacturing that is seemingly limited only by imagination. In actuality, the fullest potentials of 3DP can only be realized through innovative breakthroughs in printing technologies and build materials. Whereas equipment for 3DP has experienced considerable development, molecular-scale programming of function, adaptivity, and responsiveness in 3DP is burgeoning. This review aims to summarize the state-of-the-art in stimuli-responsive materials that are being explored in 3DP. First, we discuss stimuli-responsiveness as it is used to enable 3DP. This highlights the diverse ways in which molecular structure and reactivity dictate energy transduction that in turn enables 3D processability. Second, we summarize efforts that have demonstrated the use of 3DP to create materials, devices, and systems that are in their final stage stimuli-responsive. This section encourages the artistic license of advanced manufacturing to be applied toward leveraging, or enhancing, energy transduction to impart device function across multiple length scales.

In this study, bortezomib (BTZ, a cytotoxic water-insoluble anticancer drug) was encapsulated in micellar nanoparticles having a catechol-functionalized polycarbonate core through a pH-sensitive covalent bond between phenylboronic acid (PBA) in BTZ and catechol, and these drug-loaded micelles were incorporated into hydrogels to form micelle/hydrogel composites. A series of injectable, biodegradable hydrogels with readily tunable mechanical properties were formed and optimized for sustained delivery of the BTZ-loaded micelles through ionic coacervation between PBA-functionalized polycarbonate/poly(ethylene glycol) (PEG) "ABA" triblock copolymer and a cationic one having guanidinium- or thiouronium-functionalized polycarbonate as "A" block. An in vitro release study showed the pH dependence in BTZ release. At pH 7.4, the BTZ release from the micelle/hydrogel composite remained low at 7%, whereas in an acidic environment, ∼85% of BTZ was released gradually over 9 days. In vivo studies performed in a multiple myeloma MM.1S xenograft mouse model showed that the tumor progression of mice treated with BTZ-loaded micelle solution was similar to that of the control group, whereas those treated with the BTZ-loaded micelle/hydrogel composite resulted in significant delay in the tumor progression. The results demonstrate that this hydrogel has great potential for use in subcutaneous and sustained delivery of drug-loaded micelles with superior therapeutic efficacy.

To exploit tumor and intracellular microenvironments, pH-responsive diblock copolymers of poly(ethylene glycol) and catechol-functionalized polycarbonate with acid-labile acetal bond as the linker are synthesized to prepare micellar nanoparticles that shed the shell at acidic tumor tissues and inside cancer cells, hence accelerating drug release at the target. The pH-dependent cleavage of the shell is demonstrated at pH 5.0 and 6.5 using 1H NMR. Bortezomib (BTZ, an anticancer drug containing a phenylboronic acid group) is conjugated to the polymers through formation of pH-responsive boronate ester bond between boronic acid and catechol in the polymers. Dual pH-responsive bortezomib-polymer conjugates (BTZ-PC) self-assemble into micellar nanoparticles of small size (<110 nm) with narrow size distribution and high drug loading capacity. Acidic pH accelerates BTZ release from BTZ-PC micelles and enhances intracelluar uptake of the micelles, hence increasing in vitro cytotoxicity against human breast cancer cells. More importantly, the BTZ-PC micelles achieve a stronger antitumor effect in a human breast cancer BT-474 xenograft mouse model than free BTZ and mitigate in vivo hepatotoxicity of BTZ. These dual pH-responsive shell-cleavable nanoparticles are a potentially promising carrier for BTZ delivery.

Biodegradable polycarbonate-based ABA triblock copolymers were synthesized via organocatalyzed ring-opening polymerization and successfully formulated into chemically cross-linked hydrogels by strain-promoted alkyne-azide cycloaddition (SPAAC). The synthesis and cross-linking of these polymers are copper-free, thereby eliminating the concern over metallic contaminants for biomedical applications. Gelation occurs rapidly within a span of 60 s by simple mixing of the azide- and cyclooctyne-functionalized polymer solutions. The resultant hydrogels exhibited pronounced shear-thinning behavior and could be easily dispensed through a 22G hypodermic needle. To demonstrate the usefulness of these gels as a drug delivery matrix, doxorubicin (DOX)-loaded micelles prepared using catechol-functionalized polycarbonate copolymers were incorporated into the polymer solutions to eventually form micelle/hydrogel composites. Notably, the drug release rate from the hydrogels was significantly more gradual compared to the solution formulation. DOX release from the micelle/hydrogel composites could be sustained for 1 week, while the release from the micelle solution was completed rapidly within 6 h of incubation. Cellular uptake of the released DOX from the micelle/hydrogel composites was observed at 3 h of incubation of human breast cancer MDA-MB-231 cells. A blank hydrogel containing PEG-(Cat)12 micelles showed almost negligible toxicity on MDA-MB-231cells where cell viability remained high at >80% after treatment. When the cells were treated with the DOX-loaded micelle/hydrogel composites, there was a drastic reduction in cell viability with only 25% of cells surviving the treatment. In all, this study introduces a simple method of formulating hydrogel materials with incorporated micelles for drug delivery applications.

Effective antimicrobial agents are important arsenals in our perennial fight against communicable diseases, hospital-acquired and surgical site multidrug-resistant infections. In this study, we devise a strategy for the development of highly efficacious and skin compatible yet inexpensive water-soluble macromolecular antimicrobial polyionenes by employing a catalyst-free, polyaddition polymerization using commercially available monomers. A series of antimicrobial polyionenes are prepared through a simple polyaddition reaction with both polymer-forming reaction and charge installation occurring simultaneously. The compositions and structures of polymers are modulated to study their effects on antimicrobial activity against a broad spectrum of pathogenic microbes. Polymers with optimized compositions have potent antimicrobial activity with low minimum inhibitory concentrations of 1.95 -7.8 mu g/mL and high selectivity over mammalian cells. In particular, a killing efficiency of more than 99.9% within 2 min is obtained. Moreover, the polymers demonstrate high antimicrobial efficacy against various clinically-isolated multidrug-resistant microbes, yet exhibit vastly superior skin biocompatibility in mice as compared to other clinically used surgical scrubs (chlorhexidine and betadine). Microbicidal activity of the polymer is mediated via membrane lysis as demonstrated by confocal microscopy. Unlike small molecular antibiotics, repeated use of the polymer does not induce drug resistance. More importantly, the polymer shows excellent bactericidal activity in a P. aeruginosa-contaminated mouse skin model. Given their rapid and efficacious microbicidal activity and skin compatibility, these polymers have tremendous potential to be developed as surgical scrubs/hand sanitizers to prevent multidrug-resistant infections. (C) 2017 Elsevier Ltd. All rights reserved.

In this study, antimicrobial polymers are synthesized by the organocatalytic ring-opening polymerization of an eight-membered heterocyclic carbonate monomer that is subsequently quaternized with methyl iodide. These polymers demonstrate activity against clinically relevant Gram-positive Staphylococcus epidermidis and Staphylococcus aureus, Gram-negative Escherichia coli and Pseudomonas aeruginosa, and fungus Candida albicans with fast killing kinetics. Importantly, the polymer efficiently inhibits biofilm growth and lyses existing biofilm, leading to a reduction in biomass and cell viability. In addition, the macromolecular antimicrobial is less likely to induce resistance as it acts via a membrane-lytic mechanism. The polymer is not cytotoxic toward mammalian cells with LD50 of 99.0 ± 11.6 mg kg-1 in mice through i.v. injection. In an S. aureus blood stream infection mouse model, the polymer removes bacteria from the blood more rapidly than the antibiotic Augmentin. At the effective dose, the polymer treatment does not damage liver and kidney tissues or functions. In addition, blood electrolyte balance remains unchanged after the treatment. The low cost of starting materials, ease of synthesis, nontoxicity, broad spectrum activity with fast killing kinetics, and in vivo antimicrobial activity make these macromolecular antimicrobials ideal candidates for prevention of sepsis and treatment of infections.

There is a growing interest in modern healthcare to develop systems able to fight antibiotic resistant bacteria. Antimicrobial cationic biodegradable polymers able to mimic antimicrobial peptides have shown to be effective against both Gram-positive and Gram-negative bacteria. In these systems, the hydrophilic-hydrophobic ratio and the cationic charge density play a pivotal role in defining the killing efficiency. Nevertheless, many of these antimicrobial polymers show relatively low selectivity as defined by the relative toxicity to mammalian cells or hemolysis relative to pathogens. In this study, a series of polycarbonates containing pendant quaternary ammoniums are used to understand the role of different counter-anions including chloride, citrate, malonate, benzoate, acetate, lactate and trifluoroacetate, and the antibiotic penicillin on antimicrobial efficacy and selectivity. Interestingly, it is found that in spite of the strong antimicrobial activity of trifluoroacetate and benzoate anions, they prove to be much less hemolytic than chloride anion. It is believed that the proper selection of the anion could enhance the potential of antimicrobial polymers to fight against clinically relevant pathogenic infections, while concurrently mitigating harmful side effects.

Cost-effective macromolecular antimicrobials were synthesized to explore a variety of chemical functional groups that target antimicrobial performance and reduce cytotoxicity.

Postpolymerization modification is a critical strategy for the development of functional polycarbonate scaffolds for medicinal applications. To expand the scope of available postpolymerization functionalization methods, polycarbonates containing pendant thioether groups were synthesized by organocatalyzed ring-opening polymerization. The thioether group allowed for the postpolymerization ring-opening of functional epoxides, affording a wide variety of sulfonium-functionalized A-B diblock and A-B-A triblock polycarbonate copolymers. The pendant thioether groups were found to be compatible with previously developed postsynthesis functionalization methods allowing for selective and orthogonal modifications of the polycarbonates.

PEI was chemically-modified with carbohydrates and carbohydrate-mimetics to improve biocompatibility.

Carboxylated oligothiophenes were evaluated as interfacial modifiers between the organic poly(3-hexylthiophene) (P3HT) and inorganic TiO2 layers in bilayer hybrid polymer solar cells. Carboxylated oligothiophenes can be isolated using conventional purification techniques resulting in pure, monodisperse molecules with 100% carboxylation. Device prototypes using carboxylated oligothiophenes as interfacial modifiers showed improved performance in the open-circuit voltage and fill factor over devices using unmodified oligothiophenes as interfacial modifiers. X-ray photoelectron spectroscopy (XPS) studies supported the idea that interface layer adhesion was improved by functionalizing oligothiophenes with a carboxyl moiety. Wide-field fluorescence images revealed that devices made using carboxylated oligothiophenes had fewer aggregates in the P3HT layers atop the modified TiO2 surface. Hysteresis seen in the fluorescence intensity as a function of applied bias, obtained from In-Device Fluorescence Voltage Spectroscopy (ID-FVS), was found to be a diagnostic criterion of the quality of the hybrid interface modification. The best interfaces were found using oligothiophenes functionalized with carboxylates, which created smooth layers on TiO2, and showed no hysteresis, suggesting elimination of interfacial charge traps. However, this hysteresis could be re-introduced by increasing the scan rate of the applied bias, suggesting that smooth P3HT layers created by carboxylated oligothiophene interface modifiers were necessary but not sufficient for sustaining improved photovoltaic properties especially during long-term device operation.

Biodegradable polycarbonate-based ABA triblock copolyelectrolytes were synthesized and formulated into physically cross-linked hydrogels. These biocompatible, cationically, and anionically charged hydrogel materials exhibited pronounced shear-thinning behavior, making them useful for a variety of biomedical applications. For example, we investigated the antimicrobial activity of positively charged thiouronium functionalized hydrogels by microbial growth inhibition assays against several clinically relevant Gram-negative and Gram-positive bacteria. It is noteworthy that these hydrogels exhibited broad spectrum killing efficiencies approaching 100%, thereby rendering these thixotropic materials attractive for treatment of skin and other surface bound infections. Finally, cationic trimethylammonium containing hydrogels and anionic carboxylic acid functionalized hydrogels were utilized to sustain the release of negatively charged (diclofenac) and positively charged (vancomycin) therapeutics, respectively. Collectively, the present work introduces a simple method for formulating charged hydrogel materials that are capable of interacting with various analytes of interest through noncovalent interactions.

(Bio)degradable poly(ethylene imine-co-glycine)s (P(EI-co-Gly)) were synthesized through efficient and controlled oxidation of linear poly(ethylene imine) (LPEI) using hydrogen peroxide in a methanol/water mixture. Temperature, peroxide concentration, and reaction time were varied to adjust the degree of oxidation (DO). At low temperatures, the oxidation process was found to be well-controlled with almost 85% of ethylene imine units converted to the corresponding amide. Importantly, oxidation of more than 10% of the LPEI rendered the polymers water-soluble. The oxidation reaction and molecular structure of P(EI-co-Gly)s were studied in detail by various nuclear magnetic resonance (NMR) methods, infrared (IR) spectroscopy, and size exclusion chromatography (SEC). The introduction of backbone amide groups to the P(EI-co-Gly)s facilitated its (bio)degradation under acidic conditions or by proteases. Moreover, the P(EI-co-Gly)s exhibited negligible cytotoxicity, particularly relative to LPEI. The interaction of the copolymers with serum-containing medium was investigated showing no indication of coagulation. Preliminary studies indicate that P(EI-co-Gly) is a promising biodegradable polymer with negligible toxicity in human cell lines.

Poly(ethylene glycol) (PEG) represents the gold standard for stealth polymers in polymer-based therapeutic delivery. Unfortunately, PEG has some limitations which warrant the examination of alternative polymers. High molecular weight PEG (>40 kDa) can accumulate in tissue, and in some patients, PEG can provoke an immunological response and/or an accelerated blood clearance upon repeated exposure. As an alternative to PEG, water-soluble, nonfouling polycarbonates have been developed. These hydrophilic polycarbonates, prepared by acid-catalyzed ring-opening polymerization, contain hydroxyl groups attached to the polymer side chain via an amide linkage. These materials offer an enzymatically and hydrolytically degradable alternative to PEG. The results of cell viability studies and LD50 studies indicate that these materials have minimal toxicity. Nonfouling behavior and the ability to resist/reduce aggregation with proteins were demonstrated. Diblock copolymers were also synthesized to demonstrate that these polymers can be utilized for micellar drug delivery systems.

Conjugated polymers in the solid state usually exhibit low fluorescence quantum yields, which limit their applications in many areas such as light-emitting diodes. Despite considerable research efforts, the underlying mechanism still remains controversial and elusive. Here, the nature and properties of excited states in the archetypal polythiophene are investigated via aggregates suspended in solvents with different dielectric constants ( ɛ ). In relatively polar solvents ( ɛ >∼ 3), the aggregates exhibit a low fluorescence quantum yield (QY) of 2–5%, similar to bulk films, however, in relatively nonpolar solvents ( ɛ <∼ 3) they demonstrate much higher fluorescence QY up to 20–30%. A series of mixed quantum-classical atomistic simulations illustrate that dielectric induced stabilization of nonradiative charge-transfer (CT) type states can lead to similar drastic reduction in fluorescence QY as seen experimentally. Fluorescence lifetime measurement reveals that the CT-type states exist as a competitive channel of the formation of emissive exciton-type states.