Modular Integration of Hydrogel Neural Interfaces.

Thermal drawing has been recently leveraged to yield multifunctional, fiber-based neural probes at near kilometer length scales. Despite its promise, the widespread adoption of this approach has been impeded by (1) material compatibility requirements and (2) labor-intensive interfacing of functional features to external hardware. Furthermore, in multifunctional fibers, significant volume is occupied by passive polymer cladding that so far has only served structural or electrical insulation purposes. In this article, we report a rapid, robust, and modular approach to creating multifunctional fiber-based neural interfaces using a solvent evaporation or entrapment-driven (SEED) integration process. This process brings together electrical, optical, and microfluidic modalities all encased within a copolymer comprised of water-soluble poly(ethylene glycol) tethered to water-insoluble poly(urethane) (PU-PEG). We employ these devices for simultaneous optogenetics and electrophysiology and demonstrate that multifunctional neural probes can be used to deliver cellular cargo with high viability. Upon exposure to water, PU-PEG cladding spontaneously forms a hydrogel, which in addition to enabling integration of modalities, can harbor small molecules and nanomaterials that can be released into local tissue following implantation. We also synthesized a custom nanodroplet forming block polymer and demonstrated that embedding such materials within the hydrogel cladding of our probes enables delivery of hydrophobic small molecules in vitro and in vivo. Our approach widens the chemical toolbox and expands the capabilities of multifunctional neural interfaces.

Combination of irreversible electroporation with sustained release of a synthetic membranolytic polymer for enhanced cancer cell killing.

Irreversible electroporation (IRE) is used clinically as a focal therapy to ablate solid tumors. A critical disadvantage of IRE as a monotherapy for cancer is the inability of ablating large tumors, because the electric field strength required is often too high to be safe. Previous reports indicate that cells exposed to certain cationic small molecules and surfactants are more vulnerable to IRE at lower electric field strengths. However, low-molecular-weight IRE sensitizers may suffer from suboptimal bioavailability due to poor stability and a lack of control over spatiotemporal accumulation in the tumor tissue. Here, we show that a synthetic membranolytic polymer, poly(6-aminohexyl methacrylate) (PAHM), synergizes with IRE to achieve enhanced cancer cell killing. The enhanced efficacy of the combination therapy is attributed to PAHM-mediated sensitization of cancer cells to IRE and to the direct cell killing by PAHM through membrane lysis. We further demonstrate sustained release of PAHM from embolic beads over 1 week in physiological medium. Taken together, combining IRE and a synthetic macromolecular sensitizer with intrinsic membranolytic activity and sustained bioavailability may present new therapeutic opportunities for a wide range of solid tumors.

Mucoadhesive wafers composed of binary polymer blends for sublingual delivery and preservation of protein vaccines.

The objective of this study is to develop a simple biopolymer platform of mucoadhesive wafers that enables effective sublingual delivery and preservation of protein vaccines. The wafers were composed of a series of binary polymer blends of carboxymethylcellulose (CMC) and alginate (ALG). Varying the ratio between CMC and ALG resulted in wafers with different microstructure, mechanical properties, disintegration time, and release kinetics of model compounds. Wafers with high CMC content were highly mucoadhesive to sublingual mucosal tissue and could withstand extensive washing, leading to improved protein permeation into the tissue. On the other hand, wafers with high ALG content were not only mechanically robust, but also able to protect a model enzyme (ß-galactosidase) against lyophilization and heat challenge. HIV gp140 protein loaded in wafers of the optimal composition could be stored and transported without cold chain, while maintaining antigen-specific immunogenicity after sublingual vaccination in mice. These findings established that the CMC/ALG binary blend polymer wafers have the potential to improve the sublingual delivery and storage stability of protein-based vaccines.

Polymer-Based Dual-Responsive Self-Emulsifying Nanodroplets as Potential Carriers for Poorly Soluble Drugs.

A biodegradable amphiphilic liquid polymer was designed to form self-emulsifying nanodroplets in water for delivering poorly soluble drugs. The polymer was composed of multiple short blocks of poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) connected through acid-labile acetal linkages. With an overall average molecular weight of over 18 kDa, the polymer remained as a viscous liquid under room and physiological temperatures. Dispersing the polymer in an aqueous buffer gave rise to highly stable micelle-like nanodroplets with an average size of approximately 15-20 nm. The nanodroplet dispersions underwent reversible temperature-sensitive aggregation with cloud points ranging from 45 to 50 °C, depending on polymer concentration. Nuclear magnetic resonance (NMR) and dynamic light scattering analyses revealed that while the nanodroplets were stable at pH 7.4 for several days, hydrolysis of the acetal linkages in the polymer backbone was much accelerated under mildly acidic pH 5.0, resulting in the formation of large microdroplets. Nile red (NR), a poorly water-soluble fluorophore, can be solubilized in the nanodroplets, and efficient intracellular delivery of NR was achieved. The hydrophobic indocyanine green (ICG) was also encapsulated in the nanodroplets. Near-infrared (NIR) fluorescence imaging and in vivo biocompatibility of the ICG-loaded nanodroplets were demonstrated in mice. In summary, the self-emulsifying nanodroplets of amphiphilic liquid polymer would be a promising material system for poorly soluble drug delivery and imaging in vivo.

EDTA-Inspired Polydentate Hydrogels with Exceptionally High Heavy Metal Adsorption Capacity as Reusable Adsorbents for Wastewater Purification.

Water pollution by heavy metal ions is a critical threat to public health. To remove the heavy metal pollutants from large waterbodies, we have synthesized a biocompatible, cost-effective, metal ion non-specific, and ethylenediaminetetraacetic acid (EDTA)-inspired polydentate hydrogel with exceptionally high adsorption capacity and reusability. The hydrogel was synthesized by the transamidation reaction between hydrolyzed polyacrylamide and branched polyethylenimine (BPEI). The mechanical strength of the synthesized hydrogel displayed an increasing trend with the wt % of the cross-linker (BPEI) and achieved a maximum storage modulus (Gmax') of 1093 Pa. Scanning electron microscopy revealed a porous network structure of the hydrogel (pore size: 30-70 µm), resulting in a very high swelling ratio of 5800%. The porous hydrogel manifested the maximum adsorption capacity of 482.2 mg/g when adsorbing from a mixture of metal ions (Cr3+, Cu2+, Zn2+, Cd2+, Hg2+, and Pb2+), higher than any EDTA-grafted material known to date. The high adsorption capacity of the hydrogel was attributed to the existence of numerous EDTA-mimicking coordinating functional groups, as confirmed by X-ray photoelectron spectroscopy. In addition, the hydrogel showed the self-healing property and preserved more than 85% adsorption efficiency even after five cycles of reuse. Furthermore, the hydrogels showed no or moderate toxicity toward mammalian cells.

Knowledge and Acceptability of HIV pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in Ghana.

In Ghana, men who have sex with men (MSM) are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) is a biomedical intervention that reduces the risk of HIV infection but is not currently available in Ghana. This paper explores knowledge and acceptability of HIV PrEP among Ghanaian MSM. Qualitative content analysis was conducted on 22 focus group discussions (N = 137) conducted between March and June 2012 in Accra, Kumasi, and Manya Krobo. Overall, participants reported low knowledge of PrEP. However, once information about PrEP was provided, there was high acceptability. The primary reason for acceptability was that PrEP provided an extra level of protection against HIV. Acceptability of PrEP was conditioned on it having minimal side effects, being affordable and efficient in preventing HIV infection. No acceptability of PrEP was attributed to limited knowledge of side effects and perceived lack of effectiveness. The reasons provided to utilize PrEP and condoms were that condoms protect against other STIs, and sexual partner factors. This is the first known study to explore PrEP knowledge and acceptability among Ghanaian MSM. It is important that key stakeholders preemptively address potential barriers to PrEP acceptability, uptake, and adherence, especially among MSM, once PrEP becomes available in Ghana.

Heterogeneous Aqueous CO2 Reduction Using a Pyrene-Modified Rhenium(I) Diimine Complex.

The development of molecular catalysts and materials that can convert carbon dioxide (CO2) into a value-added product is a great chemical challenge. Molecular catalysts set benchmarks in catalyst investigation and design, but their incorporation into solid-state materials, and optimization of the electrochemical operating conditions, is still needed. For example, rhenium(I) diimine catalysts show almost quantitative selectivity for the conversion of CO2 to carbon monoxide (CO) in acetonitrile (MeCN), but the modification of diimine backbones can be challenging if the goal is to incorporate such molecules into materials. Presented here is a rhenium(I) complex with a 2-(2'-quinolyl)benzimidazole (QuBIm-H) ligand, where N-alkylation with a pyrene derivative allows access to a catalyst that can be adsorbed onto electrodes for aqueous CO2 reduction chemistry. The rhenium(I) catalysts are inactive for homogeneous CO2 reduction in MeCN. However, when adsorbed on edge-plane graphite, the same complexes show good activity for heterogeneous aqueous CO2 reduction, with 90% selectivity for CO. Comparative electrochemical studies between covalent and noncovalent modification of the graphite surfaces were also carried out for related rhenium(I) tricarbonyl complexes.

Well-defined star polymers for co-delivery of plasmid DNA and imiquimod to dendritic cells.

Co-delivery of antigen-encoding plasmid DNA (pDNA) and immune-modulatory molecules has importance in advancing gene-based immunotherapy and vaccines. Here novel star polymer nanocarriers were synthesized for co-delivery of pDNA and imiquimod (IMQ), a poorly soluble small-molecule adjuvant, to dendritic cells. Computational modeling and experimental results revealed that the polymers formed either multimolecular or unimolecular core-shell-type micelles in water, depending on the nature of the outer hydrophilic shell. Micelles loaded with both IMQ and pDNA were able to release IMQ in response to intracellular pH of the endo-lysosome and transfect mouse dendritic cells (DC2.4 line) in vitro. Importantly, IMQ-loaded micelle/pDNA complexes displayed much enhanced transfection efficiency than IMQ-free complexes. These results demonstrate the feasibility of co-delivery of pDNA and IMQ to antigen-presenting cells by multifunctional polymer nanocarriers with potential use in gene-based vaccine approaches.

Co-Delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-Responsive Star Polymer that Forms Unimolecular Micelles in Water.

Dual functional unimolecular micelles based on a pH-responsive amphiphilic star polymer ß-CD-(PLA-b-PDMAEMA-b-PEtOxMA)21 have been developed for the co-delivery of imiquimod and plasmid DNA to dendritic cells. The star polymer with well-defined triblock arms was synthesized by combining activator regenerated by electron-transfer atom-transfer radical polymerization with ring-opening polymerization. Dissipative particle dynamics simulation showed that core-mesophere-shell-type unimolecular micelles could be formed. Imiquimod-loaded micelles had a drug loading of 1.6 wt % and a larger average size (28 nm) than blank micelles (19 nm). The release of imiquimod in vitro was accelerated at the mildly acidic endolysosomal pH (5.0) in comparison to physiologic pH (7.4). Compared with blank micelles, a higher N:P ratio was required for imiquimod-loaded micelles to fully condense DNA into micelleplexes averaging 200⁻400 nm in size. In comparison to blank micelleplexes, imiquimod-loaded micelleplexes of the same N:P ratio displayed similar or slightly higher efficiency of gene transfection in a mouse dendritic cell line (DC2.4) without cytotoxicity. These results suggest that such pH-responsive unimolecular micelles formed by the well-defined amphiphilic star polymer may serve as promising nano-scale carriers for combined delivery of hydrophobic immunostimulatory drugs (such as imiquimod) and plasmid DNA with potential application in gene-based immunotherapy.

Pushing the limits of neutral organic electron donors: a tetra(iminophosphorano)-substituted bispyridinylidene.

A new ground-state organic electron donor has been prepared that features four strongly π-donating iminophosphorano substituents on a bispyridinylidene skeleton. Cyclic voltammetry reveals a record redox potential of -1.70 V vs. saturated calomel electrode (SCE) for the couple involving the neutral organic donor and its dication. This highly reducing organic compound can be isolated (44 %) or more conveniently generated in situ by a deprotonation reaction involving its readily prepared pyridinium ion precursor. This donor is able to reduce a variety of aryl halides, and, owing to its redox potential, was found to be the first organic donor to be effective in the thermally induced reductive SN bond cleavage of N,N-dialkylsulfonamides, and reductive hydrodecyanation of malonitriles.

Powerful Bispyridinylidene Organic Reducing Agents with Iminophosphorano π-Donor Substituents.

Four members of a new family of powerful bispyridinylidene organic reducing agents have been prepared, which exploit iminophosphorano (-N=PR3; R = Ph, Cy) π-donor substituents. Electrochemical studies show exceptionally high oxidation potentials, ranging from 1.30 to 1.51 V versus SCE. These new reductants were shown to effectively convert 1-bromonaphthalene to naphthalene under mild reaction conditions. From the redox potentials, substituent constants (σp(+)) for the iminophosphorano groups Ph3P=N- (-1.82) and Cy3P=N- (-2.21) were determined, demonstrating their superior π-donating properties compared to traditional amino substituents.

The Association of HIV Stigma and HIV/STD Knowledge With Sexual Risk Behaviors Among Adolescent and Adult Men Who Have Sex With Men in Ghana, West Africa.

Ghanaian men who have sex with men (MSM) have a high HIV seroprevalence, but despite a critical need to address this public health concern, research evidence has been extremely limited on influences on sexual risk behavior among MSM in Ghana. To investigate associations between HIV/STD knowledge, HIV stigma, and sexual behaviors in a sample of MSM in Ghana, we conducted a secondary data analysis of cross-sectional survey data from a non-probability sample of Ghanaian MSM (N = 137). Nearly all the men (93%) had more than one current sex partner (M = 5.11, SD = 7.4). Of those reported partners, the average number of current female sexual partners was 1.1 (SD = 2.6). Overall, knowledge levels about HIV and STDs were low, and HIV stigma was high. There was no age-related difference in HIV stigma. Younger MSM (≤25 years) used condoms less often for anal and vaginal sex than did those over 25. Relative frequency of condom use for oral sex was lower in younger men who had higher STD knowledge and also was lower in older men who reported high HIV stigma. Knowledge and stigma were not associated with condom use for anal or vaginal sex in either age group. These descriptive data highlight the need for the development of intervention programs that address HIV/STD prevention knowledge gaps and reduce HIV stigma in Ghanaian communities. Intervention research in Ghana should address age-group-specific HIV prevention needs of MSM youth.

Predictors of condom use among peer social networks of men who have sex with men in Ghana, West Africa.

Ghanaian men who have sex with men (MSM) have high rates of HIV infection. A first step in designing culturally relevant prevention interventions for MSM in Ghana is to understand the influence that peer social networks have on their attitudes and behaviors. We aimed to examine whether, in a sample of Ghanaian MSM, mean scores on psychosocial variables theorized to influence HIV/STI risk differed between peer social networks and to examine whether these variables were associated with condom use. We conducted a formative, cross-sectional survey with 22 peer social networks of MSM (n = 137) in Ghana. We assessed basic psychological-needs satisfaction, HIV/STI knowledge, sense of community, HIV and gender non-conformity stigmas, gender equitable norms, sexual behavior and condom use. Data were analyzed using analysis of variance, generalized estimating equations, and Wilcoxon two sample tests. All models were adjusted for age and income, ethnicity, education, housing and community of residence. Mean scores for all psychosocial variables differed significantly by social network. Men who reported experiencing more autonomy support by their healthcare providers had higher odds of condom use for anal (AOR = 3.29, p<0.01), oral (AOR = 5.06, p<0.01) and vaginal (AOR = 1.8, p<0.05) sex. Those with a stronger sense of community also had higher odds of condom use for anal sex (AOR = 1.26, p<0.001). Compared to networks with low prevalence of consistent condom users, networks with higher prevalence of consistent condom users had higher STD and HIV knowledge, had norms that were more supportive of gender equity, and experienced more autonomy support in their healthcare encounters. Healthcare providers and peer social networks can have an important influence on safer-sex behaviors in Ghanaian MSM. More research with Ghanaian MSM is needed that considers knowledge, attitudes, and norms of their social networks in the development and implementation of culturally relevant HIV/STI prevention intervention strategies.

Evaluation of citrus fibers as a tablet excipient.

The consumption of fibers is associated with many health benefits, such as a reduction of cardiovascular and gastrointestinal diseases, control of body weight, and prevention of diabetes. Despite the widespread use of fiber supplements such as capsules or tablets, there is an almost complete lack of information concerning the technological properties of functional fibers used in nutraceutical formulations. The aim of this work was to characterize the technological properties of citrus fibers necessary for their use as a processing aid in tableting. The results obtained showed that citrus fibers share many properties of other polysaccharides used as tableting excipients, such as thermal behavior and compaction mechanism, together with an appreciable tabletability. However, the most interesting properties resulted from their disintegration power. Citrus fibers behaved in a similar manner to the well-known super disintegrant croscarmellose sodium and resulted to be little susceptible to their concentration, to lubricant type, and lubricant concentration. Thus, this work supports the idea of a potential use of citrus fibers as "active" substances and processing aid in the tableting of nutraceutical products and also as functional excipient in pharmaceutical tablets formulation.

Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue.

Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein ß-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/ß-Klotho-PI3K-Akt1-BAD signaling network.