Sodium hyaluronate-g-2-((N-(6-aminohexyl)-4-methoxyphenyl)sulfonamido)-N-hydroxyacetamide with enhanced affinity towards MMP12 catalytic domain to be used as visco-supplement with increased degradation resistance.

The present paper describes the functionalization of sodium hyaluronate (NaHA) with a small molecule (2-((N-(6-aminohexyl)-4-methoxyphenyl)sulfonamido)-N-hydroxyacetamide) (MMPI) having proven inhibitory activity against membrane metalloproteins involved in inflammatory processes (i.e. MMP12). The obtained derivative (HA-MMPI) demonstrated an increased resistance to the in-vitro degradation by hyaluronidase, viscoelastic properties close to those of healthy human synovial fluid, cytocompatibility towards human chondrocytes and nanomolar affinity towards MMP 12. Thus, HA-MMPI can be considered a good candidate as viscosupplement in the treatment of knee osteoarticular disease.

Chemical modification strategies for viscosity-dependent processing of gellan gum.

Recently, the hydrogel-forming polysaccharide gellan gum (GG) has gained popularity as a versatile biomaterial for tissue engineering purposes. Here, we examine the modification strategies suitable for GG to overcome processing-related limitations. We emphasize the thorough assessment of the viscoelastic and mechanical properties of both precursor solutions and final hydrogels. The investigated modification strategies include purification, oxidation, reductive chain scission, and blending. We correlate polymer flow and hydrogel forming capabilities to viscosity-dependent methods including casting, injection and printing. Native GG and purified NaGG are shear thinning and feasible for printing, being similar in gelation and compression behavior. Oxidized GGox possesses reduced viscosity, higher toughness, and aldehydes as functional groups, while scissored GGsciss has markedly lower molecular weight. To exemplify extrudability, select modification products are printed using an extrusion-based bioprinter utilizing a crosslinker bath. Our robust modification strategies have widened the processing capabilities of GG without affecting its ability to form hydrogels.

Agarose Stearate-Carbomer940 as Stabilizer and Rheology Modifier for Surfactant-Free Cosmetic Formulations.

Some commonly used surfactants in cosmetic products raise concerns due to their skin-irritating effects and environmental contamination. Multifunctional, high-performance polymers are good alternatives to overcome these problems. In this study, agarose stearate (AS) with emulsifying, thickening, and gel properties was synthesized. Surfactant-free cosmetic formulations were successfully prepared from AS and carbomer940 (CBM940) mixed systems. The correlation of rheological parameter with skin feeling was determined to study the usability of the mixed systems in cosmetics. Based on rheological analysis, the surfactant-free cosmetic cream (SFC) stabilized by AS-carbomer940 showed shear-thinning behavior and strongly synergistic action. The SFC exhibited a gel-like behavior and had rheological properties similar to commercial cosmetic creams. Scanning electron microscope images proved that the AS-CBM940 network played an important role in SFC's stability. Oil content could reinforce the elastic characteristics of the AS-CBM940 matrix. The SFCs showed a good appearance and sensation during and after rubbing into skin. The knowledge gained from this study may be useful for designing surfactant-free cosmetic cream with rheological properties that can be tailored for particular commercial cosmetic applications. They may also be useful for producing medicine products with highly viscous or gel-like textures, such as some ointments and wound dressings.

Polypseudorotaxane and polydopamine linkage-based hyaluronic acid hydrogel network with a single syringe injection for sustained drug delivery.

Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.

A novel injectable starch-based tissue adhesive for hemostasis.

Hemorrhage remains one of the direct causes of high mortality. The development of ideal hemostatic materials with sound ability to deal with severe wound is urgent needed. Although starch-based hemostatic powder has been widely used, hydrous physiological environments severely hamper its binding to the target tissue, thereby limiting the effectiveness in hemostasis. Herein, inspired by mussel adhesive protein, a novel injectable tissue-adhesive hydrogel (St-Dopa hydrogel) composed of starch, succinic anhydride and dopamine was developed in situ by enzymatic crosslinking. The results show that St-Dopa hydrogels were intimately integrated with biological tissue and formed robust barriers to reduce blood loss. St-Dopa hydrogels exhibited superior capacity for in vitro and in vivo hemostasis as compared with chitin hydrogels. In addition to the ease of operation, St-Dopa hydrogels exhibited rapid sol-gel transition, porous microscopic morphology, good swelling ratio and biodegradability, tissue-like elastomeric mechanical properties and excellent cyto/hemo-compatibility. These results suggest that this newly developed St-Dopa hydrogel is a promising biological adhesive and hemostatic material.

Liver transplantation in Jehovah's Witnesses: a case series / Experiencia en trasplante hepático para testigos de Jehová: serie de casos

Abstract Introduction: Orthotopic liver transplantation (OLT) is a procedure characterized by high bleeding rates and a significant likelihood of exposure to blood products. Objectives: This case series shows the experience at a referral center for Jehovah's Witnesses (JW) with end-stage liver disease, undergoing OLT. Materials and methods: A search was conducted in our database of JW undergoing OLT between July 2007 and August 2012. The information about their pre-operative condition and progress up to 30 days post-transplantation. Results: Four subjects were identified (3F/1M) with an average age of 42 years (range 22-55). All of them received a multidisciplinary management which included pre-operative optimization of red cell mass, antifibrinolytic prophylaxis, and cell salvage (mean volume of 344mL [range 113-520]). The average intraoperative bleeding volume was of 625mL (range 300-1000). One of the patients presented with a primary graft dysfunction and died, while the rest had a normal postoperative course. Conclusion: It is possible to offer OLT to patients who refuse to receive allogeneic blood transfusions, through a comprehensive approach that includes perioperative hematologic optimization and the use of blood conservation measures, without a significant impact on the outcomes.

Resumen Introducción: El trasplante hepático ortotópico (THO) es un procedimiento caracterizado por índices significativos de sangrado y alta probabilidad de exposición a hemocomponentes. Objetivos: Esta serie de casos muestra la experiencia de un centro de referencia en la atención de testigos de Jehová (TJ) con enfermedad hepática terminal llevados a THO. Materiales y métodos: Se realizó una búsqueda en nuestra base de datos de TJ que hubiesen sido llevados a THO entre julio de 2007 y agosto de 2012. Se registraron datos correspondientes a su estado preoperatorio, manejo perioperatorio y evolución hasta los 30 días postrasplante. Resultados: Se encontraron cuatro sujetos (3M/1H) con una edad promedio de 42 años (rango de 22-55). Todos recibieron un manejo multidisciplinario que incluyó la optimización preoperatoria de su masa eritrocitaria, profilaxis antifibrinolítica y salvamento celular [volumen promedio de 344 ml (rango de 113-520)]. El volumen promedio de sangrado intraoperatorio fue de 625 ml (rango de 300-1000). Uno de los pacientes presentó disfunción primaria del injerto y muerte, mientras que los demás tuvieron un curso posoperatorio convencional. Conclusiones: Es posible ofrecer la posibilidad de THO para sujetos que se niegan a recibir transfusiones alogénicas, por medio de un abordaje integral que incluya la optimización hematológica perioperatoria y la utilización de medidas de conservación sanguínea, sin que esto afecte significativamente los resultados.

Compatibility of sodium alginate and konjac glucomannan and their applications in fabricating low-fat mayonnaise-like emulsion gels.

In this study, the compatibility of alginate (Alg) and konjac glucomannan (KGM) in aqueous solutions was evaluated by dilute solution viscometry (DSV). It was found that when Alg: KGM ratio was lower than 6:4 (w/w), Alg and KGM were compatible, which was subsequently confirmed by SEM, AFM and TEM. Moreover, by dispersing emulsified oil droplets into Alg gel matrix, followed by addition of KGM to thicken the system, where the ratio of Alg: KGM was 5:5, a class of emulsion gels with significant thixotropy and viscoelasticity could be obtained. The prepared emulsion gels displayed good thermal stability and freeze-thaw stability, with no oil droplet coalescence observed after heating at 100°C for 30 min or freezing the gels at -18°C for 24 h. Overall, the mixed Alg/KGM system is expected to provide a template for designing low-fat mayonnaise-like food emulsions.

Obtaining and Characterization of the PLA/Chitosan Foams with Antimicrobial Properties Achieved by the Emulsification Combined with the Dissolution of Chitosan by CO2 Saturation.

A new method of obtaining functional foam material has been proposed. The materials were created by mixing the poly lactic acid (PLA) solution in chloroform, chitosan (CS) dissolved in water saturated with CO2 and polyethylene glycol (PEG), and freeze-dried for removal of the solvents. The composite foams were characterized for their structural (SEM, FT-IR, density, porosity), thermal (DSC), functional (hardness, elasticity, swelling capacity, solubility), and biological (antimicrobial and cytotoxic) properties. Chitosan in the composites was a component for obtaining their foamed form with 7.4 to 22.7 times lower density compared to the neat PLA and high porosity also confirmed by the SEM. The foams had a hardness in the range of 70-440 kPa. The FT-IR analysis confirmed no new chemical bonds between the sponge ingredients. Other results showed low sorption capacity (2.5-7.2 g/g) and solubility of materials (less than 0.2%). The obtained foams had the lower Tg value and improved ability of crystallization compared to neat PLA. The addition of chitosan provides the bacteriostatic and bactericidal properties against Escherichia coli and Staphylococcus aureus. Biocompatibility studies have shown that the materials obtained are not cytotoxic to the L929 cell line.

Photoinduced chitosan-PEG hydrogels with long-term antibacterial properties.

Photochemical processes offer the possibility of preparing functional hydrogels under green conditions that are compatible with both synthetic and natural polymers. In this study, chitosan-based poly(ethylene) glycol (PEG) were successfully synthesized under light irradiation in aqueous medium. Kinetic studies under irradiation showed that less than 2 min were necessary to obtain fully cross-linked networks. Thermomechanical analyses and swelling experiments indicated that introduction of chitosan overall weakens the hydrogel network but can create domains of higher thermal stability than the PEG-alone structure. The resulting chitosan-PEG hydrogels demonstrated a tremendous inhibition (100%) of bacterial growth (Escherichia coli and Staphylococcus aureus). After 6 months' ageing, one of the hydrogels preserved a high antifouling activity against Escherichia coli. This interesting result, which could be correlated with the network features, demonstrates the strong potential of these photochemical methods to obtain robust bio-functional materials.

Viscoelastic lyotropic liquid crystals formed in a bio-based trimeric surfactant system.

Exploring the self-assembly of oligomeric surfactants is expected to bridge the gap between conventional and polymeric surfactants. Using the natural resource rosin as the starting material, a bio-based star-shaped trimeric quaternary ammonium surfactant (abbreviated tri-R-4-Phe) was synthesized. With three bulky dehydroabietic acid units in the hydrophobic group, tri-R-4-Phe has a molecular weight of 1684.9 and shows strong affinity towards both water and nonpolar organic compounds. In the presence of tri-R-4-Phe, C12EO3 was able to form lamellar lyotropic liquid crystals over a wide concentration range in water. The tri-R-4-Phe/C12EO3/water tertiary system was investigated by polarizing optical microscopy (POM), small angle X-ray scattering (SAXS) and rheological measurements. The investigated samples with different formulations all showed strong viscoelasticity, and the viscosity increased with the surfactant content. All samples showed interesting shear banding phenomena due to the shear induced mesoscale phase transition in tri-R-4-Phe/C12EO3/water systems. The present work reveals the unique behaviour of trimeric surfactant involved LLC systems and the result may be helpful in investigating delicate molecular self-assembly using natural resources.

Efficient weapon for protracted warfare to malaria: A chondroitin sulfate derivates-containing injectable, ultra-long-lasting meshy-gel system.

Progress at elimination of malaria is limited by the challenges of reaching large rural population and ensuring patient adherence to adequate pharmacologic treatment. In the present study, a novel material (octadecylamine modified chondroitin sulfate) was synthesized, to fabricate a long acting release meshy gel system as an efficient weapon for protracted warfare to malaria. Ivermectin loaded meshy gels (IVM-MG) composed of different amount of phospholipids, triglyceride and modified chondroitin sulfate were formulated. They were in aqueous state with low viscosity before injection, but rapidly turned into gel state with significantly increased viscosity upon exposure to an aqueous environment after injection. In vitro study proved a sustained released effect in different releasing media. In vivo study showed no irritation at injection site and slowly drug release over a 30-day release period in rat model. Among the three IVM-MG formulations, IVM-MG-3 with the highest amount of octadecylamine modified chondroitin sulfate presented the highest viscosity increase after solution-gel transition, the least initial burst release, and the longest sustained release effect over 30 days in rat model. Furthermore, by using mathematical models, IVM-MG system could boost the efficacy of mass drug administration toward malaria elimination goals. Meshy gel systems for long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases of which treatment adherence is essential for their efficacy.

Sulfobetaines Meet Carboxybetaines: Modulation of Thermo- and Ion-Responsivity, Water Structure, Mechanical Properties, and Cell Adhesion.

A procedure for the preparation of copolymers bearing sulfobetaine and carboxybetaine methacrylic-based monomers by free-radical polymerization is described and discussed. A combination of monomers affects the upper critical solution temperature (UCST) in water and in the presence of a simple NaCl electrolyte while retaining the zwitterionic character. In addition, hydrogel samples were prepared and showed tunable water structure and mechanical properties. The total nonfreezable water content decreases with the amount of carboxybetaine segment in the hydrogel feed and the compression moduli were in a range of 0.7-1.6 MPa. Responses to external conditions such as temperature and ion strength were investigated and a potential application such as modulated thermal detection is proposed. The presence of the carboxylate group in the carboxybetaine segment enables a small fluorescence probe and peptide bearing RDG motif to be attached to polymer and hydrogel samples, respectively. The hydrogel samples functionalized with the RGD motif exhibit controlled cell adhesion. Such synthetic strategy based on combination of different zwitterionic segments offers a simple pathway for the development of zwitterionic materials with programmable properties.

Immune Responsive Release of Tacrolimus to Overcome Organ Transplant Rejection.

Transplant rejection is the key problem in organ transplantation and, in clinic, immunosuppressive agents such as tacrolimus are directly administered to the recipients after surgery for T-cell inhibition. However, direct administration of tacrolimus may bring severe side effects to the recipients. Herein, by rational design of two hydrogelators NapPhePheGluTyrOH (1) and Nap d-Phe dPheGluTyrOH (2), a facile method of immune responsive release of tacrolimus is developed from their hydrogels to overcome organ transplantation rejection. Upon incubation with protein tyrosine kinase, which is activated in T cells after organ transplantation, the tacrolimus-encapsulating Gel 1 or Gel 2 is disassembled to release tacrolimus. Cell experiments show that both Gel 1 and Gel 2 have better inhibition effect on the activated T cells than free drug tacrolimus. Liver transplantation experiments indicate that, after 7 days of treatment of same dose tacrolimus, the recipient rats in the Gel 2 group show significantly extended median survival time of 22 days while the recipients treated with conventional tacrolimus medication have a median survival time of 13 days. It is expected herein that this "smart" facile method of immune responsive release of tacrolimus can be applied to overcome organ transplantation rejection in clinic in the near future.

Nucleoside-Based Self-Assembling Drugs for Localized Drug Delivery.

We have synthesized a range of gelators based on the nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and transmission electron microscopy. Growth inhibition studies of gemcitabine derivatives confirmed the feasibility of these compounds as novel treatments, indicating the potential of nucleoside-based gelators for localized drug delivery.

Exploring Orthogonal Hydrogen Bonding towards Designing Organic-Salt-Based Supramolecular Gelators: Synthesis, Structures, and Anticancer Properties.

A series of primary ammonium monocarboxylate (PAM) salts derived from ß-alanine derivatives of pyrene and naphthalene acetic acid, along with the parent acids, were explored to probe the plausible role of orthogonal hydrogen bonding resulting from amide⋅⋅⋅amide and PAM synthons on gelation. Single-crystal X-ray diffraction (SXRD) studies were performed on two parent acids and five PAM salts in the series. The data revealed that orthogonal hydrogen bonding played an important role in gelation. Structure-property correlation based on SXRD and powder X-ray diffraction data also supported the working hypothesis upon which these gelators were designed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell migration assay on a highly aggressive human breast cancer cell line, MDA-MB-231, revealed that one of the PAM salts in the series, namely, PAA.B2, displayed anticancer properties, and internalization of the gelator salt in the same cell line was confirmed by cell imaging.

Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation.

The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype.

Unprecedented access to strong and ductile poly(lactic acid) by introducing In Situ Nanofibrillar Poly(butylene succinate) for green packaging.

The notion of toughening poly(lactic acid) (PLA) by adding flexible biopolymers has generated enormous interest but has yielded few desirable advances, mainly blocked by the sacrifice of strength and stiffness due to uncontrollable phase morphology and poor interfacial interactions. Here the phase control methodology, that is, intense extrusion compounding followed by "slit die extrusion-hot stretching-quenching" technique, was proposed to construct well-aligned, stiff poly(butylene succinate) (PBS) nanofibrils in the PLA matrix for the first time. We show that generating nanosized discrete droplets of PBS phase during extrusion compounding is key to enable the development of in situ nanofibrillar PBS assisted by the shearing/stretching field. The size of PBS nanofibrils strongly dependent on the PBS content, showing an increased average diameter from 83 to 116 and 236 nm for the composites containing 10, 20, and 40 wt % nanofibrils, respectively. More importantly, hybrid shish-kebab superstructure anchoring ordered PLA kebabs were induced by the PBS nanofibrils serving as the central shish, conferring the creation of tenacious interfacial crystalline ligaments. The exceptional combination of strength, modulus, and ductility for the composites loaded 40 wt % PBS nanofibrils were demonstrated, outperforming pure PLA with the increments of 31, 51, and 72% in strength, modulus, and elongation at break (56.4 MPa, 1702 MPa, and 92.4%), respectively. The high strength, modulus, and ductility are unprecedented for PLA and are in great potential need for packaging applications.

5'-Guanosine monophosphate mediated biocompatible porous hydrogel of ß-FeOOH-viscoelastic behavior, loading, and release capabilities of freeze-dried gel.

The present manuscript reports the characterization, optimization of rheological properties, and loading and release capabilities of 5'-GMP mediated ß-FeOOH hydrogel. Circular dichroism (CD) analysis indicates it to contain mainly the left-handed helix similar to that of Z-DNA. The highest viscosity (>300 cP) corresponds to the sample containing 2.5 × 10(-3) mol dm(-3) of 5'-GMP (SP2H). Field emission scanning electron microscope (FESEM) and transmission electron microscope (TEM) studies indicate the freeze-dried (FD) SP2H to be porous in nature, which is also supported by its high Brunauer-Emmett-Teller (BET) surface area of 226 m(2)/g as compared to that of SP3H (75 m(2)/g). Selected area electron diffraction (SAED) analysis and Raman spectroscopy show it to contain ß-FeOOH phase. The FD SP2H exhibits the high swelling ratio (326%) and loading capacity for methylene blue (MB) dye. It displays a controlled and efficient release (>90%) for optimized [MB] (2.5 × 10(-4) mol dm(-3)) in 48 h. The low toxicity of as synthesized FD SP2H nanostructures against MDA-MB-231 (breast cancer cells) up to 100 µg/mL suggests its biocompatible nature. The high porosity, surface area, % swelling, and loading and release performance of the hydrogel indicate its potential for drug delivery and other biological applications.

Synthesis and characterization of a novel chitosan-N-acetyl-homocysteine thiolactone polymer using MES buffer.

We report a new "green" approach to synthesize a novel thiolated chitosan conjugate, chitosan-N-acetyl-homocysteine thiolactone (chitosan-AcHcys) using a "Good's buffers", 2-(N-morpholino)ethanesulfonic acid (MES). After that, the crosslinked Xr-chitosan-AcHcys was obtained only in the presence of air, without other reactants. The chitosan-AcHcys spectrum shows a partial incorporation of the thiolactone onto the polymer backbone. The derivative thermogravimetric analysis confirmed that chitosan-AcHcys is slightly less stable than starting chitosan; however, the peak profile is broadened which is indicative of deeper changes in the thermal degradation process. Also, aqueous dispersions with different concentrations of the crosslinked material (Xr-chitosan-AcHcys) were prepared and rheologically characterized. All aqueous dispersions are viscoelastic fluid with shear-thinning behavior. The viscosity of the dispersions (1-7% of chitosan-AcHcys) increases as a function of polymer concentration. So, we have achieved to disperse a high concentration of thiolated-chitosan derivative in water with different rheological characteristics, which could affect the drug release.

Novel supramolecular elastomer films based on linear carboxyl-terminated polydimethylsiloxane oligomers: preparation, characterization, biocompatibility, and application in wound dressings.

A novel supramolecular elastomer (SESi) based on multiple hydrogen bond associations between low-molecular-weight polydimethylsiloxane chains was obtained through a two-step reaction of linear carboxyl-terminated polydimethylsiloxane oligomers with diethylenetriamine and urea, and the reaction mechanism was characterized. The results of differential scanning calorimetry and X-ray diffraction analyses indicated that the supramolecular network structure is completely amorphous, endowing SESi with rubber-like elastic behavior at room temperature. The transparent SESi film prepared by hot pressing displayed nice viscoelasticity, benign water absorption, water vapor transition rates, and ideal biocompatibility; and did not show cytotoxicity or skin irritation. These properties allow the elastomer to function as an occlusive wound dressing. To demonstrate its potential in wound dressings, a detailed comparison of commercial 3M Tegaderm(™) film and the SESi film was conducted. The SESi film exhibited similar effects in wound healing, and the wound bed was covered by the SESi film without the occurrence of significant adverse reactions.