Injectable, shear-thinning, photocrosslinkable, and tissue-adhesive hydrogels composed of diazirine-modified hyaluronan and dendritic polyethyleneimine.

In the present study, we report the first synthesis of diazirine-modified hyaluronic acid (HA-DAZ). In addition, we also produced a precursor polymer solution composed of HA-DAZ and dendritic polyethyleneimine (DPI) that showed strong shear-thinning properties. Furthermore, its viscosity was strongly reduced (i.e., from 5 × 105 mPa s at 10-3 s-1 to 6 × 101 mPa s at 103 s-1), substantially, which enhanced solution injectability using a 21 G needle. After ultraviolet irradiation at 365 nm and 6 mW cm-2, the HA-DAZ/DPI solution achieved rapid gelation, as measured using the stirring method, and its gelation time decreased from 200 s to 9 s as the total concentrations of HA-DAZ and DPI increased. Following UV irradiation, the storage modulus increased from 40 to 200 Pa. In addition, reversible sol-gel transition and self-healing properties were observed even after UV irradiation. This suggests that the HA-DAZ/DPI hydrogel was crosslinked in multiple ways, i.e., via covalent bonding between the diazirine and amine groups and via intermolecular interactions, including hydrogen bonding, electrostatic interactions, and hydrophobic interactions. A lap shear test showed that the HA-DAZ/DPI hydrogel exhibited strong adhesiveness as a fibrin glue following UV irradiation. Finally, the HA-DAZ/DPI hydrogel showed higher tissue reinforcement than fibrin glue in an ex vivo burst pressure test of the porcine esophageal mucosa.

Injectable, Shear-Thinning, Self-Healing, and Self-Cross-Linkable Benzaldehyde-Conjugated Chitosan Hydrogels as a Tissue Adhesive.

Benzaldehyde-conjugated chitosan (CH-CBA) was synthesized by a coupling reaction between chitosan (CH) and carboxybenzaldehyde (CBA). The pH-sensitive self-cross-linking can be achieved through the Schiff base reaction. The degree of substitution (DS) of CH-CBA was controlled at 1.4-12.7% by optimizing the pH and reagent stoichiometry. The dynamic Schiff base linkages conferred strong shear-thinning and self-healing properties to the hydrogels. The viscosity of the 2 wt/v % CH-CBA hydrogel decreased from 5.3 × 107 mPa·s at a shear rate of 10-2 s-1 to 2.0 × 103 mPa·s at 102 s-1 at pH 7.4. The CH-CBA hydrogel exhibited excellent biocompatibility in vitro and in vivo. Moreover, the hydrogel adhered strongly to porcine small intestine, colon, and cecum samples, comparable to commercial fibrin glue, and exhibited effective in vivo tissue sealing in a mouse cecal ligation and puncture model, highlighting its potential as a biomaterial for application in tissue adhesives, tissue engineering scaffolds, etc.

Structurally Heterogeneous Amphiphilic Conetworks of Poly(vinyl imidazole) Derivatives with Potent Antimicrobial Properties and Cytocompatibility.

We report the construction of amphiphilic conetwork (APCN)-based surfaces with potent antimicrobial activity and biofilm inhibition ability. The construction strategy is based on the separation of lipophilic alkyl groups (>C6) from the cationic network to obtain good antibacterial properties. The reaction of partially alkylated poly(vinyl imidazole) with the activated halide compounds followed by coating a glass or poly(dimethylsiloxane) (PDMS) sheet leads to the formation of the APCN surface. The dangling alkyl chains, crosslinking junctions, and unreacted vinyl imidazole groups are heterogeneously distributed in the APCNs. The swelling, mechanical property, and phase morphology of the APCN films have been evaluated. Bacterial cell disrupting potency of the APCN coatings increases with increasing alkyl chain length from C6 to C18 with somewhat more of an effect on Escherichia coli as compared to Bacillus subtilis bacteria. The minimum inhibitory amount of the APCNs on glass and a hydrophobic PDMS surface is in the range of 0.02-0.04 mg/cm2 depending on the chain length of the alkyl and the degree of quaternization. The effect of the type of crosslinker for the construction of the conetwork on the antimicrobial property has been evaluated to elucidate the exclusive design of the APCNs. The APCN-based coatings provide potent biocidal activity without much negatively affecting the hemocompatibility and cytocompatibility. These APCNs provide a good model system for comparative evaluation of the biocidal property and structural effect on the biocidal activity.

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics.

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Recent advances in the potential applications of luminescence-based, SPR-based, and carbon-based biosensors.

The need for biosensors has evolved in the detection of molecules, diseases, and pollution from various sources. This requirement has headed to the development of accurate and powerful equipment for analysis using biological sensing component as a biosensor. Biosensors have the advantage of rapid detection that can beat the conventional methods for the detection of the same molecules. Bio-chemiluminescence-based sensors are very sensitive during use in biological immune assay systems. Optical biosensors are emerging with time as they have the advantage that they act with a change in the refractive index. Carbon nanotube-based sensors are another area that has an important role in the biosensor field. Bioluminescence gives much higher quantum yields than classical chemiluminescence. Electro-generated bioluminescence has the advantage of miniature size and can produce a high signal-to-noise ratio and the controlled emission. Recent advances in biological techniques and instrumentation involving fluorescence tag to nanomaterials have increased the sensitivity limit of biosensors. Integrated approaches provided a better perspective for developing specific and sensitive biosensors with high regenerative potentials. This paper mainly focuses on sensors that are important for the detection of multiple molecules related to clinical and environmental applications. KEY POINTS: • The review focusses on the applications of luminescence-based, surface plasmon resonance-based, carbon nanotube-based, and graphene-based biosensors • Potential clinical, environmental, agricultural, and food industry applications/uses of biosensors have been critically reviewed • The current limitations in this field are discussed, as well as the prospects for future advancement.

Silver-loaded carboxymethyl cellulose nonwoven sheet with controlled counterions for infected wound healing.

Carboxymethyl cellulose (CMC) is a promising material for moist wound healing, and silver loading onto CMC has been examined for anti-bacterial activity. In this study, we developed silver-loaded CMC nonwoven sheets with different counterions, namely sodium CMC (CMC-Na/Ag) and partially protonated CMC (CMC-H/Ag), to examine their anti-bacterial and wound-healing properties. Owing to the presence of counter protons, CMC-H/Ag showed slower water adsorption, dissolution, and Ag release than CMC-Na/Ag. In addition, CMC-H/Ag and CMC-Na/Ag exhibited differences in anti-bacterial activities in shake-flask and inhibition zone tests in vitro. An in vivo experiment using a pressure ulcer mouse model with Pseudomonas aeruginosa infection showed that CMC-Na/Ag significantly accelerated wound healing compared to CMC-H/Ag and a commercially available Ag-loaded CMC nonwoven sheet, Aquacel Ag. These results suggest the importance of controlling CMC counterions and the therapeutic potential of the developed product as a wound dressing.

Advancement of Biomaterial-Based Postoperative Adhesion Barriers.

Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials' efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.

Gold Nanoparticle Promoted Formation and Biological Properties of Injectable Hydrogels.

Acceleration of gelation in the biological environment and improvement of overall biological properties of a hydrogel is of enormous importance. Biopolymer stabilized gold (Au) nanoparticles (NPs) exhibit cytocompatibility and therapeutic activity. Hence, in situ gelation and subsequent improvement in the property of a hydrogel by employing Au NPs is an attractive approach. We report that stable Au NPs accelerate the conventional nucleophilic substitution reaction of activated halide-terminated poly(ethylene glycol) and tertiary amine functional macromolecules, leading to the rapid formation of injectable nanocomposite hydrogels in vivo and ex vivo with improved modulus, cell adhesion, cell proliferation, and cytocompatibility than that of a pristine hydrogel. NP surfaces with low chain grafting density and good colloidal stability are crucial requirements for the use of these NPs in the hydrogel formation. Influence of the structure of the amine functional prepolymer, the spacer connecting the halide leaving groups of the substrate, and the structure of the stabilizer on the rate promoting activity of the NPs have been evaluated with model low-molecular-weight substrates and macromolecules by 1H NMR spectroscopy, rheological experiments, and density functional theory. Results indicate a significant effect of the spacer connecting the halide leaving group with the macromolecule. The Au nanocomposite hydrogels show sustained co-release of methotrexate, an anti-rheumatic drug, and the Au NPs. This work provides insights for designing an injectable nanocomposite hydrogel system with multifunctional property. The strategy of the use of cytocompatible Au NPs as a promoter provides new opportunity to obtain an injectable hydrogel system for biological applications.

Self-Assembly of Partially Alkylated Dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties.

Key issues of injectable hydrogels are incapability of loading hydrophobic drugs due to insolubility of drugs in aqueous prepolymer solution as well as in hydrogel matrix, and high water swelling, which leads to poor mechanical and bioadhesive properties. Herein, we report that self-assembly of partially long-chain alkylated dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] copolymer in aqueous solution could encapsulate pyrene, a hydrophobic probe, griseofulvin, a hydrophobic antifungal drug, and ornidazole, a hydrophilic antibiotic. Addition of activated chloride terminated poly(ethylene glycol) (PEG) into the guest molecules loaded copolymer solution produced an injectable dextran- graft-poly[(2-dimethylamino)ethyl methacrylate]-linked-PEG conetwork hydrogel. The alkylated hydrogels exhibited zero order release kinetics and were mechanically tough (50-54 kPa storage modulus) and bioadhesive (8-9 kPa). The roles of alkyl chains and dextran on the drug loading-release behavior, degradation behavior, gelation time, and the mechanical property of the hydrogels have been studied in details. Additionally, DNA hybrid composite hydrogel was formed owing to the cationic nature of the prepolymer solution and the hydrogel. Controlled alkylation of a prepolymer thus highlights the potential to induce and enhance the hydrogel property.

Anti-organic fouling and anti-biofouling poly(piperazineamide) thin film nanocomposite membranes for low pressure removal of heavy metal ions.

Propensity towards anti-organic fouling, anti-biofouling property and low rejection of multivalent cation (monovalent counter ion) restricts the application of the state-of-art poly(piperazineamide) [poly(PIP)] thin film composite (TFC) nanofiltration (NF) membrane for the treatment of water containing toxic heavy metal ions, organic fouling agents and microbes. Herein, we report the preparation of thin film nanocomposite (TFNC) NF membranes with improved heavy metal ions rejection efficacy, anti-biofouling property, and anti-organic fouling properties compared to that of poly(PIP) TFC NF membrane. The TFNC NF membranes were prepared by the interfacial polymerization (IP) between PIP and trimesoyl chloride followed by post-treatment with polyethyleneimine (PEI) or PEI-polyethylene glycol conjugate and then immobilization of Ag NP. The IP was conducted on a polyethersulfone/poly(methyl methacrylate)-co-poly(vinyl pyrollidone)/silver nanoparticle (Ag NP) blend ultrafiltration membrane support. The TFNC membranes exhibited >99% rejection of Pb2+, 91-97% rejection of Cd2+, 90-96% rejection of Co2+ and 95-99% rejection of Cu2+ with permeate flux ∼40Lm-2h-1 at applied pressure 0.5MPa. The improved heavy metal ions rejection efficacy of the modified NF membranes is attributed to the development of positive surface charge as well as lowering of surface pore size compared to that of unmodified poly(PIP) TFC NF membrane.

Liquid Prepolymer-Based in Situ Formation of Degradable Poly(ethylene glycol)-Linked-Poly(caprolactone)-Linked-Poly(2-dimethylaminoethyl)methacrylate Amphiphilic Conetwork Gels Showing Polarity Driven Gelation and Bioadhesion.

Amphiphilic conetwork (APCN) gels suffer from lack of direct injectability due to use of organic solvent, prolonged crosslinking/polymerization process and immiscibility between hydrophilic and hydrophobic prepolymers. On the basis of prepolymers compatibility and polarity, we report the use of an advanced prepolymer liquid system for in situ construction of APCN gels. Solid elastic poly(ethylene glycol)-linked-poly(ε-caprolactone)-linked-poly(2-dimethylaminoethyl)methacrylate (PEG-l-PCL-l-PDMA) APCN gels were formed upon addition of an appropriate amount of PDMA diluted in nonreactive sacrificial liquid PEG into a compatible blend of activated halide terminated PEG and PCL liquids. Compatibility among the prepolymers allowed favorable gelation. The polarity of the prepolymer liquid greatly influenced the gelation time. PEG-l-PCL-l-PDMA APCN gels were cytocompatible/biodegradable and showed storage modulus in the range of 50-200 kPa and bioadhesive strength of 40-90 kPa. The fluorescence experiments showed that the hydrophobic probe, pyrene was distributed in both hydrophilic and hydrophobic phases of the APCN gels. These APCNs exhibited sustained release of hydrophobic and hydrophilic drugs. Effects of polarity, composition, and molecular weight of the liquid prepolymers on the gelation time, rheological property, and swelling behavior of the APCN gels have been investigated in details.

Multifunctionalization of Poly(vinylidene fluoride)/Reactive Copolymer Blend Membranes for Broad Spectrum Applications.

Simultaneous immobilization and cross-linking of antifouling/low toxic polymers, e.g., poly(ethylenimine) (PEI), dextran (Dex), agarose (Agr), poly(ethylene glycol) (PEG), PEI-Dex, and PEI-PEG conjugates, and stimuli-responsive copolymers on a porous membrane surface in mild reaction conditions is desirable for the enhancement of hydrophilicity, antifouling character, cytocompatibility, and inducing stimuli-responsive behavior. Grafting to technique is required since the precursors of most of these macromolecules are not amenable to surface-initiated polymerization. In this work, we report a versatile process for the simultaneous immobilization and cross-linking of a library of macromolecules on and into the blend membrane (PVDF-blend) of poly(vinylidene fluoride) and poly(methyl methacrylate)-co-poly(chloromethylstyrene). Sequential nucleophilic substitution reaction between activated halide moieties of the copolymer and amine groups of different macromolecules readily provided series of modified membranes. These membranes exhibited antifouling property superior to that of the unmodified membrane. The effectiveness of this technique has been demonstrated by the immobilization of pH or both pH- and temperature-responsive copolymer on PVDF-blend membrane for responsive separation of poly(ethylene oxide) and bovine serum albumin. Silver nanoparticles were also anchored on the select modified membranes surfaces for the enhancement of antibiofouling property. Our approach is useful to obtain verities of functional membranes and selection of membrane for a particular application.

Effect of Polyethylene Glycol on Properties and Drug Encapsulation-Release Performance of Biodegradable/Cytocompatible Agarose-Polyethylene Glycol-Polycaprolactone Amphiphilic Co-Network Gels.

We synthesized agarose-polycaprolactone (Agr-PCL) bicomponent and Agr-polyethylene glycol-PCL (Agr-PEG-PCL) tricomponent amphiphilic co-network (APCN) gels by the sequential nucleophilic substitution reaction between amine-functionalized Agr and activated halide terminated PCL or PCL-b-PEG-b-PCL copolymer for the sustained and localized delivery of hydrophilic and hydrophobic drugs. The biodegradability of the APCNs was confirmed using lipase and by hydrolytic degradation. These APCN gels displayed good cytocompatibility and blood compatibility. Importantly, these APCN gels exhibited remarkably high drug loading capacity coupled with sustained and triggered release of both hydrophilic and hydrophobic drugs. PEG in the APCNs lowered the degree of phase separation and enhanced the mechanical property of the APCN gels. The drug loading capacity and the release kinetics were also strongly influenced by the presence of PEG, the nature of release medium, and the nature of the drug. Particularly, PEG in the APCN gels significantly enhanced the 5-fluorouracil loading capacity and lowered its release rate and burst release. Release kinetics of highly water-soluble gemcitabine hydrochloride and hydrophobic prednisolone acetate depended on the extent of water swelling of the APCN gels. Cytocompatibility/blood compatibility and pH and enzyme-triggered degradation together with sustained release of drugs show great promise for the use of these APCN gels in localized drug delivery and tissue engineering applications.