Bone-Adhesive Anisotropic Tough Hydrogel Mimicking Tendon Enthesis.

Tendon consists of soft collagen, yet it is mechanically strong and firmly adhered to the bone owing to its hierarchically anisotropic structure and unique tendon-to-bone integration (enthesis), respectively. Despite the recent advances in biomaterials, hydrogels simultaneously providing tendon-like high mechanical properties and strong adhesion to bone-mimicking enthesis is still challenging. Here, a strong, stiff, and adhesive triple-network (TN) anisotropic hydrogel that mimics a bone-adhering tendon is shown. The tough adhesive TN hydrogel is developed by combining imidazole-containing polyaspartamide (providing multiple hydrogen bonds to the bone surface) and energy-dissipative alginate-polyacrylamide double-network. To mimic the anisotropic structure and high mechanical properties of tendons, the bone-adhered TN hydrogel is linearly stretched and subsequently fixed via secondary cross-linking. The resulting hydrogel exhibits high tensile modulus and strength while maintaining a high bone adhesion without chemical modification of the bone surface. Furthermore, a bone-ligament-bone structure with strong bone adhesion reminiscent of the natural ligament is realized.

Mucus-penetrating PEGylated polysuccinimide-based nanocarrier for intravaginal delivery of siRNA battling sexually transmitted infections.

Intravaginal delivery of siRNA for prevention of sexually transmitted infections faces obstacles such as the acidic environment and vaginal mucus barrier. To achieve effective protection and delivery of siRNA, we developed a polysuccinimide (PSI)-based nanocarrier (PSI-PEG-API-PMA, PPAP) by conjugating methoxy polyethylene glycol amine (Me-PEG-NH2, Mw 5000), 1-(3-aminopropyl)imidazole (API), and 1-pyrenemethylamine hydrochloride (PMA) to PSI. PPAP demonstrated a spherical self-assembled nanostructure before and after encapsulation of a model siRNA. Variable electrostatic interaction between API and siRNA at acidic vs. neutral pH accomplished significantly lower burst release at pH 4.2 (4 ±â€¯1%) than pH 7.0 (26 ±â€¯5%) within 1 h. PEGylation enabled siRNA-PPAP to achieve higher mucus penetration efficiency (64 ±â€¯17%) than free siRNA (27 ±â€¯5%) for 24 h. Moreover, in vitro study showed minimal toxicity, successful internalization of siRNA-PPAP in HeLa cells and improved gene knockdown (97.5 ±â€¯0.4%). Overall, PPAP is promising for developing preventative treatments for battling sexually transmitted infections.

Hydrogen bonding-based strongly adhesive coacervate hydrogels synthesized using poly(N-vinylpyrrolidone) and tannic acid.

When multiple intermolecular interactions occur simultaneously, complexed molecules undergo gelation by inter-cohesive bonding, inducing a pseudo-crosslinking effect to form a supramolecular gel. Among the number of substances that can induce supramolecular assembly, phenolic species such as 3,4-dihydroxy-l-phenylalanine (DOPA) are widely utilized for synthesizing adhesive materials. However, despite the strong adhesion capability of monomeric phenol, it lacks cohesive strength and rarely forms a supramolecular gel to secure its mechanical properties. In this study, to overcome this obstacle, we synthesized a supramolecular coacervate hydrogel by simply mixing poly(N-vinylpyrrolidone) (PVP) and tannic acid (TA), resulting in strong cohesive interactions by virtue of the larger molecular size of TA and reinforced molecular interactions attributed to the presence of galloyl groups with a high density. We further analyzed the rheological and adhesive properties of PVP-TA coacervate hydrogels, revealing that they could exhibit not only a self-healing property, but also super adhesive properties with an average adhesion strength of 3.71 MPa on a glass substrate, which is >4 times stronger than that of conventional PVP.

A Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide.

PURPOSE: Dose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT. MATERIALS AND METHODS: Patients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability. RESULTS: Of 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). CONCLUSION: Dose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.

In situ formation of PLA-grafted alkoxysilanes for toughening a biodegradable PLA stereocomplex thin film.

Poly(lactide) (PLA) has received tremendous attention recently from researchers and industrialists due to its ability to solve environmental problems related to plastic pollution. However, PLA's brittleness, poor thermal stability, low elongation at break, and poor melt processing prevent its use in a broader spectrum of applications. Herein, we produced a very tough and thermally more stable PLA stereocomplex by simply mixing PLA with organoalkoxysilane. The stereocomplex PLA/silane (sc-PLA-silane) composite was prepared by simple mixing of three types of organoalkoxysilanes in sc-PLA followed by in situ formation of a silane-based rubbery core with a cross-linked PLA shell. Mechanical and thermal properties were improved by stereocomplexation of PLA with a small amount (1-5 wt%) of PLA-grafted silanes. The addition of organoalkoxysilane with different functional groups resulted in a plasticizer of rubbery silica-PLA core-shell gel through in situ condensation and grafting of long PLA chains at the interface between the stereocomplex and silane particles. The results revealed that the toughness of sc-PLA was improved dramatically with only a small addition (only 2.5%) of 3-(triethoxysilyl)propyl isocyanate (ICPTES). The morphology and mechanical and thermal properties of the toughened stereocomplex films were characterized. The results revealed that elongation at break was increased from 16% to 120%, while other mechanical properties such as tensile strength and modulus were retained. Surface analysis confirmed that this toughness was achieved by formation of a silica-PLA core-shell gel. The mechanical properties of PLA were improved without any significant reduction in modulus and tensile strength using this simple methodology.

Polyaspartamide Functionalized Catechol-Based Hydrogels Embedded with Silver Nanoparticles for Antimicrobial Properties.

In this study, polyaspartamide-based hydrogels were synthesized by boron-catechol coordination followed by incorporation of AgNPs into the materials. Free catechol moieties were exploited to produce AgNPs. TEM analyses displayed AgNPs of less than 20 nm in diameter and with minimum aggregation, attesting the role of hydrogels to act as an efficient template for the production of dispersed particles. XRD analyses confirmed the mean particle size using the Scherrer equation. Release kinetic studies were performed in DMEM medium, showing a slow release over a long time-period. Finally, the MIC and MBC were determined, demonstrating a bacteriostatic and bactericidal effect against Gram-positive S. aureus and Gram-negative E. coli.

Self-assembled nanoparticles made from a new PEGylated poly(aspartic acid) graft copolymer for intravaginal delivery of poorly water-soluble drugs.

New amphiphilic PEGylated poly(aspartic acid) graft copolymer (PASP-PEG-Ph) was synthesized as a nanocarrier for intravaginal drug delivery of poorly water-soluble drugs. PASP-PEG-Ph self-assembled into negatively charged spherically shaped nanoparticles in the presence of pH 4.5 and pH 7.0 vaginal fluid simulants with a diameter of approximately 200 nm as evidenced by Zeta-potentiometer, scanning electron microscope (SEM), dynamic light scattering (DLS) analysis. A significant number of stable NPs could be maintained at pH 4.5, 37 °C for 13 days. The PASP-PEG-Ph NP showed no significant cytotoxicity toward the T-cell line SupT1 and human vaginal epithelial cell line Vk2/E6E7 up to 1 mg/mL. The highest encapsulation efficiency of the model drug coumarin 6 (C6) by PASP-PEG-Ph was 92.0 ± 5.7%. The sustained release profile of the encapsulated C6 was demonstrated by an in vitro release study. An in vitro cellular uptake study revealed strong cellular uptake of the C6 loaded NP by SupT1 cells within 2 h.

Self-healable mussel-mimetic nanocomposite hydrogel based on catechol-containing polyaspartamide and graphene oxide.

Stimuli-responsive and self-healing materials have a wide range of potential uses, and some significant research has focused on cross-linking of hydrogel materials by means of reversible coordination bonding. The resulting materials, however, tend to have poor mechanical properties with pronounced weakness and brittleness. In this work, we present a novel mussel-inspired graphene oxide(GO)-containing hydrogel based on modified polyaspartamide with γ-amino butyric acid (GABA), 3.4-dihydroxyphenethylamine (DOPA), and ethanolamine (EA), termed PolyAspAm(GABA/DOPA/EA). Here both GO nanosheets and boric acid (H3BO3) act as cross-linkers, interacting with polar functional groups of the PolyAspAm(GABA/DOPA/EA). Compared to PolyAspAm(GABA/DOPA/EA)/B(3+) gel without GO, the same containing 5wt% of GO yielded a 10-fold increase in both the storage and loss moduli, as well as 134% and 104% increases in the tensile and compressive strengths, respectively. In addition, the GO-containing polyaspartamide hydrogel exhibited rapid and autonomous self-healing property. Two types of bonding, boron-catechol coordination and strong hydrogen bonding interactions between PolyAspAm side chains and GO nanosheets, would impart the enhanced mechanical strength and good reversible gelation behavior upon pH stimulation to the hydrogel, making this biocompatible hydrogel a promising soft matter for biomedical applications.

Surface grafting of octylamine onto poly(ethylene-alt-maleic anhydride) gate insulators for low-voltage DNTT thin-film transistors.

This study investigates a spin-coating method for modifying the surface properties of a poly(ethylene-alt-maleic anhydride) (PEMA) gate insulator. The 60 nm-thick PEMA thin film exhibits excellent electrical insulating properties, and its surface properties could be easily modified by surface grafting of octylamine. Due to surface treatment via spin-coating, the surface energy of the PEMA gate insulator decreased, the crystal quality of the organic semiconductor improved, and consequently the performance of low-voltage organic thin-film transistors (TFTs) was enhanced. Our results suggest that the surface treatment of the PEMA gate insulator could be a simple and effective method for enhancing the performance of organic TFTs.

Volume change of double cross-linked poly(aspartic acid) hydrogels induced by cleavage of one of the crosslinks.

In the present paper we report for the first time the development of redox-responsive biocompatible polymer gels. Double cross-linked poly(aspartic acid) hydrogels were prepared using two different cross-linking agents simultaneously. One of the cross-linkers was diaminobutane (DAB), the other cystamine (CYS). The relative amounts of DAB and CYS molecules were varied over a wide range while the total amount of cross-linker molecules (DAB+CYS) was kept constant. DAB provides stable cross-links, whereas CYS contains disulfide bonds, which can be broken by reduction. The cleavage of disulfide cross-links results in enhanced swelling and a significant decrease in the elastic modulus of the gels. These novel types of stimuli-responsive gels are promising candidates for new swelling controlled release matrices.

pH-sensitive amphiphilic biodegradable graft co-polymer aggregates based on polyaspartamide for intracellular delivery.

A biodegradable, pH-sensitive amphiphilic co-polymer, o-(2-aminoethyl)-o'-methylpolyethylene glycol/1-(3-aminopropyl)imidazole/lactic acid oligomers-g-polyaspartamide (MPEG/API/LAs-g-PASPAM), was synthesized. The hydrophobic biodegradable poly (lactic acid) (PLA), the hydrophilic MPEG and the pH-sensitive API were successfully introduced into the biodegradable polysuccinimide (PSI) backbone by grafting. In its synthesis, the feed ratio of MPE to PLA was varied to provide different amphiphilic balances. FT-IR and (1)H-NMR spectroscopy were used to identify the chemical structure of the MPEG/API/LAs-g-PASPAM co-polymers synthesized. Tens to a few hundreds of nanometer-scaled aggregates, appropriate for intracellular drug-carrier applications, were developed in the simulated buffer solution, and their self-assembling behavior was significantly affected by the environmental pH. The size and morphology of self-aggregates were investigated using dynamic light scattering and transmission electron microscopy. The buffering effect was observed in the endosomal pH range. The drug loading and release experiments were conducted for a series of co-polymer aggregate systems, and it was noted that the release behavior was mostly governed by diffusion. The biodegradable kinetics was also studied to ascertain the drug-release mechanism.

Monolith-based immobilized metal affinity chromatography increases production efficiency for plasmid DNA purification.

Immobilized metal affinity monolith column as a new class of chromatographic support is shown to be superior to conventional particle-based column as plasmid DNA (pDNA) purification platform. By harnessing the affinity of endotoxin to copper ions in the solution, a majority of endotoxin (90%) was removed from the alkaline cell lysate using CuCl(2)-induced precipitation. RNA and remaining endotoxin were subsequently removed to below detection limit with minimal loss of pDNA using either monolith or particle-based column. Monolith column has the additional advantage of feed concentration and flowrate-independent dynamic binding capacity for RNA molecules, enabling purification process to be conducted at high feed RNA concentration and flowrate. The use of monolith column gives three fold increased productivity of pDNA as compared to particle-based column, providing a more rapid and economical platform for pDNA purification.

pH sensitive swelling and releasing behavior of nano-gels based on polyaspartamide graft copolymers.

pH sensitive nano-gels based on polyaspartamide graft copolymers are prepared by UV crosslinking the self-assembled nano-aggregates in the presence of a series of hydrophobic and hydrophilic grafting segments. While the physical nano-aggregates dissociate via ionization of the pH sensitive moiety, the nano-gels synthesized in this study swell instead. The chemical structure and morphology of the resulting nano-gels were analyzed using FTIR, (1)H FTNMR, and TEM. The pH dependence of the particle size, 120-250 nm, was investigated using a light scattering analyzer. The swelling behavior of the nano-cores under acidic conditions triggered abrupt release of the drug; this pH dependence occurs reversibly and quickly. The nano-gels prepared may have endosomal rupturing characteristics, as their buffering capacity is as strong as that of uncrosslinked nano-aggregates. The nano-gels synthesized as such possess potential application as sustained releasing drug carriers for intracellular delivery.

Repeated batch production of epothilone B by immobilized Sorangium cellulosum.

Production of extracellular epothilone B, one of the potent anticancer agents, by free and immobilized Sorangium cellulosum was studied using the repeated batch culture process. The concentration of alginate used in immobilization was directly related to the mass transfer rate of nutrients, mechanical stability, and the epothilone B production yield. With the optimized 3% (w/v) calcium alginate carrier, a prolonged repeated batch culture was investigated for the 5 repeated batches for 24 days. The maximum productivity of epothilone B obtained from the alginate-immobilized cells was 5.03 mg/l/day, which is 3 times higher than that of free cells (1.68 mg/l/day).