Biomedical applications of functional hydrogels: Innovative developments, relevant clinical trials and advanced products.

Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.

Antibiotic-Polyphosphate Nanocomplexes: A Promising System for Effective Biofilm Eradication.

Purpose: The eradication of bacterial biofilms poses an enormous challenge owing to the inherently low antibiotic susceptibility of the resident microbiota. The complexation of antibiotics with polyphosphate can substantially improve antimicrobial performance. Methods: Nanoparticular complexes of the model drug colistin and polyphosphate (CP-NPs) were developed and characterized in terms of their particle size and morphology, polydispersity index (PDI), zeta potential, and cytotoxicity. Enzyme-triggered monophosphate and colistin release from the CP-NPs was evaluated in the presence of alkaline phosphatase (AP). Subsequently, antimicrobial efficacy was assessed by inhibition experiments on planktonic cultures, as well as time-kill assays on biofilms formed by the model organism Micrococcus luteus. Results: The CP-NPs exhibited a spherical morphology with particle sizes <200 nm, PDI <0.25, and negative zeta potential. They showed reduced cytotoxicity toward two human cell lines and significantly decreased hemotoxicity compared with native colistin. Release experiments with AP verified the enzymatic cleavage of polyphosphate and subsequent release of monophosphate and colistin from CP-NPs. Although CP-NPs were ineffective against planktonic M. luteus cultures, they showed major activity against bacterial biofilms, outperforming native colistin treatment. Strongly elevated AP levels in the biofilm state were identified as a potential key factor for the observed findings. Conclusion: Accordingly, polyphosphate-based nanocomplexes represent a promising tool to tackle bacterial biofilm.

Design of charge converting lipid nanoparticles via a microfluidic coating technique.

It was the aim of this study to design charge converting lipid nanoparticles (LNP) via a microfluidic mixing technique used for the preparation and coating of LNP. LNP consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, N-(carbonyl-methoxypolyethyleneglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG-2000-DSPE), and various cationic surfactants were prepared at diverging flow rate ratios (FRR) via microfluidic mixing. Utilizing a second chip in the microfluidic set-up, LNP were coated with polyoxyethylene (9) nonylphenol monophosphate ester (PNPP). LNP were examined for their stability in different physiologically relevant media as well as for hemolytic and cytotoxic effects. Finally, phosphate release and charge conversion of PNPP-coated LNP were evaluated after incubation with alkaline phosphatase and on Caco2-cells. LNP produced at an FRR of 5:1 exhibited a size between 80 and 150 nm and a positive zeta potential. Coating with PNPP within the second chip led to LNP exhibiting a negative zeta potential. After incubation with 1 U/ml alkaline phosphatase for 4 h, zeta potential of the LNP containing 1,2-dioleoyloxy-3-trimethylammonium-propane chloride (DOTAP) as cationic component shifted from - 35 mV to approximately + 5 mV. LNP prepared with other cationic surfactants remained slightly negative after enzymatic phosphate cleavage. Manufacturing of LNP containing PNPP and DOTAP via connection of two chips in a microfluidic instrument proves to show efficient change in zeta potential from negative to positive after incubation with alkaline phosphatase.

Overcoming intestinal barriers by heparanase-responsive charge-converting nanocarriers.

In this study, we present a novel approach for overcoming intestinal barriers by utilizing heparanase-responsive charge-converting nanocarriers (NCs). These NCs are designed to undergo charge conversion in response to the activity of heparanase (HPSE), an enzyme commonly overexpressed in cancer cells. Nanostructured lipid carriers (NLCs) and solid lipid nanocarriers (SLNs) with a positively charged core were coated with heparin (Hep), resulting in a negative surface charge and a size between 195 and 220 nm. However, upon encountering heparanase, heparin undergoes enzymatic cleavage, resulting in zeta potential shift from -22.1 to +8.3 mV for NLC-Hep and from -19.8 to +5.1 mV for SLN-Hep. Heparin-coated NCs showed more than 6-fold higher mucus permeating properties compared to the uncoated NCs. In vitro experiments using the heparanase-expressing cancer cell line HT29 demonstrated an up to 4-fold improved cellular uptake of the heparin coated NCs compared to co-incubation with the HPSE inhibitor suramin. Furthermore, cellular uptake was investigated on Caco-2 cells and on a Caco-2/HT29-MTX co-culture. Overall, this study highlights the potential of heparanase-responsive charge-converting NCs as a promising strategy for overcoming intestinal barriers and enhancing cellular uptake.

Thiolated Cellulose: A Dual-Acting Mucoadhesive and Permeation-Enhancing Polymer.

This study aims to design an anionic, thiolated cellulose derivative and to evaluate its mucoadhesive and permeation-enhancing properties utilizing enoxaparin as a model drug. 2-Mercaptosuccinic acid-modified cellulose (cellulose-mercaptosuccinate) was synthesized by the reaction of cellulose with S-acetylmercaptosuccinic anhydride. The chemical structure of the target compound was confirmed by FTIR and 1H NMR spectroscopy. The thiol content was determined by Ellman's test. The conjugate exhibited 215.5 ± 25 µmol/g of thiol groups and 84 ± 16 µmol/g of disulfide bonds. Because of thiolation, mucoadhesion on porcine intestinal mucosa was 9.6-fold enhanced. The apparent permeability (Papp) of the model dye Lucifer yellow was up to 2.2-fold improved by 0.5% cellulose-mercaptosuccinate on a Caco-2 cell monolayer. Enoxaparin permeation through rat intestinal mucosa increased 2.4-fold in the presence of 0.5% cellulose-mercaptosuccinate compared with the drug in buffer only. In vivo studies in rats showed an oral bioavailability of 8.98% using cellulose-mercaptosuccinate, which was 12.5-fold higher than that of the aqueous solution of the drug. Results of this study show that the modification of cellulose with 2-mercaptosuccinic acid provides mucoadhesive and permeation-enhancing properties, making this thiolated polymer an attractive excipient for oral drug delivery.

Self-emulsifying drug delivery systems (SEDDS): In vivo-proof of concept for oral delivery of insulin glargine.

In spite of recent progress made in the field of peptide and protein delivery, oral administration of insulin and similar drugs remains a challenge. In this study, lipophilicity of insulin glargine (IG) was successfully increased via hydrophobic ion pairing (HIP) with sodium octadecyl sulfate to enable incorporation into self-emulsifying drug delivery systems (SEDDS). Two SEDDS formulations (F1: 20% Labrasol®ALF, 30% polysorbate 80, 10% Croduret 50, 20% oleyl alcohol, 20% Maisine® CC; F2: 30% Labrasol®ALF, 20% polysorbate 80, 30% Kolliphor® HS 15, 20% Plurol® oleique CC 497) were developed and loaded with the IG-HIP complex. Further experiments confirmed increased lipophilicity of the complex, achieving LogDSEDDS/release medium values of 2.5 (F1) and 2.4 (F2) and ensuring sufficient amounts of IG within the droplets after dilution. Toxicological assays indicated minor toxicity and no toxicity inherent to the incorporated IG-HIP complex. SEDDS formulations F1 and F2 were administered to rats via oral gavage and resulted in a bioavailability of 0.55% and 0.44%, corresponding to a 7.7-fold and 6.2-fold increased bioavailability, respectively. Thus, incorporation of complexed insulin glargine into SEDDS formulations provides a promising approach to facilitate its oral absorption.

Reversible Multielectron Release from Redox-Active Three-Dimensional Molecular Barrels with Ruthenium-Alkenyl Moieties.

Three-dimensional molecular barrels Ru6-4 and Ru6-5 were synthesized in high yields from dinuclear ruthenium-vinyl clamps and tritopic triphenylamine-derived carboxylate linkers and characterized by multinuclear NMR spectroscopy including 1H-1H COSY and 1H DOSY measurements, high-resolution electrospray ionization mass spectrometry, and X-ray crystallography. The metal frameworks of the cages adopt the shape of twisted trigonal prisms, and they crystallize as racemic mixtures of interdigitating Δ- and Λ-enantiomers with a tight columnar packing in Ru6-4. Electrochemical studies and redox titrations revealed that the cages are able to release up to 11 electrons on the voltammetric timescale and that their cage structures persist up to the hexacation level. IR and UV-vis-near-infrared spectroelectrochemical studies confirm substituent-dependent intramolecular electronic communication within the π-conjugated 1,3-divinylphenylene backbone in the tricationic states, where all three divinylphenylene-bridged diruthenium clamps are present in mixed-valent radical cation states. The formation of 1:3 charge-transfer salts with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane as the electron acceptor is also demonstrated.

Digestion of lipid excipients and lipid-based nanocarriers by pancreatic lipase and pancreatin.

The digestion behaviour of lipid-based nanocarriers (LNC) has a great impact on their oral drug delivery properties. In this study, various excipients including surfactants, glycerides and waxes, as well as various drug-delivery systems, namely self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were examined via the pH-stat lipolysis model. Lipolysis experiments with lipase and pancreatin revealed the highest release of fatty acids for medium chain glycerides, followed by long chain glycerides and surfactants. Waxes appeared to be poor substrates with a maximum digestion of up to 10% within 60 min. Within the group of surfactants, the enzymatic cleavage decreased in the following order: glycerol monostearate > polyoxyethylene (20) sorbitan monostearate > PEG-35 castor oil > sorbitan monostearate. After digestion experiments of the excipients, SEDDS, SLN and NLC with sizes between 30 and 300 nm were prepared. The size of almost all formulations was increasing during lipolysis and levelled off after approximately 15 min except for the SLN and NLC consisting of cetyl palmitate. SEDDS exceeded 6000 nm after some minutes and were almost completely hydrolysed by pancreatin. No significant difference was observed between comparable SLN and NLC but surfactant choice and selection of the lipid component had an impact on digestion. SLN and NLC with cetyl palmitate were only digested by 5% whereas particles with glyceryl distearate were decomposed by 40-80% within 60 min. Additionally, the digestion of the same SLN or NLC, only differing in the surfactant, was higher for SLN/NLC containing polyoxyethylene (20) sorbitan monostearate than PEG-35 castor oil. This observation might be explained by the higher PEG content of PEG-35 castor oil causing a more pronounced steric hindrance for the access of lipase. Generally, digestion experiments performed with pancreatin resulted in a higher digestion compared to lipase. According to these results, the digestion behaviour of LNC depends on both, the type of nanocarrier and on the excipients used for them.