Tuning bio-aerogel properties. Part 3: Exploring silica-pectin composite aerogels for drug delivery.

The release of the model drug theophylline from silica-pectin aerogels was investigated. The composite aerogels were prepared via impregnation of pectin alcogels with silica sol, followed by in situ silica gelation and drying with supercritical CO2. The structural and physico-chemical properties of the aerogels were tuned via the preparation conditions (type of silica sol, calcium crosslinking of pectin or not). Theophylline was loaded via impregnation and its release into simulated gastric fluid was studied during 1 h followed by release into simulated intestinal fluid. The swelling, mass loss and theophylline release behavior of the composites were analyzed and correlated with material properties. It followed that only aerogels prepared with calcium-crosslinked pectin and polyethoxydisiloxane were stable in aqueous systems, exhibiting a slow theophylline release governed by near-Fickian diffusion.

Roadmap on multifunctional materials for drug delivery.

This Roadmap on drug delivery aims to cover some of the most recent advances in the field of materials for drug delivery systems (DDSs) and emphasizes the role that multifunctional materials play in advancing the performance of modern DDSs in the context of the most current challenges presented. The Roadmap is comprised of multiple sections, each of which introduces the status of the field, the current and future challenges faced, and a perspective of the required advances necessary for biomaterial science to tackle these challenges. It is our hope that this collective vision will contribute to the initiation of conversation and collaboration across all areas of multifunctional materials for DDSs. We stress that this article is not meant to be a fully comprehensive review but rather an up-to-date snapshot of different areas of research, with a minimal number of references that focus upon the very latest research developments.

Advanced Functional Polymers for Unmet Medical Challenges.

A significant part of medicine relies on biomaterials, which are designed to interact with biological tissues for therapeutic or diagnostic purposes. A number of major trends can be distinguished in the multidisciplinary field of biomaterials science, including the precise synthesis of biomaterial building blocks, elucidation of biomaterial processing-structure-property correlations, as well as clarification of the interactions between living tissues and biomaterials. Moreover, advances in biofabrication facilitate the development of tailored implants with improved functionality, whereas recent achievements in medical imaging allow for a detailed evaluation of the performance and spatiotemporal behavior of medical devices and nanomedicine formulations.

Hyaluronic Acid Aerogels Made Via Freeze-Thaw-Induced Gelation.

The biodegradability, biocompatibility, and bioactivity of hyaluronic acid (HA), a natural polysaccharide, combined with the low density, high porosity, and high specific surface area of aerogels attract interest for biomedical applications such as wound dressings. In this work, physically cross-linked HA aerogels were prepared via the freeze-thaw (FT) induced gelation method, solvent exchange, and drying with supercritical CO2. The morphology and properties of HA aerogels (volume shrinkage, density, and specific surface area) were investigated as a function of several process parameters: HA concentration, solution pH, number of FT cycles, and type of nonsolvent used during solvent exchange. We demonstrate that the HA solution pH plays a key role in the aerogel formation, as not all conditions result in materials with high specific surface area. HA aerogels were of low density (<0.2 g/cm3), high specific surface area (up to 600 m2/g), and high porosity (≥90%). Scanning electron microscopy pictures revealed that HA aerogels present a porous structure with meso- and small macropores. The results show that HA aerogels are promising biomaterials with tunable properties and internal structure that offer high potential as, e.g., wound dressings.

Release Kinetics of Dexamethasone Phosphate from Porous Chitosan: Comparison of Aerogels and Cryogels.

Porous chitosan materials as potential wound dressings were prepared via dissolution of chitosan, nonsolvent-induced phase separation in NaOH-water, formation of a hydrogel, and either freeze-drying or supercritical CO2 drying, leading to "cryogels" and "aerogels", respectively. The hydrophilic drug dexamethasone sodium phosphate was loaded by impregnation of chitosan hydrogel, and the release from cryogel or aerogel was monitored at two pH values relevant for wound healing. The goal was to compare the drug-loading efficiency and release behavior from aerogels and cryogels as a function of the drying method, the materials' physicochemical properties (density, morphology), and the pH of the release medium. Cryogels exhibited a higher loading efficiency and a faster release in comparison with aerogels. A higher sample density and lower pH value of the release medium resulted in a more sustained release in the case of aerogels. In contrast, for cryogels, the density and pH of the release medium did not noticeably influence release kinetics. The Korsmeyer-Peppas model showed the best fit to describe the release from the porous chitosan materials into the different media.

Tuning bio-aerogel properties for controlling drug delivery. Part 2: Cellulose-pectin composite aerogels.

The release of the model drug theophylline from cellulose-pectin composite aerogels was investigated. Cellulose and pectin formed an interpenetrated network, and the goal was to study and understand the influence of each component and its solubility in simulated gastric and intestinal fluids on the kinetics of release. Cellulose was dissolved, coagulated in water, followed by impregnation with pectin solution, crosslinking of pectin with calcium (in some cases this step was omitted), solvent exchange and supercritical CO2 drying. Theophylline was loaded via impregnation and its release into simulated gastric fluid was monitored for 1 h followed by release into simulated intestinal fluid. The properties of the composite aerogels were varied via the cellulose and pectin concentrations as well as the calcium content in the precursor solutions. The release kinetics was correlated with aerogel specific surface area, bulk density as well as network swelling and erosion. The Korsmeyer-Peppas model was employed to identify the dominant release mechanisms during the various stages of the release.

Crosslinker-Free Hyaluronic Acid Aerogels.

Aerogels based on hyaluronic acid (HA) were prepared without any chemical crosslinking by polymer dissolution, network formation via nonsolvent-induced phase separation, and supercritical CO2 drying. The influence of solution pH, concentration of HA, and type of nonsolvent on network volume shrinkage, aerogel density, morphology, and specific surface area was investigated. A marked dependence of aerogel properties on solution pH was observed: aerogels with the highest specific surface area, 510 m2/g, and the lowest density, 0.057 g/cm3, were obtained when the HA solution was at its isoelectric point (pH 2.5). This work reports the first results ever on neat HA aerogels and constitutes the background for their use as advanced materials for biomedical applications.

Tuning the properties of porous chitosan: Aerogels and cryogels.

Highly porous chitosan-based materials were prepared via dissolution, non-solvent induced phase separation and drying using different methods. The goal was to tune the morphology and properties of chitosan porous materials by varying process parameters. Chitosan concentration, concentration of sodium hydroxide in the coagulation bath and aging time were varied. Drying was performed via freeze-drying leading to "cryogels" or via drying with supercritical CO2 leading to "aerogels". Cryogels were of lower density than aerogels (0.03-0.12 g/cm3vs 0.07-0.26 g/cm3, respectively) and had a lower specific surface area (50-70 vs 200-270 m2/g, respectively). The absorption of simulated wound exudate by chitosan aerogels and cryogels was studied in view of their potential applications as wound dressing. Higher absorption was obtained for cryogels (530-1500%) as compared to aerogels (200-610%).

Tuning bio-aerogel properties for controlling theophylline delivery. Part 1: Pectin aerogels.

A comprehensive study of release kinetics of a hydrophilic drug from bio-aerogels based on pectin was performed. Pectin aerogels were made by polymer dissolution, gelation (in some cases this step was omitted), solvent exchange and drying with supercritical CO2. Theophylline was loaded and its release was studied in the simulated gastric fluid during 1 h followed by the release in the simulated intestinal fluid. Pectin concentration, initial solution pH and concentration of calcium were varied to tune the properties of aerogel. The kinetics of theophylline release was monitored and correlated with aerogel density, specific surface area, and aerogel swelling and erosion. Various kinetic models were tested to identify the main physical mechanisms governing the release.

Biorefinery Approach for Aerogels.

According to the International Energy Agency, biorefinery is "the sustainable processing of biomass into a spectrum of marketable bio-based products (chemicals, materials) and bioenergy (fuels, power, heat)". In this review, we survey how the biorefinery approach can be applied to highly porous and nanostructured materials, namely aerogels. Historically, aerogels were first developed using inorganic matter. Subsequently, synthetic polymers were also employed. At the beginning of the 21st century, new aerogels were created based on biomass. Which sources of biomass can be used to make aerogels and how? This review answers these questions, paying special attention to bio-aerogels' environmental and biomedical applications. The article is a result of fruitful exchanges in the frame of the European project COST Action "CA 18125 AERoGELS: Advanced Engineering and Research of aeroGels for Environment and Life Sciences".

Double hydrophilic block copolymers self-assemblies in biomedical applications.

Double-hydrophilic block copolymers (DHBCs), consisting of at least two different water-soluble blocks, are an alternative to the classical amphiphilic block copolymers and have gained increasing attention in the field of biomedical applications. Although the chemical nature of the two blocks can be diverse, most classical DHBCs consist of a bioeliminable non-ionic block to promote solubilization in water, like poly(ethylene glycol), and a second block that is more generally a pH-responsive block capable of interacting with another ionic polymer or substrate. This second block is generally non-degradable and the presence of side chain functional groups raises the question of its fate and toxicity, which is a limitation in the frame of biomedical applications. In this review, following a first part dedicated to recent examples of non-degradable DHBCs, we focus on the DHBCs that combine a biocompatible and bioeliminable non-ionic block with a degradable functional block including polysaccharides, polypeptides, polyesters and other miscellaneous polymers. Their use to design efficient drug delivery systems for various biomedical applications through stimuli-dependent self-assembly is discussed along with the current challenges and future perspectives for this class of copolymers.

Synergistic anti-fouling and bactericidal poly(ether ether ketone) surfaces via a one-step photomodification.

Implants of poly(ether ether ketone) (PEEK) are gaining importance in surgical bone reconstruction of the skull. As with any implant material, PEEK is susceptible to bacterial contamination and occasionally PEEK implants were removed from patients because of infection. To address this problem, a combination of anti-fouling and bactericidal polymers is grafted onto PEEK. The originality is that anti-fouling (modified poly(ethylene glycol)) and bactericidal (quaternized poly(dimethylaminoethyl acrylate)) moieties are simultaneously and covalently grafted onto PEEK via UV photoinsertion. The functionalized PEEK surfaces are evaluated by water contact angle measurements, FTIR, XPS and AFM. Grafting of anti-fouling and bactericidal polymers significantly reduces Staphylococcus aureus adhesion on PEEK surfaces without exhibiting cytotoxicity in vitro. This study demonstrates that grafting combinations of anti-fouling and bactericidal polymers synergistically prevents bacterial adhesion on PEEK implants. This approach shows clinical relevance as grafting is rapid, does not modify PEEK properties and can be conducted on pre-formed implants.

Cellulose Aerogel Microparticles via Emulsion-Coagulation Technique.

Cellulose aerogel microparticles were made via emulsification/nonsolvent induced phase separation/drying with supercritical CO2. Cellulose was dissolved in NaOH-based solvent with and without additives in order to control solution gelation. Two emulsions, cellulose solution/oil and cellulose nonsolvent/oil, were mixed to start nonsolvent induced phase separation (or coagulation) of cellulose inside each cellulose droplet leading to the formation of so-called microgels. Different options of triggering coagulation were tested, by coalescence of droplets of cellulose solution and cellulose nonsolvent and by diffusion of nonsolvent partly soluble in the oil, accompanied by coalescence. The second option was found to be the most efficient for stabilization of the shape of coagulated cellulose microgels. The influence of gelation on particle formation and aerogel properties was investigated. The aerogel particles' diameter was around a few tens of microns, and the specific surface area was 250-350 m2/g.

Double-Hydrophilic Block Copolymers Based on Functional Poly(ε-caprolactone)s for pH-Dependent Controlled Drug Delivery.

The use of double-hydrophilic block copolymers (DHBCs) in biomedical applications is limited by their lack of degradability. This additional functionality has been obtained in the past through multistep chemical strategies associated with low yields. In this work, a series of DHBCs composed of a bioeliminable poly(ethylene glycol) (PEG) block and hydrolyzable functional poly(ε-caprolactone) (PCL) blocks bearing carboxylic (PEG-b-PCL(COOH)), amino (PEG-b-PCL(NH2)), or hydroxyl side groups (PEG-b-PCL(OH)) is synthesized in only three steps. DHBCs with 50% substitution degree with respect to the CL units are obtained for all functional groups. The pH-dependent self-assembly behavior of the DHBCs is studied showing critical micelle concentration (CMC) variations by a factor of 2 upon pH changes and micellar mean diameter variations of 20-30%. The potential of these partly degradable DHBCs as drug-loaded polyion complex micelles is further exemplified with the PEG-b-PCL(COOH) series that is associated with the positively charged anticancer drug doxorubicin (DOX). Encapsulation efficiencies, drug loadings, pH-controlled release, and cytotoxicity of the DOX-loaded micelles toward cancer cells are demonstrated. This set of data confirms the interest of the proposed straightforward chemical strategy to generate fully bioeliminable and partly degradable DHBCs with potential as pH-responsive drug-delivery systems.

Ultrafast in situ forming poly(ethylene glycol)-poly(amido amine) hydrogels with tunable drug release properties via controllable degradation rates.

Fast in situ forming, chemically crosslinked hydrogels were prepared by the amidation reaction between N-succinimidyl ester end groups of multi-armed poly(ethylene glycol) (PEG) and amino surface groups of poly(amido amine) (PAMAM) dendrimer generation 2.0. To control the properties of the PEG/PAMAM hydrogels, PEGs were used with different arm numbers (4 or 8) as well as different linkers (amide or ester) between the PEG arms and their terminal N-succinimidyl ester groups. Oscillatory rheology measurements showed that the hydrogels form within seconds after mixing the PEG and PAMAM precursor solutions. The storage moduli increased with crosslink density and reached values up to 2.3 kPa for hydrogels based on 4-armed PEG. Gravimetrical degradation experiments demonstrated that hydrogels with ester linkages between PEG and PAMAM degrade within 2 days, whereas amide-linked hydrogels were stable for several months. The release of two different model drugs (fluorescein isothiocyanate-dextran with molecular weights of 4·103 and 2·106 g/mol, FITC-DEX4K and FITC-DEX2000K, respectively) from amide-linked hydrogels was characterized by an initial burst followed by diffusion-controlled release, of which the rate depended on the size of the drug. In contrast, the release of FITC-DEX2000K from ester-containing hydrogels was governed mainly by degradation of the hydrogels and could be modulated via the ratio between ester and amide linkages. In vitro cytotoxicity experiments indicated that the PEG/PAMAM hydrogels are non-toxic to mouse fibroblasts. These in situ forming PEG/PAMAM hydrogels can be tuned with a broad range of mechanical, degradation and release properties and therefore hold promise as a platform for the delivery of therapeutic agents.

Reversibly core-crosslinked PEG-P(HPMA) micelles: Platinum coordination chemistry for competitive-ligand-regulated drug delivery.

HYPOTHESIS: The presence of pendant thioether groups on poly(ethylene glycol)-poly(N(2-hydroxypropyl) methacrylamide) (PEG-P(HPMA)) block copolymers allows for platinum-mediated coordinative micellar core-crosslinking, resulting in enhanced micellar stability and stimulus-responsive drug delivery. EXPERIMENTS: A new PEG-P(HPMA) based block copolymer with pendant 4-(methylthio)benzoyl (MTB) groups along the P(HPMA) block was synthesized by free radical polymerization of a novel HPMA-MTB monomer using a PEG based macro-initiator. As crosslinker the metal-organic linker [ethylenediamineplatinum(II)]2+ was used, herein called Lx, which is a coordinative linker molecule that has been used for the conjugation of drug molecules to a number of synthetic or natural carrier systems such as hyperbranched polymers and antibodies. FINDINGS: The introduction of Lx in the micellar core results in a smaller size, a lower critical micelle concentration and a better retention of the hydrophobic drug curcumin thanks to coordination bonds between the central platinum atom of Lx and thioether groups on different polymer chains. The drug release from Lx crosslinked micelles is significantly accelerated under conditions mimicking the intracellular environment due to competitive coordination and subsequent micellar de-crosslinking. Because of their straightforward preparation and favorable drug release characteristics, core-crosslinked Lx PEG-P(HPMA) micelles hold promise as a versatile nanomedicine platform.

Stabilization of poly(ethylene glycol)-poly(ε-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties.

HYPOTHESIS: The functionalization of poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) block copolymers with moieties allowing for core-crosslinking is expected to result in improved micellar stability and drug delivery properties. EXPERIMENTS: PEG-(PCL)8 star block copolymers were functionalized with pendant benzylthioether (BTE) groups by applying an anionic post-polymerization modification technique followed by photoradical thiol-yne addition of benzyl mercaptan. The micellar properties of PEG-(PCL)8 and PEG-(PCL-BTE)8 were studied and compared in terms of critical micelle concentration (CMC), size, morphology, drug loading and release and in vitro cytotoxicity. FINDINGS: In comparison with unmodified PEG-(PCL)8 micelles, PEG-(PCL-BTE)8 micelles exhibited a 15-fold lower CMC, a 15-fold smaller size and a 50% higher drug loading and encapsulation efficiency thanks to the presence of pendant benzyl groups which provide the possibility for micellar core-crosslinking via supramolecular π-π stacking and additional hydrophobic interactions. Whereas the PEG-(PCL)8 micelles showed significant aggregation during in vitro cytotoxicity experiments, the PEG-(PCL-BTE)8 micelles showed no signs of aggregation and were capable of solubilizing high concentrations of curcumin, resulting in a significant decrease in MCF-7 cell viability after 48 h. Their ease of synthesis combined with promising results regarding drug delivery make the PEG-(PCL-BTE)8 micelles appealing for application in the field of encapsulation.

Hydrogels for Therapeutic Delivery: Current Developments and Future Directions.

Hydrogels are attractive materials for the controlled release of therapeutics because of their capacity to embed biologically active agents in their water-swollen network. Recent advances in organic and polymer chemistry, bioengineering and nanotechnology have resulted in several new developments in the field of hydrogels for therapeutic delivery. In this Perspective, we present our view on the state-of-the-art in the field, thereby focusing on a number of exciting topics, including bioorthogonal cross-linking methods, multicomponent hydrogels, stimuli-responsive hydrogels, nanogels, and the release of therapeutics from 3D printed hydrogels. We also describe the challenges that should be overcome to facilitate translation from academia to the clinic and last, we share our ideas about the future of this rapidly evolving area of research.

Redox Reducible and Hydrolytically Degradable PEG-PLA Elastomers as Biomaterial for Temporary Drug-Eluting Medical Devices.

With the aim to develop biomaterials for temporary medical devices, a series of novel reducible and/or degradable elastomers has been prepared from PLA-b-PEG-b-PLA copolymers photo-crosslinked with diallyl sulfide or pentaerythritol tetrakis(3-mercaptopropionate). Thermal and mechanical properties, including elastic limit and Young modulus, are assessed. Degradation is then evaluated under standard hydrolytic conditions. Reducibility of a selected elastomer is then illustrated using 2-mercaptoethanol or glutathione as reducing agents. The redox-sensitivity of the selected elastomer and the possibility to modulate the degradability are shown. Considering drug-eluting elastomeric devices applications, anti-inflammatory drug ibuprofen loading is illustrated with the two simplest elastomer formulations. A rapid or slow linear release is observed as a function of the low or high molecular weight of the triblock pre-polymers. Finally, the cytocompatibility of the degradable elastomers is assessed with regard to their potential to favor or inhibit L929 murine fibroblasts proliferation as a function of the hydrophilicity/hydrophobicity of the triblock copolymers.

Release behavior and intra-articular biocompatibility of celecoxib-loaded acetyl-capped PCLA-PEG-PCLA thermogels.

In this study, we investigated the in vitro and in vivo properties and performance of a celecoxib-loaded hydrogel based on a fully acetyl-capped PCLA-PEG-PCLA triblock copolymer. Blends of different compositions of celocoxib, a drug used for pain management in osteoarthritis, and the acetyl-capped PCLA-PEG-PCLA triblock copolymer were mixed with buffer to yield temperature-responsive gelling systems. These systems containing up to 50 mg celecoxib/g gel, were sols at room temperature and converted into immobile gels at 37 °C. In vitro, release of celecoxib started after a ∼10-day lag phase followed by a sustained release of ∼90 days. The release was proven to be mediated by polymer dissolution from the gels. In vivo (subcutaneous injection in rats) experiments showed an initial celecoxib release of ∼30% during the first 3 days followed by a sustained release of celecoxib for 4-8 weeks. The absence of a lag phase and the faster release seen in vivo were likely due to the enhanced celecoxib solubility in biological fluids and active degradation of the gel by macrophages. Finally, intra-articular biocompatibility of the 50 mg/g celecoxib-loaded gel was demonstrated using µCT-scanning and histology, where no cartilage or bone changes were observed following injection into the knee joints of healthy rats. In conclusion, this study shows that celecoxib-loaded acetyl-capped PCLA-PEG-PCLA hydrogels form a safe drug delivery platform for sustained intra-articular release.