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.

Self-assembly and photo-cross-linking of eight-armed PEG-PTMC star block copolymers.

Eight-armed poly(ethylene glycol)-poly(trimethylene carbonate) star block copolymers (PEG-(PTMC)(8)) linked by a carbamate group between the PEG core and the PTMC blocks were synthesized by the metal-free, HCl-catalyzed ring-opening polymerization of trimethylene carbonate using an amine-terminated eight-armed star PEG in dichloromethane. Although dye solubilization experiments, nuclear magnetic resonance spectroscopy, and dynamic light scattering clearly indicated the presence of aggregates in aqueous dispersions of the copolymers, no physical gelation was observed up to high concentrations. PEG-(PTMC(9))(8) was end-group-functionalized using acryloyl chloride and photopolymerized in the presence of Irgacure 2959. When dilute aqueous dispersions of PEG-(PTMC(9))(8)-Acr were UV irradiated, chemically cross-linked PEG-PTMC nanoparticles were obtained, whereas irradiation of more concentrated PEG-(PTMC(9))(8)-Acr dispersions resulted in the formation of photo-cross-linked hydrogels. Their good mechanical properties and high stability against hydrolytic degradation make photo-cross-linked PEG-PTMC hydrogels interesting for biomedical applications such as matrices for tissue engineering and controlled drug delivery systems.

Self-aggregation of gel forming PEG-PLA star block copolymers in water.

The aggregation behavior and dynamics of poly(ethylene glycol) (PEG) and poly(lactide) (PLA) chains in a homologous series of eight-armed PEG-PLA star block copolymers ((PEG(65)-NHCO-PLA(n))(8) with n = 11, 13, and 15) in water at different concentrations and temperatures were studied by means of (1)H and (13)C NMR spectroscopy and (1)H longitudinal relaxation time analysis. The state of water in these systems was also investigated through the combined use of (1)H and (2)H longitudinal relaxation time measurement. On the basis of the NMR experimental findings and of dynamic light scattering measurements, (PEG(65)-NHCO-PLA(n))(8) in water can be described as self-aggregated systems with quite rigid hydrophobic domains made of PLA chains and aqueous domains where both PEG chains and water molecules undergo fast dynamics. A smaller number of rigid domains was found for (PEG(65)-NHCO-PLA(11))(8) with respect to the homologous copolymers with longer PLA chains. At low concentrations, the PLA domains are mainly formed by chains belonging to the same molecule, thus giving rise to unimolecular micelles. At intermediate concentrations, that is, above the critical association concentration (CAC) but below the critical gel concentration (CGC), nanogels are formed by interconnection of several PLA domains through shared unimers. Above the CGC, the network is extended to the entire system, giving rise to macroscopic gels. In all cases, a fraction of PLA chains remains quite mobile and exposed to water due to topological constraints of the star architecture.

Influence of amide versus ester linkages on the properties of eight-armed PEG-PLA star block copolymer hydrogels.

Water-soluble eight-armed poly(ethylene glycol)-poly(l-lactide) star block copolymers linked by an amide or ester group between the PEG core and the PLA blocks (PEG-(NHCO)-(PLA)(8) and PEG-(OCO)-(PLA)(8)) were synthesized by the stannous octoate catalyzed ring-opening polymerization of l-lactide using an amine- or hydroxyl-terminated eight-armed star PEG. At concentrations above the critical gel concentration, thermosensitive hydrogels were obtained, showing a reversible single gel-to-sol transition. At similar composition PEG-(NHCO)-(PLA)(8) hydrogels were formed at significantly lower polymer concentrations and had higher storage moduli. Whereas the hydrolytic degradation/dissolution of the PEG-(OCO)-(PLA)(8) takes place by preferential hydrolysis of the ester bond between the PEG and PLA block, the PEG-(NHCO)-(PLA)(8) hydrogels degrade through hydrolysis of ester bonds in the PLA main chain. Because of their relatively good mechanical properties and slow degradation in vitro, PEG-(NHCO)-(PLA)(8) hydrogels are interesting materials for biomedical applications such as controlled drug delivery systems and matrices for tissue engineering.

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.

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.

Hydrogels in a historical perspective: from simple networks to smart materials.

Over the past decades, significant progress has been made in the field of hydrogels as functional biomaterials. Biomedical application of hydrogels was initially hindered by the toxicity of crosslinking agents and limitations of hydrogel formation under physiological conditions. Emerging knowledge in polymer chemistry and increased understanding of biological processes resulted in the design of versatile materials and minimally invasive therapies. Hydrogel matrices comprise a wide range of natural and synthetic polymers held together by a variety of physical or chemical crosslinks. With their capacity to embed pharmaceutical agents in their hydrophilic crosslinked network, hydrogels form promising materials for controlled drug release and tissue engineering. Despite all their beneficial properties, there are still several challenges to overcome for clinical translation. In this review, we provide a historical overview of the developments in hydrogel research from simple networks to smart materials.

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.