Designing hydrogels for controlled drug delivery

Abstract

Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

Figure 1. Multiscale properties of hydrogels

a| The macroscopic design of hydrogels includes the size and porous structure. Hydrogels can be either non-porous or contain macroscopic pores of 10–500 μm. b| The spacing between polymer molecules in the network (that is, the mesh size) is tuneable from around 5 to around 100 nm. c| At the molecular (or atomistic) scale, drugs can interact with the polymer chains via a range of mechanisms; shown here is a covalent linkage to a polymer chain.

Figure 2. Macroscopic design determines the delivery route

a| Macroscopic hydrogels are used for transepithelial delivery and placement inside the body. Injectable macroscopic hydrogels that can be delivered via syringe-needle injection include (b) in situ-gelling hydrogels such as a hydrogel formed with tetrazine-norbornene chemistry, (c) shear-thinning hydrogels such as alginate hydrogels cross-linked with multivalent ions and (d) macroporous hydrogels that can undergo reversible dramatic volumetric change. In addition to transepithelial and local injection, microgels (e) are suitable for oral, pulmonary and intrabony delivery and nanogels (f) are suitable for systemic administration of drugs.

Figure 3. Mesh size mediates drug diffusion

a| A small drug relative to the mesh size diffuses rapidly through the hydrogel, resulting in a short release duration. b| When the size of drug approaches the mesh size (r_mesh/r_drug ≈ 1), drug release is dramatically slowed. c| When the drug is larger than the mesh size (r_mesh/r_drug <1), drugs are physically entrapped inside the network. To release the originally immobilized drugs, the mesh size can be enlarged through network degradation (d), swelling (e), or via applying deformation to disrupt the network (f). The gray dashed lines refer to the diffusion pathway of drugs.

Figure 4. Chemical interactions mediate drug release

Representative chemical interactions between a drug and polymer chains. a| Highly stable covalent linkages immobilize the drugs inside the hydrogel. Strategies include the formation of amide bonds and the use of long-chain poly(ethylene glycol) (PEG) linkages. b| Cleavable covalent linkages release the drug as a result of hydrolysis or the activity of enzymes like proteases. c| Electrostatic interactions between a charged drug and the polymer chain can slow release. This can be exploited using polymers carrying charges, such as carboxylate groups and those mimicking heparin-binding groups. d| Hydrophobic drugs associate with hydrophobic domains such as aliphatic chains and cyclodextrin.

Figure 5. Drug release property chart of hydrogels

Each dot represents the burst release and half-life of release taken from the literature (see the Supplementary information for the particular reference corresponding to each dot). The inset shows a representative release profile, for which the half-life (t_1/2) is determined by the time when the fraction of released drug reaches 50% and the burst release parameter (k) is determined by the drug release fraction at 24 hours. The coloured circles refer to different drug release mechanisms: diffusion-controlled mechanism (red), degradation-controlled mechanism (purple), affinity-controlled mechanisms based on cleavable covalent conjugation (orange), electrostatic interactions (blue), and hydrophobic association (green), as well as a combination of degradation-controlled and hydrophobic association-controlled mechanisms (brown). The two dashed lines were calculated using equation (2) with n = 0.5 and 1.0.