Self-heating hydrogel for mechanically-controlled drug release

Abstract

Due to our active lifestyle, knee cartilage is at risk for focal defects. Unfortunately, the native healing properties of the articular cartilage are very limited. New strategies to treat cartilage defects are then developed such as the local delivery of growth factors. For this particular approach, the delivery mode and timing are essential. In parallel, mechanical loading has been demonstrated to activate growth factor receptors involved in the healing process of the cartilage. It is thus proposed that using mechanical loading to control the growth factor release can increase its efficiency. However, a delay of 5 to 20 minutes is necessary for the activation of cell receptors following the initiation of a mechanical stimulation. The synergic effect between the mechanical loading and the delivery of growth factor could then be maximized by delaying the delivery of the growth factor following the initiation of the mechanical stimulation. The development of a hydrogel system allowing to delay the delivery of a pay-load following a mechanical stimulation is the primary objective of this thesis. The main conceptual idea for developing the delayed delivery is to utilize the viscous dissipated energy of the hydrogel submitted to cyclic mechanical loading. Under specific conditions, the dissipated energy will induce a temperature increase in the hydrogel after a certain amount of time, and will then locally trigger the release of a drug incorporated in the hydrogel. With this approach, a new concept of drug release following a mechanical stimulation is developed, where the duration of the mechanical stimulation, before the drug release, can be controlled by the dissipative properties of the hydrogel. The proposed hydrogel system is composed of two components: a hydrogel matrix and thermosensitive nanogel particles. The hydrogel matrix is a chemically cross-linked hydrogel with high dissipative properties. The dissipation of the hydrogel under loading conditions results in a certain temperature increase several minutes after cyclic loading. Incorporated in this hydrogel matrix are thermosensitive nanogel particles, which can respond to the temperature increase when the temperature surpasses their Least Critical Solution Temperature (LCST) and trigger the drug release. In this way, we can provide a time delay between the initiation of the mechanical load and the release of the drug. We followed four steps to develop such a smart drug delivery system. In the first step, we developed a finite element model to study the heat transfer mechanism in knee cartilage. We also used this model to estimate the heat power required by the hydrogel under several minutes of mechanical loading to reach a local temperature increase of about 2°C. In the second step, we designed and optimized a self-heating hydrogel structure based on Hydroxyethyl Methacrylate (HEMA) with high dissipative properties and resistance to fracture under load. The developed hydrogel could dissipate sufficiently to cause an increase in temperature several minutes after the initiation of a mechanical load. In the third step we demonstrated the proof of concept for delayed drug release following a mechanical loading by combining the developed self-heating HEMA-based hydrogel with the themosensitive poly(N-isopropyl acrylamide) (PNIPAM) nanogel particles. [...]