Self-heating hydrogel for mechanically-controlled drug release

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. [...

Characterization of viscoelastic properties of PDMS silicon rubbers

In this project we target a desired viscoelastic properties of PDMS for the application of thin wall membrane uses as a container to support soft test sample biomaterials during mechanical compression tests. The biocompatible PDMS membrane is produced by a custom made PDMS seal. This axisymmetric chamber is made by reaction injection molding. In this project student should synthesize different PDMS by changing some parameters and polymerization process and do some standard mechanical tests on them using INSTRON machine to optimize the viscoelastic properties of produced material to reach to the best composition with less viscosity modulus good stiffness and as thin as possible membrane

Measuring the mesh size of hydrogels

Hydrogels are cross-linked, water-swollen polymer networks that are widely used as a biomaterial. Because of high amount of water, they are mechanically poor and soft. This aspect limits their applications. The suitability of hydrogels as biomedical materials, especially as drug delivery systems depend on their bulk structure. The most important parameters used to characterize the network structure of hydrogels are the polymer volume fraction in the swollen state, the molecular weight of the polymer chain between two neighboring crosslinking points, and the corresponding mesh size. Among hydrogel matrixes HEMA (hydroxyl ethyl methacrylate) base hydrogels are of great interest and they have many applications in biomedical fields like artificial organs and drug delivery system. The stiffness of this family of hydrogels is tunable by changing water ratio during polymerization. The goal of this project is to calculate the mesh size of this hydrogel through rubber elasticity theory formulation, which involved interesting experimental works to measure required parameters for this calculation. Experiments consist of hydrogel synthesize via UV polymerization, measuring swelling ratio, polymer volume fraction, polymer density measurement through bouncy technique and measuring elastic modulus of hydrogels in tension. Each experiment provides the operator with fundamental skills in hydrogels characterization for who are interested to work with hydrogels in any biomedical application

Modeling a zero-order drug release pattern with multi-laminated hydrogels

Diffusion-controlled hydrogel polymeric matrix devices have been among the most widely used drug delivery systems. How ever in homogeneous hydrogel the diffusional distance increase with time and hence, the release rate decreases. That results in high release of drug during first hours and days of implantation, which may is not necessary and sometimes it can cause side effects. To overcome this disadvantage of first-order diffusion behavior, various approaches have been developed to achieve constant release rates in polymeric matrix devices. As an alternative technique in this project we are interested to model the constant release profile by polymerizing some multi-laminated HEMA base hydrogels. HEMA hydrogel are widely used in biomedical applications and their diffusion properties and their porosity can be tuned by changing the water ratio during polymerization and also the amount of cross-linker. Having a multi-laminated hydrogel from different HEMA-crosslinker-water ratio can propose a solution for controlling the overall release profile and provide a constant release over time

Biodegradable HEMA-based hydrogels with enhanced mechanical properties

Hydrogels are widely used in the biomedical field. Their main purposes are either to deliver biological active agents or to temporarily fill a defect until they degrade and are followed by new host tissue formation. However for this latter application, biodegradable hydrogels are usually not capable to sustain any significant load. The development of biodegradable hydrogels presenting load-bearing capabilities would open new possibilities to utilize this class of material in the biomedical field. In this work, an original formulation of biodegradable photo-crosslinked hydrogels based on hydroxyethyl methacrylate (HEMA) is presented. The hydrogels consist of short-length poly(2-hydroxyethyl methacrylate) (PHEMA) chains in a star shape structure, obtained by introducing a tetra-functional chain transfer agent in the backbone of the hydrogels. They are cross-linked with a biodegradable N,O-dimethacryloyl hydroxylamine (DMHA) molecule sensitive to hydrolytic cleavage. We characterized the degradation properties of these hydrogels submitted to mechanical loadings. We showed that the developed hydrogels undergo long-term degradation and specially meet the two essential requirements of a biodegradable hydrogel suitable for load bearing applications: enhanced mechanical properties and low molecular weight degradation products

Improving hydrogels’ toughness by increasing the dissipative properties of their network

The weak mechanical performance and fragility of hydrogels limit their application as biomaterials for load bearing applications. The origin of this weakness has been explained by the low resistance to chains breakage composing the hydrogel and to the cracks propagation in the hydrogel submitted to loading conditions. These low resistance and crack propagation were in turn related to an insufficient energy dissipation mechanism in the hydrogel structure. The goal of this study is to evaluate the dissipation mechanism in covalently bonded hydrogels so that tougher hydrogels can be developed while keeping for the hydrogel a relatively high mechanical stiffness. By varying parameters such as cross-linker type or concentration as well as water ratio, the dissipative properties of HEMA-based hydrogels were investigated at large deformations. Different mechanisms such as special friction-like phenomena, nanoporosity, and hydrophobicity were proposed to explain the dissipative behavior of the tested hydrogels. Based on this analysis, it was possible to develop hydrogels with increased toughness properties

Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel

Temperature has been extensively explored as a trigger to control the delivery of a payload from environment-sensitive polymers. The need for an external heat source only allows limited spatiotem- poral control over the delivery process. We propose a new approach by using the dissipative properties of a hydrogel matrix as an internal heat source when the material is mechanically loaded. The system is comprised of a highly dissipative hydrogel matrix and thermo-sensitive nanoparticles that shrink upon an increase in temperature. Exposing the hydrogel to a cyclic mechanical loading for a period of 5 min leads to an increase of temperature of the nanoparticles. The concomitant decrease in the volume of the nanoparticles increases the permeability of the hydrogel network facilitating the release of its payload. As a proof-of-concept, we showed that the payload of the hydrogel is released after 5e8 min following the initiation of the mechanical loading. This delivery method would be particularly suited for the release of growth factor as it has been shown that cell receptor to growth factor is activated 5e20 min following a mechanical loading

Characterizing the drug release from thermosensitive composite HEMA-Nanoparticles hydrogel under mechanical loading

HEMA hydrogels are hydrophobic biocompatible hydrogel with high mechanical and viscoelastic properties, which are widely used in biomedical application including drug delivery systems. The mechanical properties and permeability of these hydrogels can be tuned by controlling the water concentration and cross-linker during polymerization. In this study the characterization of drug release from these hydrogels are of interest, since the release profile can be nicely tunable by changing the mesh size and permeability of hydrogels. The hydrogels will be polymerized via UV polymerization and the conventional release of proteins will be measured via spectrophotometry in different time steps. Also the release under cyclic compression mechanical loading is of interest. The drug models are proteins with different sizes including Lysozyme, Pepsin and BSA. The water uptake and permeability will be characterized before drug release study

Characterization of the mesh size of hydrogels from swelling properties

Hydrogels are cross-linked, water-swollen polymer networks that are widely used as a biomaterial. The suitability of hydrogels as biomedical materials, especially as drug delivery systems depend on their bulk structure. The most important parameters used to characterize the network structure of hydrogels are the polymer volume fraction in the swollen state, the molecular weight of the polymer chain between two neighboring crosslinking points, and the corresponding mesh size. Among hydrogel matrixes HEMA (hydroxyl ethyl methacrylate) base hydrogels are of great interest and they have many applications in biomedical fields like artificial organs and drug delivery system. The stiffness of this family of hydrogels is tunable by changing water ratio during polymerization. The goal of this project is to calculate the mesh size of new HEMA-MDHA hydrogel through rubber elasticity theory formulation, which involved interesting experimental works to measure required parameters for this calculation. Experiments consist of hydrogel synthesize via UV polymerization, measuring swelling ratio, polymer volume fraction, polymer density measurement through bouncy technique and measuring elastic modulus of hydrogels in tension. Each experiment provides the operator with fundamental skills in hydrogels characterization for who are interested to work with hydrogels in any biomedical application