Thèse de doctorat en Biotechnologie, instrumentation, signal et imagerie pour la biologie, la médecine et l'environnement
Sous la direction de Donald Martin et de Philippe Cinquin.
Soutenue le 26-07-2017
à l'Université Grenoble Alpes (ComUE) , dans le cadre de École doctorale ingénierie pour la santé, la cognition, l'environnement (Grenoble) , en partenariat avec Techniques de l’ingénierie médicale et de la complexité - Informatique, mathématiques et applications (Grenoble) (laboratoire) .
Le président du jury était Christophe A. Marquette.
Le jury était composé de Harald Fischer.
Les rapporteurs étaient Daniel George, Séverine Le Gac.
La délivrance stimulée des molécules thérapeutiques des hydrogels à l'aide des ultrasons
Le doctorant n'a pas fourni de résumé en français.
The research described in this thesis is directed to study an externally stimulated DDS that incorporates a hydrogel as the matrix for the therapeutic agent. The research does not investigate a particular site for the delivery of the therapeutic agent. However, the aim of this research program is to develop various hydrogel formulations with desirable characteristics and structures from which the drug release can be controlled with applied external energy in the form of low-frequency ultrasound. To accomplish this, two types of natural hydrogels from agarose and chitosan and one type of synthetic hydrogel from PVA were fabricated. Parameters that affect the structure were varied for each type of hydrogel in order to study the effect of structural changes on drug loading and release capacity of hydrogels. Next, the obtained hydrogels were assessed for the delivery of Theophylline as the model drug.Among the three types of hydrogels, chitosan was found to have the fastest swelling rates and the higher water uptakes while the least swelling was found with PVA hydrogels and then agarose hydrogels crosslinked at pH 12. Regarding the mechanical stability of hydrogels, the ranking of the elastic modulus was PVA hydrogels (highest), then agarose hydrogels and chitosan copolymers (lowest). It seemed that the more mechanically stable structure of the PVA hydrogels correlated with a reduced mobility of water, in comparison to the greater mobility of water in the mechanically weaker chitosan copolymers.The stimulated and passive release of Theophylline from those hydrogel carriers showed how ultrasound, as an external energy, stimulates and controls the release of the drug. The measurements confirmed that it is only the energy imparted by the longitudinal ultrasonic waves that act on the polymeric network. The mechanism by which the ultrasound affects the release is considered as a form of a ratchet motor. The polymer chains play the role of the “ratchet” steps and the ultrasonic waves accelerate the particle movement in the release media. Hence, once the ultrasound is applied, the particles descend chain-to-chain (i.e. step-by-step) driven down their concentration gradient by the applied energy until they reach the surface of the hydrogel and hence are released into the surrounding media.Increasing the ultrasound intensity vastly accelerates the drug release. Indeed a higher intensity equals a higher energy transferred from the ultrasonic waves to the drug particles, resulting in faster and less controlled release. This also depends on the type of drug carrier structure. If the hydrogel carrier is mechanically stable, such as the PVA samples or the agarose hydrogels crosslinked at pH 12, the effect of high ultrasound intensity is much less compared to a less mechanically stable carrier such as the chitosan blends. Ultrasound applied for a longer period of time increases the amount of drug released, with the consequent effect of increasing the amount of heat generated in the hydrogel. Generally, a longer duration of the applied energy results in a greater amount of energy absorption, and an increase in friction and heat generation. These effects are important considerations in relation to the heat sensitivity of the drug to be delivered and the thermal characteristics of the polymeric carrier.This PhD research has demonstrated that both natural and synthetic hydrogels coupled to an ultrasonic energy source provides a controllable DDS, which provide some novel outcomes and contributions to the body of knowledge in the field of controlled drug delivery.
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