Thèse Conception de Systèmes Hybrides Intelligents Nanofibres-Hydrogel Sensibles au Proche Infrarouge pour l'Administration Contrôlée de Médicaments et la Régénération Tissulaire H/F Doctorat.Gouv.Fr

Établissement : Institut National Polytechnique de Toulouse École doctorale : SDM - SCIENCES DE LA MATIERE - Toulouse Laboratoire de recherche : LGP - Laboratoire Génie de Production Direction de la thèse : Tiphaine MÉRIAN ORCID 0009000534721716 Début de la thèse : 2027-09-01 Date limite de candidature : 2026-11-23T23:59:59 Les lésions tissulaires liées aux traumatismes, interventions chirurgicales, brûlures ou maladies dégénératives restent un défi majeur en médecine régénérative. Les biomatériaux avancés doivent à la fois fournir un environnement hydraté favorable à la réparation des tissus et permettre la délivrance locale et contrôlée d'agents thérapeutiques.
Ce projet de thèse vise à développer des biomatériaux hybrides intelligents associant des nano/microfibres polymères biodégradables, produites par Solution Blow Spinning (SBS), à des hydrogels à base de chitosane. Les fibres, notamment en polycaprolactone (PCL), ne seront pas considérées uniquement comme un renfort mécanique : elles pourront également servir de réservoir thérapeutique et moduler les voies de transport au sein de l'hydrogel. Différentes architectures fibreuses, monolithiques ou coeur-coquille, formulations d'hydrogel, stratégies de réticulation et localisations du médicament seront comparées.
Une fonctionnalité photothermique reposant sur la polydopamine (PDA) sera intégrée sous différentes formes : nanoparticules dispersées dans l'hydrogel, revêtements ou inclusions dans les fibres, ou nanocapsules associées à la molécule thérapeutique. Sous irradiation proche infrarouge à 808 nm, la PDA convertira la lumière en chaleur localisée afin de modifier l'organisation du réseau, la mobilité moléculaire et, potentiellement, la libération du médicament à la demande.
Les matériaux seront caractérisés par spectroscopies FTIR et UV-visible, microscopie électronique à balayage, rhéologie, essais mécaniques, mesures de gonflement, taille de pores et dégradation, ainsi que thermographie infrarouge. Les profils de libération seront comparés avec et sans irradiation. L'objectif est d'établir les relations entre composition, architecture, localisation des composants, réponse photothermique et performances fonctionnelles, puis d'identifier des formulations reproductibles présentant des propriétés mécaniques, de transport et de libération adaptées à la régénération tissulaire.
Le projet sera mené en collaboration entre l'UTTOP/LGP en France et l'UFRJ/BIOPOLI au Brésil, dans un environnement multidisciplinaire associant science des polymères, ingénierie des hydrogels, fabrication de nanofibres, caractérisation des biomatériaux et délivrance contrôlée de médicaments. Tissue damage resulting from trauma, surgery, burns, degenerative diseases or other pathological conditions remains a major challenge in regenerative medicine. Beyond providing a temporary physical support, advanced biomaterials should create a hydrated and permissive microenvironment while enabling the localized and controlled delivery of therapeutic agents when required.
Hydrogels are particularly attractive for biomedical applications because of their high water content, three-dimensional network structure, conformability and ability to encapsulate and transport bioactive molecules. Chitosan is especially interesting because it is a biocompatible and biodegradable polysaccharide that can be formulated into hydrogels using different physical and chemical crosslinking strategies. However, conventional hydrogels may exhibit limited mechanical stability and may not provide sufficient control over molecular transport and drug release. The properties of chitosan-based hydrogels are strongly dependent on parameters such as polymer molecular weight, concentration, degree of crosslinking and network architecture.
Nanofibrous polymeric structures provide a complementary approach. Their high specific surface area, tunable morphology and interconnected porosity make them attractive for drug delivery and tissue-engineering applications. Solution Blow Spinning (SBS) is particularly promising because it enables the rapid fabrication of polymeric micro- and nanofibres from biocompatible and biodegradable polymers, including the possibility of producing core-shell architectures through coaxial configurations.
The combination of nanofibres and a hydrogel can therefore generate a hybrid material in which each component provides specific functions. The nanofibre phase can act as a reinforcing network, modify the architecture and transport pathways of the hydrogel, and serve as a reservoir for a therapeutic molecule. The hydrogel can provide hydration, conformability, molecular transport and additional drug-loading capacity. The resulting material is thus not simply a reinforced hydrogel, but a multiphase and multifunctional delivery platform in which the spatial distribution of the different components can be deliberately designed.
A further level of control can be introduced through photothermal activation. Polydopamine (PDA) is able to convert near-infrared irradiation into localized heat, offering a non-invasive approach to remotely modulate the properties of a biomaterial. Under irradiation at 808 nm, the resulting temperature increase could affect hydrogel network organization, molecular mobility and transport properties, thereby providing a means to regulate drug release on demand. In this PhD project, PDA-based photothermal components and NIR irradiation will therefore be investigated as an external stimulus for controlling the behaviour of the hybrid nanofibre-hydrogel systems.
The PhD project will focus on introducing biocompatible and biodegradable SBS nano/microfibres, such as polycaprolactone (PCL), into a chitosan-based hydrogel network. It will investigate how nanofibre characteristics, hydrogel network structure, drug localization, PDA localization and morphology, and NIR-induced heating can be combined to control the physicochemical and functional behaviour of the resulting hybrid materials.
The overall objective of this PhD project is to develop smart hybrid materials combining biodegradable polymeric nanofibres and a chitosan-based hydrogel for the controlled and near-infrared (NIR)-triggered delivery of therapeutic molecules, with potential applications in tissue regeneration.

The specific objectives are to:

1-Fabricate biodegradable polymeric nano/microfibres, particularly based on polycaprolactone (PCL), using Solution Blow Spinning (SBS), and investigate different architectures, including monolithic and, where relevant, core-shell fibres.
2-Develop chitosan-based hydrogels with properties suitable for controlled molecular delivery, investigating in particular the influence of polymer molecular weight, concentration and crosslinking strategies on network structure and properties.
3-Design nanofibre-hydrogel hybrid systems by varying nanofibre content, morphology and architecture in order to control the three-dimensional structure, swelling, mechanical properties and molecular transport.
4-Introduce a polydopamine (PDA)-based photothermal functionality and investigate different PDA morphologies and localization strategies within the hybrid system.
5-Investigate different strategies for therapeutic molecule localization, including incorporation within the nanofibres, hydrogel, both phases and/or PDA-based structures, in order to evaluate their influence on molecular retention and release.
6-Evaluate the effect of 808 nm NIR irradiation on temperature, hydrogel network response and molecular transport, in order to determine whether NIR stimulation can enable controlled and reproducible modulation of drug release.
7-Establish relationships between material composition and architecture, structure, physicochemical and mechanical properties, therapeutic molecule localization, and release behaviour. This PhD project aims to develop smart hybrid biomaterials combining biodegradable polymeric nanofibres and chitosan-based hydrogels for controlled and NIR triggered drug delivery, with potential applications in tissue regeneration. The project will investigate how the architecture of the fibrous phase, the structure of the hydrogel network, the localization of the therapeutic molecule and photothermal stimulation can be combined to control the physicochemical and functional properties of the resulting hybrid materials.
The originality of the approach lies in considering the nanofibres not only as a reinforcing phase, but also as a potential drug reservoir and transport-regulating component within the hydrogel. Depending on their architecture and formulation and characteristics, the fibrous phase may provide different environments for drug loading, retention and release. The hydrogel will provide a hydrated and conformable three-dimensional environment, while the incorporation of nanofibres and PDA-based photothermal components will introduce an additional structural and functional levels to the system.
Key research steps of the PhD project include:
Biodegradable nano/microfibre fabrication: Biocompatible and biodegradable polymeric nano/microfibres, such as polycaprolactone (PCL), will be produced by Solution Blow Spinning (SBS) in collaboration with the Brazilian partner. Monolithic fibres and, where relevant, core-shell fibres produced using a coaxial SBS configuration will be investigated. The influence of polymer composition, fibre architecture, morphology, diameter and fibre content on the properties of the hybrid materials will be studied.
Chitosan hydrogel development: Chitosan-based hydrogels will be developed using different chitosan molecular weights, polymer concentrations and crosslinking strategies. Both physical and chemical crosslinking approaches may be considered. Their influence on gel formation, rheological and mechanical properties, swelling, porosity, degradation and stability will be investigated in order to identify formulations suitable for molecular transport and controlled drug release.
Nanofibre-hydrogel integration: The SBS nano/microfibres will be incorporated into the chitosan hydrogel to produce hybrid nanofibre-hydrogel systems. The effect of fibre incorporation and fibre content on the three-dimensional architecture, pore structure, swelling, mechanical and rheological properties and stability of the hydrogel will be investigated. Particular attention will be paid to fibre dispersion and to the interactions between the fibrous phase and the hydrogel network.
PDA-based photothermal functionality: Different PDA morphologies and localization strategies will be investigated, including PDA nanoparticles dispersed within the hydrogel, PDA coatings on SBS fibres, PDA incorporated into the fibrous phase, and PDA-based nanocapsules associated with the therapeutic molecule. Their photothermal response and compatibility with the hybrid systems will be evaluated under 808 nm NIR irradiation.
Therapeutic molecule localization: A model therapeutic molecule will be incorporated into the nanofibre phase, hydrogel phase, both phases and/or PDA-based structures, depending on the selected configuration. Where relevant, different fibre architectures (monolithic and core-shell may be explored to investigate their potential for modifying drug loading and retention. The influence of the spatial localization of the molecule on passive and NIR-triggered release will be evaluated.
NIR-triggered drug release and functional characterization: Selected hybrid formulations will be exposed to 808 nm NIR irradiation, with temperature evolution monitored by infrared thermography. The relationships between PDA localization and morphology, NIR-induced heating, hydrogel response, molecular transport and drug release will be investigated. Drug-release experiments under irradiated and non-irradiated conditions will be performed to determine whether NIR stimulation can provide a reproducible modification of the release behaviour.
Physicochemical and functional characterization: The developed materials will be characterized using complementary techniques, including FTIR spectroscopy, UV-Visible spectroscopy, scanning electron microscopy, rheology, mechanical testing, swelling and water uptake measurements, porosity characterization, degradation studies and infrared thermography. These analyses will be used to establish the relationships between material composition and architecture, hydrogel structure, swelling and porosity, mechanical behaviour, drug localization and release.
A first part of the work will focus on the development and characterization of the individual components and their functionalization. Biodegradable polymeric nano/microfibres, including PCL-based fibres, with different architectures will be produced by SBS in Brazil, including monolithic and, where relevant, core-shell fibres. Chitosan-based hydrogels with different molecular weights and crosslinking strategies will also be formulated and characterized. In parallel, different PDA-based photothermal configurations will be investigated, including PDA nanoparticles, PDA coatings and PDA-based nanocapsules loaded with the therapeutic molecule. The influence of the processing and formulation parameters on fibre morphology, hydrogel formation, network structure, swelling, rheological and mechanical properties, as well as the photothermal response of the PDA-based systems, will be evaluated.
A second part will focus on the integration and functional design of the nanofibre-hydrogel systems. The SBS nano/microfibres and selected PDA-based photothermal components will be incorporated within the chitosan hydrogel, within the fibres, or at the interface between the two phases, according to different architectures and functional configurations. In particular, the influence of PDA localization and morphology on the properties and photothermal response of the hybrid systems will be investigated. Different fibre contents, fibre morphologies and fibre architectures will be investigated to determine how the fibrous phase and PDA-based components modify the three-dimensional structure, swelling, mechanical and rheological properties of the hybrid material. Different strategies for localizing the therapeutic molecule will also be compared, including its incorporation within the nanofibres, within the hydrogel, within both phases, or within PDA-based nanocapsules. The aim will be to determine how the spatial distribution of the different components influences drug loading, retention and molecular transport.
A third part will focus on the NIR-responsive behaviour and externally triggered drug release of the optimized hybrid systems. Selected formulations will be exposed to 808 nm NIR irradiation, and their temperature evolution will be monitored by infrared thermography. The relationship between PDA localization and morphology, NIR-induced heating, hydrogel network response, swelling, molecular transport and drug release will be investigated. Drug-release experiments under irradiated and non-irradiated conditions will be performed to determine the nanofibre-hydrogel architecture, drug localization and PDA-based photothermal functionality can be used to modulate drug release.
The PhD candidate will work in a multidisciplinary environment combining polymer processing, nanofibre fabrication, hydrogel science, biomaterials characterization and drug delivery. The research will be conducted in collaboration between laboratories in France and Brazil, with the opportunity to develop complementary expertise in Solution Blow Spinning and advanced hybrid biomaterial design. The results will be disseminated through scientific publications and presentations at international conferences.