Giant congenital diaphragmatic hernia is a rare congenital malformation with a high morbidity and mortality rate even today despite the fabulous progress of neonatal resuscitation and antenatal follow-up. These advances have made possible to bring increasingly severe forms of hernia to surgery, requiring the development of new research and progress in the field of surgical repair. Currently, these hernias are treated surgically during the first week of life in specialized hospital and university centers by interposition of a prosthesis in the vast majority of cases. Almost 30% of these children will present a release of this prosthesis during their childhood significantly increasing the morbidity and mortality of this congenital malformation throughout the development of the child; this makes it a priority axis of the national rare disease plan with the designation of reference center (CHU de Lille, collaborator of this project) and competence centers (CHU Strasbourg, project leader). In recent years, we have been able to prove the link between recurrence by releasing the prosthesis and certain non-optimal biomechanical characteristics of prostheses currently used in hospitals: insufficient colonization and lack of neoangiogenesis covering these prostheses, mechanical properties unsuitable for growing organisms. The DIAPID project aims to develop new prostheses responding to this double challenge: - better adapted mechanical properties: better stretchability thus adapting to the growth of the child while maintaining good mechanical resistance thanks to the electrospinning process of materials meeting the requirements of a medical device) - and a monolithic bifacial structure with a dual objective: to limit the colonization of the implant by the host on the abdominal side of the prosthesis and to optimize this colonization and rapid neoangiogenesis on the thoracic side for lasting tissue integration. The encouraging preliminary results allow us to propose a design of prostheses with a fibrous and functionalized face on the thoracic side and optimal biomechanical characteristics theoretically limiting the risks of release during childhood and therefore the morbidity and mortality of this pathology. The first results in mechanical and biological analysis must be deepened by additional experimental tests ex vivo and then in vivo on large animals. The strength of this project lies in having been able to combine the skills of laboratories and researchers in complementary fields of expertise with, on the one hand, pediatric surgeons recognized for their expertise in the field of this rare disease, researchers specializing in electrospinning, in biomechanics, bioengineering, biological functionalization and finally the reference center for diaphragmatic hernias having developed an animal model of diaphragmatic hernia.

The fast spread of multi-resistant microorganisms represents a threat to public health that urgently needs new therapeutic approaches less prone to the development of resistant strains. Our objectives are the design, synthesis and in-depth biophysical studies of new antimicrobial peptide-photosensitizer (AMP-PS) conjugates for synergistic and selective inactivation of pathogens. The chosen AMPs will selectively drive the porphyrinic PS inside the bacteria while near IR light excitation will destroy them by creation of reactive oxygen species (ROS), without inducing bacterial resistance or damage to host tissues. This photoinactivation approach provides a promising treatment for chronic skin and periodontal infections. Thus, an AMP-PS hydrogel will be developed for topical applications. A consortium of three partners specialized in peptide and porphyrin synthesis, biophysical and antibacterial studies, and design of biomaterials, will provide the skills and implementation necessary for the success of the project.

Supramolecular materials can be considered as living chemical systems since they rely on non-covalent, dynamic bonds and can thus be responsive to external stimuli. Yet the drawback of the weakness of the interactions between the constituting molecules is that the materials often show weak mechanical strength. This difficulty has been circumvented by incorporating supramolecular hydrogels into "permanent" (host) gels (agarose for example). The non-permanent character of supramolecular assemblies has judiciously been exploited by nature allowing cells to respond to their environment: actin fibers play an essential role in cell motility for instance. Nature controls the supramolecular assembly both in space and time through enzymatically initiated self-assembly, the enzymes transforming locally proteins from a "non-interacting" into an 'interacting" state. Spatial control of these self-assemblies is carried out by specific localization of enzymes (i) at biological interfaces or (ii) through local concentration gradient distributions in cells or tissues. Temporal control is ensured by production of enzymes at a suitable moment. Such processes can be mimicked by using enzyme-assisted self-assembly (EASA). In EASA, enzymes are used to transform non self-assembling molecules into self-assembling ones and initiating the formation of supramolecular networks. Our goal is to develop a new generation of dynamic and spatially structured hydrogels based on EASA of low molecular weight hydrogelator (LMWH), such as peptides, taking place in host gels and leading to supramolecular networks interpenetrated with the host hydrogels. In addition our goal is to localize the self-assembly processes by distributing the enzymes in a predefined manner in the host gel or around functionalized mesoscopic particles embedded in the host gel. This should allow introducing supramolecular network gradients extending over length scales ranging from centimeters down to a few 100 nanometers within the host gel. The presence of a network in the host gel should also change its mechanical properties over such length scales. Mechanical properties are important parameters guiding cell adhesion processes and stem cell fate. Both aspects will be investigated featuring interesting applications in tissue engineering. Based on our strong expertise and also our very recent developments in the trigger and control of supramolecular networks under the action of alkaline phosphatase we will use this enzyme to localized the self-assembly of LMWH within a host hydrogel. We will use hydroxypropylmethyl cellulose (HPMC) functionalized with silanol groups as host gels because they proved to be very weakly interacting with cells. This will allow initiating cell interactions specifically through the supramolecular network. New types of HPMC gels incorporating hyaluronic acid will also be developed in order to render the host gels degradable in time for cell development within the material. We will in particular investigate the effect of network gradients on cell migration processes and how the supramolecular network can be used to guide stem cell differentiation with embedded cells. The great interest of our gels is that their properties can be tuned both in space (localized EASA) and in time by programmed addition of peptides onto the host gel. This opens new opportunities for cell guidance that will be explored. The EASA project relies on the complementarity of three research groups: one expert in surface chemistry and supramolecular assembly (ICS UPR22-CNRS), a second one who developed highly suitable hydrogels (HPMC) for cell viability over very long times (INSERM U1229) and a last one who has a strong experienced in biomaterials and tissue engineering (INSERM U1121).

Pulp pathologies generated by infectious diseases or by trauma have an impact on the maintenance of the integrity of the dental organ and thus its function in the long term. Indeed, the treatment of these pathologies is still based on care techniques, root canal treatments, which do not allow the healing of the damaged tissue. The tooth therefore loses its biological response to future attacks. Currently, many protocols are being studied to preserve and restore the integrity of the dental pulp. These protocols are based on the use of materials with a bioactive potential as well as on the local control of the tissue reaction through the formation of a blood clot. We are therefore witnessing a paradigm shift in endodontics. However, for the time being the proposed therapies are limited by their clinical indications (partial pulpectomy, apexification of immature teeth). Part of the problem is therefore not yet solved. This is particularly the case when there is a lesion of the entire pulpal tissue on a mature tooth and endodontic treatment is still indicated. The RooTRaCE project addresses this issue by testing and understanding a new mode of treatment whose goal is to generate healing of the pulp tissue. The project is based on the advances already obtained by several international teams on the subject, showing in particular that a material is necessary in these therapeutics. The idea is therefore to develop a medical device in the form of a cone that could be inserted into the canal of a tooth following a conventional root canal preparation, which could support the formation of a blood clot in the first instance and then the formation of a replacement neo tissue. It is therefore a project at the frontier of materials science and biology. It aims to develop a new material in our case: electrospinned polymers (PLA and PCL to form a three-dimensional structured architecture) mixed with tannic acid (for its antibacterial properties). It is also intended to study the secretion of a blood clot. The study of the elements released by a blood clot and their repercussions on the stem cells surrounding the tooth is essential not only for our project but also to understand the messages underlying the techniques currently in use so that they can be made more effective and safe. The project ranges from material development to in vivo testing in a mouse model. It is intended to be the prerequisite for an in vivo study on large animals, which is the only animal model currently available to simulate endodontic treatment. At the end of this project we should therefore have a prototype of a cone that can be used in a dental practice to allow the realization of a root treatment to reach the regeneration of the dental pulp. We will also have the elements to understand the biological events allowing pulp healing. We will therefore be able to share these advances with other groups working on this tissue.

Background : Head and Neck cancers are common, 4th ranking in terms of incidence. Total (pharyngo) laryngectomy (T(P)L) is a common surgery for the treatment of pharyngo-laryngeal cancers and results in the definitive separation of the respiratory and digestive (neo-pharyngeal) tracts. The main issue with this surgery is salivary fistula (SF) (incidence of 20 to 65%), causing leaks of saliva between the sutures of the neo-pharynx. One of the main risk factors is a history of irradiation. Saliva, by flowing into the neck, causes high morbidity i.e. increased length of hospitalization, surgical revision, risk of vascular rupture and death i.e. incidence of carotid blowout syndrome around 3%. There is no current solution to reduce the incidence of SF. Objectives and means: The BIOFISS project aims to develop an innovative biomaterial (MD) in the form of a double-layer film based on biopolymers, alginate and chitosan, for the prevention of SF. The project brings together a suitable consortium with a hospital specialized in oncology (IUCT-O), 2 academic research laboratories specialized in biomaterials (CIRIMAT and INSERM UMR 1121) and 2 industrial partners (RESCOLL and Brothier) including a MD manufacturer specialized in alginate, one of the constituents of the MD. This project is based on preliminary results concerning the design of alginate-based biomaterials (CIRIMAT laboratory). The 4 main objectives of the BIOFISS project are 1) development of MD to obtain the physico-chemical and biological properties suitable for the prevention of SF; 2) characterization of its in vitro properties (biocompatibility, mechanical properties, bioadhesion, degradation time); 3) in vivo evaluation; 4) transfer and valorization Materials and Methods: This project is planned over a total of 48 months and is divided into 5 scientific axes (WP): 1. WP0: project coordination (IUCT-O/all partners) 2. WP1: Optimization of MD for SF prevention with 2 tasks: 1) development of the impermeable layer; 2) development of the absorbent layer. This axis will be coordinated by CIRIMAT using the technologies of RESCOLL and INSERM UMR 1121. Brothier will provide the alginate and will contribute its knowledge on these materials. 3. WP2: in vitro characterization of the physicochemical properties of MD; this axis will be coordinated by INSERM 1121 in collaboration with CIRIMAT. 3 tasks will be carried out: 1) evaluation of biocompatibility; 2) evaluation of healing properties; 3) evaluation of antimicrobial properties. 4. WP 3: in vivo evaluation (IUCT-O) with 4 tasks: 1) evaluation of biocompatibility and bioadhesion in a rat pharyngotomy model; 2) development of an irradiated mini-pig model; 3) development of a laryngectomized mini-pig model; 4) evaluation of the efficacy of MD on laryngectomized pigs with or without irradiation with a control group. 5. WP4: Evaluation of results, transfer and valorisation of technologies (Brothier laboratory) Expected results: In accordance with the ANR Call for Proposals, the goal of our project is to design an innovative MD aimed to reduce the rate of SF in T(P)L patients undergoing T(P)L surgery. Based on a strong consortium, all data collected during the project will provide evidence of the efficacy and safety of the new MD for the initiation of a clinical trial in the prevention of the risk of SF after neck surgery. The field of use of the biomaterial could be wider than the T(P)L, i.e. useful for many cervico-facial surgeries (cancer or not) or even in digestive surgery. BIOFISS will make it possible to perpetuate the collaboration between industrial partners for the commercialization of this new biomaterial. A new production line, which will require the recruitment of qualified personnel, will be created within Brothier for the manufacture of this new MD.