Skin loss through non-fatal burns and ulcers are a leading cause of morbidity, including prolonged hospitalization. It is often poorly managed, requiring the frequent changing of single-use wound dressings. This generates a significant amount of contaminated waste globally that is either incinerated or disposed of in landfill. The complexity of burn and chronic skin ulceration wound healing, compared to other skin injuries, requires the development of sustainable and advanced regenerative wound dressings. This proposal aims to develop a biodegradable 3D bioprinted hydrogel wound dressing. This device will encapsulate immortalized foetal keratinocytes and fibroblasts or their extracted secretome. The secretome can accelerate wound healing by inducing the stimulation of skin stem cells. The wound dressing will provide controlled therapeutic levels of biomolecule delivery, protection from wound-secreted proteases, and an external abrasions safeguard. The device will employ engineered biodegradable and compostable biomaterials, contributing to the transition from a major waste stream to a sustainable alternative wound healing device.

The current therapeutic options for chronic pain are limited and often come with significant side effects, including the potential for addiction. To address this challenge, the MyPainkiller project focuses on harnessing a natural product derived from actinomycetes, known as mycolactone, which has demonstrated potent long-acting pain-relieving properties at doses one thousand lower than morphine in rodents. Advantageously, mycolactone does not impede motricity. By formulating mycolactone into poly-cyclodextrin-based nanoparticles (referred to as pCD-ML), we have dramatically improved its physicochemical properties, positioning it as a promising drug candidate for pain management. This innovative product, recently patented by our institutions (INSERM / CNRS), marks the culmination of collaborative efforts among four multidisciplinary teams over the past decade: IPL (Institut Pasteur de Lille), ISMO (Institut de Sciences Moléculaires d’Orsay), INCIT (Immunologie et Nouveaux Concepts en Immunothérapie, Nantes), and IGF (Institut de Génomique Fonctionnelle, CNRS, Montpellier). Building on this strong foundation, our project aims to address key gaps in mycolactone's development. Firstly, we will focus on assessing the long-term stability of pCD-ML formulation, its tissue diffusion, and early ADME (absorption, distribution, metabolism, and excretion) characteristics. Advanced techniques, such as MALDI-MS imaging and 13C-labeling of mycolactone, will be employed to investigate tissue diffusion and to detect metabolites. Secondly, we will decipher the mechanisms by which the pCD carrier potentiates the mycolactone analgesic properties. Given recent research on the involvement of AT2R (Angiotensin II Receptor Type 2) in mycolactone's effects, we will delve into its engagement at the cellular and subcellular levels. This entails deciphering the signaling pathways involved in mycolactone's action within neurons, macrophages, and their interplay, leveraging innovative technologies like APEX for intracellular signaling analysis and primary macrophage-neuron co-cultures coupled with image-based analysis. Finally, we will evaluate the efficacy of the pCD-ML formulation in three mouse models of peripheral pain, building upon previous experiments with mycolactone alone. This collaborative effort represents an opportunity to bridge complementary expertise and overcome barriers together. MyPainkiller project aims to meet the urgent societal need for effective pain management and to provide solid foundation for the establishment of a public-private partnership for further preclinical development of the product.

Multi-resistant bacteria regularly emerge throughout the world. They can be found in soldiers' wounds and in health care facilities where they cause nosocomial diseases. Some of these bacteria have become resistant to the best products available to treat multi-resistant bacteria. The consequences can be serious for the patients affected: prosthetic replacement, amputation or even death; but also for society with high induced costs. In general, there are no antibiotics currently available for clinicians for which no bacterial resistance has been reported. However, despite the introduction of 30 new antibiotics since 2000, the pipeline of new drugs for all pathogens is drying up. It is therefore essential to explore new approaches to the development of innovative antibacterial approaches. Innate immunity is the first-line barrier to prevent microbial invasion. The aim of this dual project is to develop multispecific proteins capable of stimulating cells of the innate immune system to inactivate two pathogenic bacteria of defence/civil interest. This innovative approach will help to reach bacteria regardless of their antibiotic resistance status and therefore those against which no effective antibiotic is available. It also offers the potential to be transposable to other pathogenic bacteria.

Our project focuses on the regulatory properties of a subset of microbiota-specific TR1-like regulatory T (Treg) cells, for which we have already shown an unprecedented association with the clinical outcome of patients in various inflammatory diseases, for a therapeutic use in inflammatory bowel diseases (IBD). IBD is a disabling chronic inflammatory process that affects young individuals and causes many life-altering symptoms, and represents a risk factor for colon cancer. Existing treatments are complex, with most people requiring lifelong medications as well as dietary and lifestyle modifications, and some requiring surgery. In this context, the development of new therapeutic approaches appears essential and immunotherapy and cell-based therapy are particularly promising strategies for this disease. Teams from Nantes have a strong expertise in the field of human immunology, mucosal immunology and immunotherapeutic strategies applied to various pathological conditions, including gut inflammatory diseases. They recently identified a novel microbiota-induced Treg subset, associated with good prognosis in IBD patients, thus representing a promising candidate for innovative immunotherapeutic approaches. Based on the limitation to develop immunotherapy approach for human diseases by using animal models due to immune system specificities/differences and ethical considerations, we opted for the development of an ex vivo human preclinical model that will reconstitute the physiological complexity of the human gut. Teams from Strasbourg have a strong experience and already set-up models of organoids in different pathological systems, that will perfectly fit to be used as ex vivo preclinical models for this project. This proposal aims thus at providing a pre-clinical package including i) the proof of concept that a cellular immunotherapy using the identified Tregs subset represents a treatment for IBDs and ii) the reglementary pre-clinical in vitro and in vivo toxicity.