A fundamental limitation with current approaches aiming to bioprint tissues and organs is an inability to generate constructs with truly biomimetic composition and structure, resulting in the development of engineered tissues that cannot execute their specific function in vivo. This is perhaps unsurprising, as many tissues and organs continue to mature postnatally, often taking many years to attain the compositional and structural complexity that is integral to their function. A potential solution to this challenge is to engineer tissues that are more representative of an earlier stage of development, using bioprinting to not only generate such constructs, but to also provide them with guiding structures and biochemical cues that supports their maturation into fully functional tissues or organs within damaged or diseased in vivo environments. It has recently been demonstrated that such developmental processes are better recapitulated in ‘microtissues’ or ‘organoids formed from self-organizing (multi)cellular aggregates, motivating their use as biological building blocks for the engineering of larger scale tissues and organ. The main goal of micro2MACRO (m2M) is to develop a new bioprinting platform capable of spatially patterning numerous cellular aggregates or microtissues into scaled-up, personalised durable load-bearing grafts and guiding their (re)modelling into fully functional tissues in vivo within damaged or diseased environments. This will be achieved using a converged bioprinting approach capable of rapidly depositing cells and microtissues into guiding scaffold structures with high spatial resolution in a rapid, reliable, reproducible and quantifiable manner. These guiding structures will then function to direction the fusion and remodelling of cellular aggregates and microtissues into structurally organised tissues in vitro and in vivo, as well as providing medium-term (3-5 years) mechanical support to the regenerating tissue.

InterLynk aims to develop multi-tissue 3D patient-specific scaffolds by providing a portfolio of highly compatible and biofunctional composite inks and biomaterials, and streamlining their co-processing using an upgraded AM equipment. Unprecedented biofunctionality in the synthetic reconstruction of complex interfacial tissues is expected to be obtained. A double network photocrosslinkable biomaterial system based on human plasma-derived Platelet Lysates (PL) will be used as base matrix. The PL-based hydrogels will be further combined with mechanically reinforcing biomaterials, namely CaP-based bioceramics and PCL-LA polymers, to produce bone-like and fibrous structures, respectively, and will be able to be blended with natural drug carriers (flavonoid-loaded nanomicelles). Compositional and structural variations will be enabled by combining photo-assisted printing and MEW/ESP in a single-step hybrid AM process. New computational tools will support the mechanobiological optimization of all biomaterials and final parts, as well as the AM process design. Superior biofunctionality of the InterLynk’ scaffolds will be validated in an highly complex multi-tissue interfacial biosystem, the temporomandibular joint. InterLynk will implement comprehensive strategies to engage key groups of stakeholders (clinical, engineering, regulatory and market-related) in the development of biological scaffolds, establishing a truly multidisciplinary co-creation process. These scaffolds are expected to have no counterpart in both fabrication and multi-tissue regeneration, avoiding time-consuming and costly procedures in both dimensions. This will increase current AM (bio)fabrication capabilities and application range, widely extending its use. Their high flexibility and unique performance will considerably reduce immune rejection, risk of contamination and, inherently, rehabilitation time of multi-tissue injuries resulting in increasing wellbeing and healthcare costs reduction.

Metatissue is focused on the design, production and commercialization of chemically modified human-derived proteins to prepare hydrogels, sponges and bioinks to improve 3D cell culture and disease modelling for drug discovery and development, tissue engineering, and personalized medicine advancements. Metatissue has developed a bioactive platelet-rich plasma derivative precursor that can be cured upon light exposure to form soft materials with tunable mechanical properties. Such materials provide functional support for cell growth and interact with cells to control their function, guiding the process of tissue morphogenesis. This platform is the first to offer complete human-based material for 3D cell culture and an easy-to-use solution for clinical purposes. This deep technology enables researchers to culture human cells in a physiologically relevant microenvironment for applications in cell culture research, drug screening and development, cancer research, tissue engineering, replacement of animal testing and therapeutic applications. This technology will have a significant impact on the 3D cell culture market and pharmaceutical industry by accelerating drug screening and development reducing associated costs.These materials present an alternative to the gold standard materials that are currently used in cell culture assays, which generally comprise animal-derived proteins that form a gel under corporal conditions. TechTissue intend to achieve the current Metatissue strategy by exploiting its business opportunity and setting a successful business strategy and commercialization plan based on the technical optimisation of the product, the assessed market requirements, the end-user needs and the competitor analysis.

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.

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.