According to the WHO Osteoarthritis (OA) is one major course of years lived with disability in the elderly and considered a high burden disease, which makes it a research priority in Europe. There is no cure for OA and SoA treatments need to be reconsidered. Current pharmacological interventions consist of analgesic, anti-inflammatory drugs as well as intraarticular steroids and hyaluronic acid (IA-HA) with moderate efficacy and associated long-term side effects. New medications are thus needed both to alleviate pain and slow down disease progression. Taking advantage of the explosion of RNA technologies in the last years, SINPAIN aims to develop a pipeline of siRNA-based therapy built on the combination of current technologies (dyanmic IA-HA and nanocarriers) that will be designed step-by-step in order to reach a successful management of inflammation and innervation therapy for the treatment of early (grade 0-1) and later stages (grade 3-4) of knee osteoarthritis (OA). To do so, a nanoformulation composed of functional IA-HA that can be loaded with vectors, for the delivery of siRNA targeting IL1? and NGF, and nanocarriers will be developed. In parallel, large effort will focus on understanding the pathological mechanisms of OA. To validate efficacy in relevant potency assays, 3D coculture models will be developed with human cells and tested in unique bioreactors mimicking joint environment and biomechanics. With the identified cell targets, IA-HA will be modified with immunomodulator peptide which will activate the adaptive immune response, responsible for OA regeneration. The 4 pipeline products of SINPAIN will be validated in vivo in a relevant OA model with SoA techniques that will demonstrate the reduced inflammation and pain, as well as the cartilage regeneration for the last product. Taking advantage of all the data obtained during the project, a decision-making tool based on machine learning will be validated to offer patients a personalized therapy.

Due to life style changes and ageing of our industrialized nations, bone traumatic injuries and osteoporosis induced fragile fracture are an enormous medical and socio-economic challenge. State-of-the-art therapies have failed until now in keeping their promises of reliable bone regenerative solutions. The cmRNAbone project aim to create a novel bone regenerative therapeutic approach based on combination of chemically modified RNAs (cmRNAs)-vectors embedded in a 3D-printed guiding biomaterial ink tailored to patients need. To achieve our goal, sema3a, vegf, pdgf-bb and bmp7 cmRNAs targeting neurogenesis, vasculogenesis and osteogenesis will be synthesized, vectors based on lipids and polysaccharide nanocapsules for the delivery of cmRNAs will be developed. A functional Hyaluronan-Calcium Phosphate biomaterial ink that 1) can be loaded with cmRNAs-vectors and release them, 2) having intrinsic osteoinductivity and presenting laminin-derived peptides for guiding sensory neurons and endothelial cells ingrowth, and 3) being amenable to an extrusion-based 3D-bioprinting process will be formulated in conjunction to a 3D-printer for fabrication of patient specific regenerative solution. In the following step, a large effort will focus on deciphering regenerative mechanisms and optimizing dosage and ratio of cmRNAs, loading of cmRNAs-vectors in the ink, 3D-printing, etc, to demonstrate regenerative capabilities in vitro and in vivo. Selected candidate formulations will be taken to clinically relevant preclinical proof of concepts. Finally, an overreaching effort on preparing a 1st in human trial will be taken, consisting on partners facilities auditing and clinical experts group support, etc, to ensure that GMP-like production for all regenerative tools, and regulatory and commercial strategies are realized.

The management and reconstruction of bone defects is a significant global healthcare challenge. While autografts offer ideal compatibility, they are often not suitable for large bone defects, and allografts suffer from potential immunorejection.The limited efficacy of conventional treatment strategies for large bone defects and the increasing aged population, has inspired the consortium to propose a SMART RESORBABLE BONE (SRB) IMPLANT embedding stem cells and bioactive agents with the aim of a controllable and fast restoration. The proposed solution includes 3D printed medical grade polymers enriched with electrospun fibers (for increased mechanical properties) that can be customized for patient physiology, pathology, and gender. The scaffold design will ensure easy and minimal Injury placement, and will embed different sensors for monitoring e.g. pressure, pH value and temperature based on biocompatible conductive inks. The smart implant will thus be able to provide vital information of implant performance in terms of bone growth and infection/inflammation. The proposed method is unique because it includes a customized smart implant (3D printed parts with adjustable sensors and communication electronic system), together with tissue engineering methods i.e. in-vitro programming of stem cells for embedding into the smart implant. The proposed solution introduces an innovative regenerative chain, from early testing and characterization (identification/adjustement of the proper specifications) and embedding regenerative stem cells and particulate bioactive agents into the smart implant in preclinical research (in-vitro). The in vivo proof of concept of SBR solution will be tested in (large animal model) preclinical studies within the scope of the project. Finally the regulatory and commercialization strategy on how to further explore the proposed concept and deliver it for clinical testing will be elaborated.