Leading to disability and morbidity, neurodegenerative disorders (NDs) have a profound socio-economic impact. Given the aging of the population, they are raising remarkable concerns. Several active compounds for NDs treatment showed promising results in-vitro but failed in-vivo due to unfavorable biodistribution and limited biocompatibility. The nanocarriers (NC) proposed in the last decade have certainly improved brain delivery of active compounds, however, the limited bioavailability of the drug and biocompatibility issues make NDs treatment still a hot topic in neuroscience. With BRAVERY, I aim to achieve the spatiotemporal controlled drug release improving the bioavailability of neuroactive compounds in the brain without causing neurotoxicity. To do so, I propose to develop a novel biocompatible multi-drug NC capable of efficiently targeting the brain and releasing the loaded drugs in a controlled manner in response to specific stimuli, after intranasal administration. The proposed NC has three fundamental features: 1) It is mucoadhesive; 2) It degrades in response to two specific stimuli that allow achieving a spatiotemporally controlled release of the carried drugs in the brain; 3) Both NC and products of its degradation are biocompatible, thus limiting neurotoxicity. The biocompatibility and biodistribution of the NC will be evaluated by in-vitro, in-vivo, and ex-vivo analysis. As a proof of concept, the carrier will be loaded with active compounds and the biological effect observed will be compared with the one achieved by the free drugs. The project could have an immediate impact on NDs treatment improving the biological efficacy of the anti-prion protein drug used in this project as model drug. Such a versatile biocompatible multi-drug NC will pave the way toward a new era of NDs treatments, with a remarkable impact on society and health care systems worldwide.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are widespread in EU and worldwide, and put substantial burden due to disability, mortality, high cost of treatment, and risk for development of cardiovascular diseases (CVD). Both CKD and AKI are projected to grow due to many factors, including general population aging and increase in diabetes prevalence. Evaluating global and EU regional epidemiology of CKD and AKI is extremely important for understanding current trends and future challenges, and revealing differences of kidney disease in diverse populations. The current proposal is aimed to develop a single database and bibliographic web-based tool for collecting available evidence on CKD and AKI epidemiology worldwide; develop and apply bibliographic search strategy to obtain literature sources and extract multiple epidemiologic parameters for CKD, AKI, and their connection to CVD; produce advanced models for CKD and AKI estimates on the global, regional, and country levels; strengthen existing international collaboration in studying CKD and AKI epidemiology; disseminate results to scientific community, public health authorities, and general public; increase future competiveness and prepare ER for tenure-track position in academic institutions in the EU-member states. The proposal assumes inter-disciplinary approach and international cooperation, contains several innovative elements, intended to produce multiple new deliverables, strength EU-based research, provide substantial career development for the researcher. Major issues in the proposal are directly related to consequences of population aging and increasing the burden of chronic diseases, as well as interconnections between acute and chronic diseases. The results are expected to provide important information for public health planning in EU and worldwide for comparing morbidity, mortality, and provision of medical care.

This proposal aims to capitalize on my unique multi-disciplinary expertise in nanotechnology, tissue engineering, polymer/inorganic hybrids, and microsurgical techniques, while acquiring new proficiencies in the creation of breakable hybrid organosilica nanocapsules, mesoporous silica nanoparticles, and nanocomposite hydrogels. I am driven to tackle the unmet needs, opportunities, and challenges in the fields of nanocomposite hydrogel design and nervous system repair by combing my current expertise with these new proficiencies to innovate nanocomposite hydrogels that are environmentally and spatially actuable. Specifically, the goal of my proposal is to pioneer spatially distinct and environmentally responsive actuation of nanocomposite hydrogels in response to matrix metalloproteinase-9 (MMP-9) peptide cleavage, focusing on applications in peripheral nerve repair. In order to achieve this ambitious objective, I will develop MMP-9 degradable polyethylene glycol (PEG)/mesoporous silica nanoparticle composites and MMP-9 breakable organosilica nanocapsules through the incorporation of MMP-9 cleavable peptides into silica nanoparticle structures. MMP-9 can therefore be used to induce: 1) hydrogel degradation, 2) release of encapsulated therapeutics, and 3) capture of molecules by cleaved nanoparticle scavengers. This proposal details a highly interdisciplinary approach to create a plug-and-play nanocomposite hydrogel system to overcome obstacles needed to improve regeneration outcomes by combining neuroscience and microsurgical nerve repair with chemistry, drug delivery, biomaterials science, and tissue engineering. Finally, nanocomposite nerve guidance conduits will be tested in a peripheral nerve injury model to demonstrate in vivo MMP-9 actuation of these hydrogels.

Many therapeutic applications of stem cells require accurate control of their differentiation. To this purpose there is a major ongoing effort in the development of advanced culture substrates to be used as “synthetic niches” for the cells, mimicking the native ones. The goal of this project is to use a synthetic niche cell culture model to test my revolutionary hypothesis that in stem cell differentiation, nuclear import of gene-regulating transcription factors is controlled by the stretch of the nuclear pore complexes. If verified, this idea could lead to a breakthrough in biomimetic approaches to engineering stem cell differentiation. I investigate this question specifically in mesenchymal stem cells (MSC), because they are adherent and highly mechano-sensitive to architectural cues of the microenvironment. To verify my hypothesis I will use a combined experimental-computational model of mechanotransduction. I will a) scale-up an existing three-dimensional synthetic niche culture substrate, fabricated by two-photon laser polymerization, b) characterize the effect of tridimensionality on the differentiation fate of MSC cultured in the niches, c) develop a multiphysics/multiscale computational model of nuclear import of transcription factors within differentially-spread cultured cells, and d) integrate the numerical predictions with experimentally-measured import of fluorescently-labelled transcription factors. This project requires the synergic combination of several advanced bioengineering technologies, including micro/nano fabrication and biomimetics. The use of two-photon laser polymerization for controlling the geometry of the synthetic cell niches is very innovative and will highly impact the fields of bioengineering and biomaterial technology. A successful outcome will lead to a deeper understanding of bioengineering methods to direct stem cell fate and have therefore a significant impact in tissue repair technologies and regenerative medicine.