Project

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ENTER: Engineering Technologies for the Rejuvenation of Endothelia

Applicant Ferrari Aldo
Number 188828
Funding scheme Project funding (Div. I-III)
Research institution EMPA
Institution of higher education Swiss Federal Laboratories for Materials Science and Technology - EMPA
Main discipline Other disciplines of Engineering Sciences
Start/End 01.01.2020 - 31.12.2023
Approved amount 541'192.00
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All Disciplines (3)

Discipline
Other disciplines of Engineering Sciences
Cellular Biology, Cytology
Clinical Cardiovascular Research

Keywords (6)

Biomaterials; Endothelial Cells; Surface Engineering; Senescence; Endothelial Inflammation; Endothelialization

Lay Summary (Italian)

Lead
Tecnologie ingegneristiche per il ringiovanimento dei tessuti endoteliali.
Lay summary

L’endotelio umano è formato da un monostrato di cellule che delinea i vasi sanguinei e linfatici. Svolge una funzione essenziale nel regolare l’interazione con il sangue, modulare la risposta immunitaria ed il trasporto di nutrienti ai tessuti. Un endotelio funzionale è capace di adattarsi ed integrare vari stimoli di natura biologica e meccanica, generati dal flusso sanguineo e da fattori circolanti. La funzione endoteliale deteriora con l’età, in un processo di invecchiamento che tipicamente accompagna le malattie cardiovascolari. Numerose evidenze sperimentali indicano che un contributo fondamentale al processo di senescenza è apportato dalla variazione, non fisiologica, delle condizioni emodinamiche. Laddove il flusso sanguineo è disturbato si incontrano con maggiore probabilità cellule la cui funzione è alterata. Queste regioni del sistema vascolare sono ad alto rischio di sviluppare processi infiammatori, che nel tempo portano alla perdita della copertura endoteliale ed alla conseguente formazione di placche arteriosclerotiche. Tali osservazioni supportano l’ipotesi che l’insieme di elementi meccanici che circondano le cellule, regoli il delicato equilibrio tra funzionalità endoteliale ed il suo declino nella senescenza.

Con queste premesse, lo scopo di ENTER sarà quello di selezionare, fabbricare e validare elementi razionalmente ingegnerizzati in grado di indurre un processo di ringiovanimento delle cellule e dei tessuti endoteliali. Tale piattaforma tecnologica farà uso di bioreattori per il controllo delle condizioni emodinamiche e di substrati sagomati con superfici controllate e proprietà meccaniche adattate al contesto fisiologico. Il processo di ringiovanimento verrà valutato tramite tecniche di microscopia ottica, metabolomica ed epigenetica. Il lavoro sperimentale permetterà di comprendere aspetti fondamentali della funzione endoteliale nei processi fisiologici e patologici. Inoltre, svilupperà e testerà una strategia rigenerative con potenziali implicazioni nel trattamento delle malattie cardiovascolari.

Direct link to Lay Summary Last update: 30.09.2019

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Abstract

Endothelia are connected monolayers of endothelial cells (ECs) lining human blood and lymphatic vessels. The healthy endothelium is a dynamic tissue that integrates mechanical and biological stimuli generated by the flow and by circulating molecular factors. It is naturally developed to inhibit thrombosis, modulate the response to infective agents and inflammatory insults, control the interaction with circulating cells, and re-establish confluency upon wounding. Endothelial function decays progressively with age, in a process of tissue senescence that typically accompanies cardiovascular disease (CVD). Disturbed hemodynamic conditions are among the signals supporting aging in ECs. In vivo, regions prone to flow recirculation or reversal typically feature senescent cells. These locations represent hotspots for the development of inflammatory processes, and are exposed to endothelial denudation and atherosclerosis, therefore indicating a link between senescence and the onset of disease. CVDs are the most common cause of death in industrialized countries including Switzerland. Perspective studies foresee an increasing trend of casualties associated with CVDs due to the ageing of the Western population. The deployment of a cardiovascular implant (vascular grafts and stents, and ventricular assist devices) represents the treatment of choice for many patients. Severe adverse events, including inflammation and thrombosis, are stirred by the interaction between artificial materials and blood. Complete and durable hemocompatibility can only be bestowed by a living autologous tissue covering the device’s luminal surface. The quest to obtain a healthy endothelium at the luminal surface of cardiovascular implants (i.e. the process of endothelialization) has therefore motivated intense research efforts. These investigations demonstrated that endothelialization requires a sufficient pool of ECs able to generate a healthy monolayer and maintain its in vivo integrity. Loss of endothelial function in cardiovascular patients has so far tainted the successful clinical application of endothelialization strategies for the long term integration of cardiovascular devices. Experimental evidence supports the hypothesis that the cell mechanical environment critically controls the balance between endothelial health and senescence. The aim of the ENTER project is the design, fabrication and validation of rationally engineered substrates for the rejuvenation of human endothelia. The technological platform will integrate on-demand hemodynamic conditioning in combined bioreactors with microengineered substrates prepared by lithographic techniques and featuring controlled surface topography and mechanical properties. The validation and exploitation of the proposed technology will be pursued by live-cell microscopy, molecular biology techniques, metabolomic and epigenetic analysis. The rejuvenation strategy will base on the following fundamental aspects:•A biomechanical fingerprint of endothelial function in health and disease. The typical response to hemodynamic loads, inflammatory insults, interaction with cellular effectors of inflammation, and local discontinuities in the monolayer will be investigated at different scales to reveal typical adaptive or maladaptive patterns and link them to the activation of inflammatory or protective molecular pathways. This activity will take advantage of ECs obtained from animal and human models of CVDs and senescence. •The rational development of combined mechanical and topographic stimuli to revert maladaptive endothelial responses (i.e. to rejuvenate) and develop or select a healthy cell population.•The validation of the rejuvenation process using patient specific human ECs. The work will significantly add to our fundamental knowledge on the biology of endothelia in health and disease. Additionally, it well develop and test a novel regenerative strategy with potential implications in the long-term integration of cardiovascular implants.
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