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Coronary stent -in-a-box and -on-a-chip Development and innovation of alternatives to swine coronary stent models for preclinical cardiovascular research.

Projectomschrijving

Ronde 2017 Module Maatschappelijke Partners: Het Erasmus MC, de TU Delft en de Lifetec Group gaan gezamenlijk proefdiervrije vaat- en celkweek-modellen ontwikkelen die de gezonde en zieke menselijke bloedvatwand nabootsen. Aderverkalking blijft wereldwijd een belangrijke oorzaak van sterfte. Het leidt tot klachten bij vernauwde bloedvaten, en een hartinfarct bij plotse afsluiting, meestal door een stolsel. De meest gebruikte therapie is implantatie van medicijn afgevende stents. Deze stents herstellen de bloedstroom al heel goed, maar het kan nog beter en veiliger. Verbeteringen, van nieuwe medicijnen tot betere medicijndragers, worden meestal eerst op veiligheid en effectiviteit bestudeerd in diermodellen. Dat moet anders, vinden de onderzoekers. Door ontwikkeling van nieuwe modellen, waaronder miniatuur bloedvaten in de zogenaamde “organ-on-a-chip”, willen ze onderzoek naar medicinale stents niet alleen met minder proefdieren uitvoeren, maar ook nog eens sneller en beter. Dit doen ze de komende vier jaar met steun van ZonMW.

Producten

Titel: Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model
Auteur: Francesca Razzi Jouke Dijkstra Ayla Hoogendoorn Karen Witberg Jurgen Ligthart Dirk J Duncker Jan van Esch Jolanda J Wentzel Volkert van Steijn Gijs van Soest Evelyn Regar Heleen M M van Beusekom
Magazine: Scientific Reports
Begin- en eindpagina:
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314904/
Titel: An Implantable Artificial Atherosclerotic Plaque as a Novel Approach for Drug Transport Studies on Drug-Eluting Stents
Auteur: Francesca Razzi Matija Lovrak Dovile Gruzdyte Yvette Den Hartog Dirk J Duncker Jan H van Esch Volkert van Steijn Heleen M M van Beusekom
Magazine: Advanced Healthcare Materials
Begin- en eindpagina:
Link: https://onlinelibrary.wiley.com/doi/epdf/10.1002/adhm.202101570
Titel: COMBINATION OF OPTICAL COHERENCE TOMOGRAPHY AND MALDI MASS SPECTROMETRY IMAGING TO CHARACTERIZE CORONARY ARTERY LIPIDS IN AN ATHEROSCLEROTIC SWINE MODEL
Auteur: Francesca Razzi Nuria Slijkhuis Dirk-Jan Duncker Jolanda Wentzel Volkert Van Steijn Gijs Van Soest Heleen Van Beusekom
Link: https://eas-congress.com/2022/#
Titel: Viability of coronary arteries cultured in an ex-vivo vascular bioreactor
Auteur: F Razzi A Van Der Giessen DJ Duncker M Stijnen V Van Steijn HMM Van Beusekom
Link: https://academic.oup.com/cardiovascres/article/118/Supplement_1/cvac066.037/6605415
Titel: Tissue composition influences drug concentrations as revealed by MALDI-MSI
Auteur: Francesca Razzi Heleen van Beusekom Volkert van Steijn
Link: https://iccvs.ug.edu.pl/blog/13th-mass-spectrometry-school-in-biotechnology-and-medicine-msbm/
Titel: Histologic Validation of AI-Based Plaque Characterization on Intravascular Optical Coherence Tomography
Auteur: Miao Chu, Francesca Razzi, Giovanni Luigi De Maria, Stefano Benenati, Jason Chai, Wei Yu, Juan Luis Gutiérrez-Chico, Volkert van Steijn, Shengxian Tu, Heleen van Beusekom
Link: https://www.jacc.org/doi/abs/10.1016/j.jacc.2023.09.273
Titel: Development of an Ex-Vivo Vascular Bioreactor to Investigate Viability of Coronary Arteries
Auteur: Francesca Razzi, Marco Stijnen, Dirk J Duncker, Volkert van Steijn Heleen M Van Beusekom
Link: https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.14766
Titel: Relation between pre-existing plaque size and neointimal healing in an adult porcine model of familial hypercholesterolemia
Auteur: F Razzi, E Regar, J Dijkstra, K Witberg, J Ligthart, S.A Ramlal, M Stam, I Krabbendam-Peters, A Hoogendoorn, D.J Duncker, J Van Esch, J.J Wentzel, G Van Soest, V Van Steijn, H.M.M Van Beusekom
Link: https://academic.oup.com/eurheartj/article/41/Supplement_2/ehaa946.2542/6004625
Titel: The relation between pre-existing plaque burden and strut coverage after DES implantation in familial hypercholesterolemia swine: an OCT study
Auteur: Francesca Razzi, Jouke Dijkstra, Karen Witberg, Jurgen Ligthart, Sharad Ramlal, Mathijs Stam, Ilona Krabbendam-Peters, Ayla Hoogendoorn, Dirk-Jan Duncker, Jan van Esch, Jolanda Wentzel, Gijs van Soest, Volkert van Steijn, Evelyn Regar, Heleen van Beusekom
Link: https://www.spiedigitallibrary.org/conference-proceedings-of-spie/11621/116210F/The-relation-between-pre-existing-plaque-burden-and-strut-coverage/10.1117/12.2582723.short?SSO=1
Titel: Is an Adult Familial Hypercholesterolemia, Swine Model Suited to Test Safety and Efficacy of Drug-eluting Coronary Stents?
Auteur: Francesca Razzi, Evelyn Regar, Jouke Dijkstra, Karen Witberg, Jurgen Ligthart, Sharad A ramlal, Mathijs Stam, Ilona Krabbendam-Peters, Ayla Hoogendoorn, Jolanda J Wentzel, Gijs van Soest, Jan Van Esch, Dirk J Duncker, Volkert van Steijn Heleen M Van Beusekom
Link: https://www.ahajournals.org/doi/abs/10.1161/circ.142.suppl_3.13819

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Samenvatting van de aanvraag

Coronary stent -in-a-box and -on-a-chip The development and innovation of alternatives to swine coronary stent models for preclinical cardiovascular research. Background. Cardiovascular disease is and remains a leading cause of death, taking 17.5 million lives per year. In the last decade, treatment with drug eluting stents (DES) has become an integral part of modern clinical practice. While the implantation of DES has significantly reduced the need for repeat revascularization as compared with non-DES, there is still room for improvement: stent failure in terms of long-term safety (i.e. late stent thrombosis and neo-atherosclerosis) and efficacy (i.e. re-narrowing) still occurs. Animal models. Swine coronary models are considered to be THE golden standard in cardiovascular stent research as the physiology of heart and vasculature comes close to humans. This allows the use of devices and techniques that are used in clinical routine. However, according to the FDA, 90-95% of drugs that pass animal tests fail to get to market. This is, in part, due to the lack of pre-existing disease in animal studies, and due to the failure to address differences in the background of the patient population such as age, sex, race and the presence of co-morbidities. Objective of the proposed work. The overarching aim is to innovate two existing 3R vascular models for human disease (ex-vivo and organ-on-a-chip-based) and implement these to study the effects of DES in healthy and disease mimicking circumstances to overcome the limitations of classical animal models. To develop and validate these innovative models, a multidisciplinary team of experts has been brought together with expertise in preclinical stent and atherosclerosis research (van Beusekom, EMC), intravascular imaging (van Soest, EMC), advanced ex-vivo perfusion (Stijnen, LifeTec) with engineers on design and fabrication of lab-on-a-chip technology (van Steijn), and hydrogel engineering (artificial plaque, van Esch). The three main objectives are to: 1.innovate and validate an ex-vivo coronary perfusion model (VABIO, LifeTec) for acute and chronic stent studies (cell culture based) to reduce experimental animal use. a. we will use slaughterhouse swine coronary arteries that will be treated with DES and will be studied to determine the distribution of drugs in the arterial wall as released from the DES over a period of days to weeks. Results will be validated with data obtained from previous in-vivo animal studies (biobank material, backward validation). b. We will use the same coronary perfusion model to study drug distribution in human coronary artery specimen from hearts obtained during /following heart transplantation. 2. innovate the ex-vivo coronary perfusion models by mimicking disease states as observed in human diseased coronary arteries by implanting our recently developed “artificial plaque” in healthy swine coronary arteries. This data will then be validated using biobank material of atherosclerosis studies previously performed at Erasmus MC (backward validation) and by performing perfusion studies using diseased human arteries (forward validation) obtained from fresh hearts obtained during /following heart transplantation. 3. innovate the already developed organs-on-a-chip model of a coronary artery to enable using it to study (diseased) human arterial wall upon stenting. This completely animal-free approach will be used to study vascular response (remodeling) and drug transport following the placement of a drug eluting stents (DES). The beauty of these chips is that 1: human coronary artery cells can be used to build these devices and 2: large numbers of these devices can be manufactured to allow parallel studies. This system is ultimately intended as a “fast-forward” technology in the development and testing of DES and other local drug delivery strategies. It can essentially be implemented for studying general arterial transport phenomena such as systemic drug delivery and progression and regression of atherosclerosis. The future outlook is that it will allow mathematical modelling of arterial transport phenomena in the healthy and diseased artery wall, gearing this technology towards personalized lesion specific treatment strategies. To maximize the impact of the generated knowledge and developed technology, we will involve early on relevant stakeholders (industry, clinicians, patient organizations and regulatory bodies). Besides these knowledge utilization efforts, this work also contributes to raising the next generation researchers with the idea that many classical animal models are flawed in their design, and that innovative new models as the ones developed and validated in this project that mimic human disease are the preferred strategy and may well become the golden standard in effective preclinical testing.

Onderwerpen

Kenmerken

Projectnummer:
114021510
Looptijd: 100%
Looptijd: 100 %
2018
2023
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
van Beusekom
Verantwoordelijke organisatie:
Erasmus Medisch Centrum