Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

Voisard, Rainer; Zellmann, Svenja; Müller, Fabian; Fahlisch, Felicitas; Müller, Lutz von; Baur, Regine; Braun, Jürgen; Gschwendt, Jürgen; Kountides, Margaratis; Hombach, Vinzenz; Kamenz, Joachim

doi:10.1186/1471-2261-7-15

Cited by 5 publications

(7 citation statements)

References 37 publications

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“…Interestingly, we did not detect a critical difference in lumen coverage, apoptosis or activation of the vessel wall in the two culture systems. This is not completely unexpected as the static culture was designed to replicate the vessel ring culture, with tissue specimens of 2-5mm in length (5,21-23). Previous studies have demonstrated that static culture of rings can be extended up to 56 days, and can be induced to form neointima post-injury, although we did not detect such a growth in our samples (22).…”

Section: Discussionmentioning

confidence: 99%

“…Besides the obvious ethical concerns, small rodent experiments have limited predictive capacity, resulting in the development of sub-optimal therapeutic strategies, leaving this critical medical need unmet (4). In vitro strategies for the study of vascular remodeling focus on 2D culture of vascular cells (typically smooth muscle cells) or the static culture of rings obtained from blood vessels, the latter importantly incorporates an element of intact extracellular matrix component, which is critical in the remodeling process (for an example (5)). Interestingly, some groups have demonstrated the successful use of flow bioreactors simulating the in vivo hemodynamic conditions, to culture blood vessels ex vivo and study vascular pathophysiology (6–9).…”

Section: Introductionmentioning

confidence: 99%

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3D printed bioreactor enabling the physiological culture and the study of pathological processes in large vessels

Matos

Maselli

McVey

et al. 2022

Preprint

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Routine cardiovascular interventions such as balloon angioplasty, result in vascular activation and remodeling, often requiring re-intervention. 2D in vitro culture models and small animal experiments have enabled the discovery of important molecular and cellular pathways involved in this process, however the clinical translation of these results is often underwhelming. There is a critical need for an ex vivo model representative of the human vascular physiology and encompassing the complexity of the vascular wall and the physical forces regulating its function. Vascular bioreactors for ex vivo culture of large vessels are viable alternatives, but their custom-made design and insufficient characterization often hinders the reproducibility of the experiments.The objective of the study was to design and validate a novel 3D printed cost-efficient and versatile perfusion system, capable of sustaining the viability and functionality of large porcine arteries for 7 days and enabling monitoring of post-injury remodeling.MultiJet Fusion 3D printing technology was used to engineer the ‘EasyFlow’ insert, converting a conventional 50 ml centrifuge tube into a mini bioreactor. Porcine carotid arteries either left untreated or injured with a conventional angioplasty balloon, were cultured under pulsatile flow for up to 7 days. Pressure, heart rate, medium viscosity and shear conditions were adjusted to represent the typical arterial physiology. Tissue viability, cell activation and matrix remodeling were analyzed by immunohistochemistry, and vascular function was monitored by duplex ultrasound.Physiological blood flow conditions in the EasyFlow bioreactor preserved endothelial coverage and smooth muscle organization and extracellular matrix structure in the vessel wall, as compared to static culture. Injured arteries presented hallmarks of early remodeling, such as intimal denudation, smooth muscle cell disarray and media/adventitia activation in flow culture. Duplex ultrasound confirmed physiological hemodynamic conditions, dose-dependent vasodilator response to nitroglycerin in untreated vessels and impaired dilator response in angioplastied vessels. We here validate a low-cost, robust and reproducible system to study vascular physiopathology, laying the basis for future investigations into the pathological remodeling of blood vessels and creating a platform to test novel therapies and devices ex vivo, in a patient relevant system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3D printed bioreactor enabling the physiological culture and the study of pathological processes in large vessels

Matos

Maselli

McVey

et al. 2022

Preprint

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“…drug eluting stents (DES’s) or other local devices [26,27]. Recently our group has suggested to calculate a SI/DES ratio [12] for appropriate dosing in DES’s. Due to the fact that agents are commonly underdosed after systemic administration [11] and overdosed in DES’s [12], we would like to suggest SI/MPL- and SI/DES-ratio’s of 1/100 as an orientation.…”

Section: Discussionmentioning

confidence: 99%

“…The SI/MPL-ratio was calculated in order to describe the relation between a significant inhibitory effect in vitro and the maximal plasma level after systemic administration in vivo [11,12]. …”

Section: Methodsmentioning

confidence: 99%

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Direct inhibitory effects of Ganciclovir on ICAM-1 expression and proliferation in human coronary vascular cells (SI/MPL-ratio: >1)

et al. 2011

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SummaryBackgroundTreatment of the human cytomegalovirus (HCMV) infection with ganciclovir has beneficial indirect effects on the complex interactions of HCMV with restenosis, atherosclerosis, and transplant vascular sclerosis. The current study reports on direct effects of ganciclovir on expression of ICAM-1 and cell proliferation, key events of coronary atherosclerosis/restenosis. A potential clinical relevance of the data will be evaluated with the help of SI/MPL-ratio’s.Material/MethodsDefinition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (ganciclovir: 9 μg/ml). Part I of the study investigated in cytoflow studies the effect of ganciclovir (0.05–5000 μg/mL) on TNF-a induced expression of intercellular adhesion molecule 1 (ICAM-1) in endothelial cells derived from umbilical veins (HUVEC), human coronary endothelial cells (HCAEC), and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of ganciclovir (0.05–5000 μg/mL) on cell proliferation (HUVEC, HCAEC, and HCMSMC). In part III cytotoxic effects of ganciclovir (0.05–5000 μg/mL) were studied (HUVEC, HCAEC, and HCMSMC).ResultsGanciclovir caused slight but significant inhibitory effects on expression of ICAM-1 in HUVEC, HCAEC, and HCMSMC. In all three cell types studied strong dose depending significant antiproliferative effects of ganciclovir were detected. Partially, the antiproliferative effects of ganciclovir were caused by cytotoxic effects.ConclusionsSI/MPL-ratio’s >1 in HCAEC and HCMSMC indicate that the inhibitory effects of gancliclovir on ICAM-1-expression and cell proliferation may only be expected in vivo following local high dose administration e.g. in drug eluting stents (DES).

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Soluble adhesion molecules in patients with acute coronary syndrome after percutaneous coronary intervention with drug-coated balloon, drug-eluting stent or bare metal stent

et al. 2016

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Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

Cited by 5 publications

References 37 publications

3D printed bioreactor enabling the physiological culture and the study of pathological processes in large vessels

3D printed bioreactor enabling the physiological culture and the study of pathological processes in large vessels

Direct inhibitory effects of Ganciclovir on ICAM-1 expression and proliferation in human coronary vascular cells (SI/MPL-ratio: >1)

Soluble adhesion molecules in patients with acute coronary syndrome after percutaneous coronary intervention with drug-coated balloon, drug-eluting stent or bare metal stent

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