Microfluidic Perfusable Pathological Vasculature for Atherosclerosis Drug Screening.

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Drug Discovery

Background:

• Current in vitro atherosclerosis models lack physiological relevance due to the absence of blood flow.
• This limitation hinders accurate replication of endothelial injury and drug transport dynamics in atherosclerosis (AS) development.

Purpose of the Study:

• To develop a 3-dimensional perfusable atherosclerotic vessel-on-a-chip (3D-PAVoC) platform that incorporates hemodynamic forces.
• To establish a more physiologically relevant in vitro model for studying AS and evaluating anti-atherosclerotic drug efficacy.

Main Methods:

• Engineered a flow-enabled arterial construct integrating endothelial and smooth muscle cells.
• Exposed the construct to inflammatory and hyperlipidemic stimuli to induce AS-prone conditions.
• Evaluated drug responses using rapamycin (RAP) and validated findings in ApoE knockout mice.

Main Results:

• The 3D-PAVoC platform demonstrated flow-dependent endothelial responses and more pronounced AS pathology compared to static models.
• Drug efficacy testing in 3D-PAVoC showed higher RAP half-maximal inhibitory concentration, correlating better with in vivo results.
• In vivo validation in ApoE-/- mice confirmed partial alleviation of AS progression by the identified RAP dose.

Conclusions:

• The 3D-PAVoC platform offers a superior in vitro model for atherosclerosis research by incorporating crucial hemodynamic factors.
• This model enhances the prediction of anti-atherosclerotic drug efficacy, improving the translation of in vitro findings to in vivo outcomes.
• The platform provides valuable insights into drug mechanisms under realistic vascular and pathological conditions.