Scaled-up Microfluidic Lung Assist Device for Artificial Placenta Application with High Gas Exchange Capacity.

Premature neonates with underdeveloped lungs experience respiratory issues and need respiratory support, such as mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The "artificial placenta" (AP) is a noninvasive approach that supports their lungs and reduces respiratory distress, using a pumpless oxygenator connected to the systemic circulation, and can address some of the morbidity issues associated with ECMO. Over the past decade, microfluidic blood oxygenators have garnered significant interest for their ability to mimic physiological conditions and incorporate innovative biomimetic designs. Achieving sufficient gas transfer at a low enough pressure drop for a pumpless operation without requiring a large volume of blood to prime such an oxygenator has been the main challenge with microfluidic lung assist devices (LAD). In this study, we improved the gas exchange capacity of our microfluidic-based artificial placenta-type LAD while reducing its priming volume by using a modified fabrication process that can accommodate large-area thin film microfluidic blood oxygenator (MBO) fabrication with a very high gas exchange surface. Additionally, we demonstrate the effectiveness of a LAD assembled by using these scaled-up MBOs. The LAD based on our artificial placenta concept effectively increases oxygen saturation levels by 30% at a flow rate of 40 mL/min and a pressure drop of 23 mmHg in room air, which is sufficient to support partial oxygenation for 1 kg preterm neonates in respiratory distress. When the gas ambient environment was changed to pure oxygen at atmospheric pressure, the LAD would be able to support premature neonates weighing up to 2 kg. Furthermore, our experiments reveal that the LAD can handle high blood flow rates of up to 150 mL/min and increase oxygen saturation levels by ∼20%, which is equal to an oxygen transfer of 7.48 mL/min in an enriched oxygen environment and among the highest for microfluidic AP type devices. Such performance makes this LAD suitable for providing essential support to 1-2 kg neonates in respiratory distress.

A roadmap for developing and engineering in vitro pulmonary fibrosis models.

Idiopathic pulmonary fibrosis (IPF) is a severe form of pulmonary fibrosis. IPF is a fatal disease with no cure and is challenging to diagnose. Unfortunately, due to the elusive etiology of IPF and a late diagnosis, there are no cures for IPF. Two FDA-approved drugs for IPF, nintedanib and pirfenidone, slow the progression of the disease, yet fail to cure or reverse it. Furthermore, most animal models have been unable to completely recapitulate the physiology of human IPF, resulting in the failure of many drug candidates in preclinical studies. In the last few decades, the development of new IPF drugs focused on changes at the cellular level, as it was believed that the cells were the main players in IPF development and progression. However, recent studies have shed light on the critical role of the extracellular matrix (ECM) in IPF development, where the ECM communicates with cells and initiates a positive feedback loop to promote fibrotic processes. Stemming from this shift in the understanding of fibrosis, there is a need to develop in vitro model systems that mimic the human lung microenvironment to better understand how biochemical and biomechanical cues drive fibrotic processes in IPF. However, current in vitro cell culture platforms, which may include substrates with different stiffness or natural hydrogels, have shortcomings in recapitulating the complexity of fibrosis. This review aims to draw a roadmap for developing advanced in vitro pulmonary fibrosis models, which can be leveraged to understand better different mechanisms involved in IPF and develop drug candidates with improved efficacy. We begin with a brief overview defining pulmonary fibrosis and highlight the importance of ECM components in the disease progression. We focus on fibroblasts and myofibroblasts in the context of ECM biology and fibrotic processes, as most conventional advanced in vitro models of pulmonary fibrosis use these cell types. We transition to discussing the parameters of the 3D microenvironment that are relevant in pulmonary fibrosis progression. Finally, the review ends by summarizing the state of the art in the field and future directions.