P. Nath, J-H Huang, A. Arefin, J.F. Harris, K. Balatsky, Y. Shou, D. Platts, H. Sandin, S. Iyer, R. Iyer
Los Alamos National Laboratory,
Keywords: organs on a chip, microfluidics
Summary:Motivation: The ability to recapitulate organ level functions in Micro-Physiological Systems (MPS) provides powerful, next-generation tools to support drug discovery and development. However, many human organs feature complex cellular and biophysical characteristics. Multiple MPS models are typically created to represent different isolated functions of the same organ. For instance, the human lung has distinctive regions namely the bronchioles and the alveoli, which are represented by two separate MPS models [1, 2] limiting the ability to probe critical features of the entire organ. This work has taken a stepwise approach to develop a suite of micro-engineered units, called PuLMo (Pulmonary Lung Models), to enable configurable and integrated MPS models for drug toxicity analysis. Methods: PuLMo was designed to recapitulate multiple critical features of the human lung. PuLMo incorporates the biophysical features of (1) air-liquid interface; (2) fractal airway network; (3) balloon shaped alveolar chambers; (4) cyclic stretching of the alveolar membrane; and (5) physiological breathing. PuLMo’s biological features included (1) ciliated cells; (2) mucus production; and (3) surfactant production. The platforms were fabricated using hybrid (subtractive + additive) manufacturing, allowing the integration of a wide range of materials. The microfluidic channels were made of polycarbonate film and silicone adhesives. The stretchable alveolar membranes were fabricated using polyurethane. Breathing was carried out by stretching the alveoli membrane with a novel non-pneumatic aspiration principle. While the complexity of the integrated platform can be defined by the user, complete operation of PuLMo can require the perfusion and transition of multiple media. Therefore miniaturized pumps, valves, fluid circuit boards, and reservoirs were also developed to enable integrated operations. Key Results: Figure 1 shows two different integrated platforms that were configured to incorporate different biological and biophysical functions of the human lung. The platform in Figure 1(a) features multiple generations of fractal airway network (small airways + alveoli), breathing, and the co-culture of small airway epithelial cells. The platform in Figure 1(b) has integrated bronchiolar and alveolar units to allow the co-culture of Bronchiolar Epithelial cells, Alveolar Epithelial cells, and Microvascular cells. It integrates a fluid circuit board to help facilitate at least five different media; breathing; frequent transition between liquid-liquid interface and air-liquid interface; and mucus clearance. Conclusions: PuLMo, a recipient of 2016 R&D 100 award, represents a suite of enabling platforms to obtain user defined and integrated human lung MPS models.