Lungs on a Chip Innovative drug testing INTRODUCTION (lung on a chip) ● Human “organ-on-a-chip” microfluidic technology is a relatively new concept that has changed the way that scientists research tissue development, pathophysiology, tissue-tissue interaction, various types of drug testing and internal drug transport, and even new ways to study cancers and their effects on the body. We will focus on lungs-on-a-chip and their contributions to the multiple discoveries made implementing this technology. ● This technology has circumvented problems that arise in previous strategies such as the ethics and cost of animal testing, lab cultured cells failing to maintain differentiation, and the inability to replicate the structure and mechanics of living organs. ● (wyss institute) Dongeun Huh, Ph.D is a leading researcher in this field. Human ‘organ-on-a-chip’ >Changing research methods of tissue development, pathophysiology, methods of studying cancer, and primarily introduced new ways of drug testing without the use of animals. (lung on a chip) >Circumvented problems with traditional study methods such as lab cultured cells failing to maintain differentiation and the inability to replicate the structure and mechanics of living organs. (lung on a chip) > BACKGROUND ● Biomimicry: the act of exactly emulating biological functions ● Pathophysiology: The effects resulting from disease or injury ● Microfluidics: realistic applications to the production of systems in which fluids are processed to accomplish multiplexing, automation, and high-throughput screening ● Etiology: the cause(s) of a disease or condition. ● Surfactant: a substance that reduces the surface tension of a liquid in which it dissolves ● Pulmonary edema: condition caused by excess fluid and blood clots in the lung making it difficult to breath. Can be fatal. ● ● ● Researchers have been able to develop a multifunctional microdevice that emulates key functional, structural, and mechanical characteristics of the human alveolar-capillary interface - the root functional aspect of the living lung researchers used a lung on a chip to test the cancer chemotherapy drug IL-2 (interleukin-2) in order to find a way to reduce or eliminate the side effect of pulmonary edema METHODS/MATERIALS (human lung on a chip) 1. Chips are modeled after computer microchips and are made with a transparent, flexible polymer (about the size of a memory stick) that has hollow channels. 2. The channels are separated by a flexible, thin, porous membrane. 3. One side of the membrane is lined with human epithelial lung cells from the air sack and exposed to air, human capillary blood cells are on the other side with a medium flowing over the them. 4. A vacuum is applied to the side channels, the tissue-tissue interface stretches and contracts, recreating human breathing. DATA AND RESULTS ● (Wyss institute) “Pulmonary edema is a major toxic side effect of IL-2, which is a deadly condition in which the lungs fill with fluid and blood clots. When IL-2 was injected into the blood channel of the lung-on-a-chip, fluid leaked across the membrane and two tissue layers, reducing the volume of air in the other channel and compromising oxygen transport – just as it does in lungs of human patients when it is administered at the equivalent and over the same time course. Blood plasma proteins also crossed into the air channel, leading to the formation of blood clots in the air space, as they do in humans treated with IL-2. ○ Via the lung chip they found that the physical act of breathing greatly enhanced the effects of IL-2 in pulmonary edema. Turning on the vacuum attached to the chip to simulate breathing increased fluid leakage by more than three times. This suggests that doctors treating patients on respirators with IL-2 should reduce the tidal volume of air being pushed into the lungs, to minimize the side effects ● ● (wyss institute) possible new way doctors treat patients on respirators with IL-2 “organs-on-a-chip represents a new approach to model the structure, biology, and function of human organs, as evidenced by the complex breathing action of the engineered lung. This breathing action was key to providing new insight into the etiology of pulmonary edema” – Dr. James M. Anderson, M.D. ● Results show that the epithelial cells on the chip remained viable, increased surfactant production, enhanced structural integrity, and maintained normal barrier permeability in the biomimetic microsystem Pulmonary edema was able to be replicated in the lung chip when IL-2 when injected into the blood channel of the lung chip. The lung chip had the same response as seen in human lungs of patients being treated with IL-2: fluid leaking across the membrane reduces air volume resulting in compromised oxygen transport and blood plasma proteins crossing into the air channel creating blood clots. Turning on the vacuum of the lung chip enabled researchers to discover that the physical act of breathing increased the effects of IL-2 in pulmonary edema by more than 3X This suggests that when treating patients on respirators with IL-2 doctors should decrease the tidal volume of air being pushed into the lungs. “organs-on-a-chip represents a new approach to model the structure, biology, and function of human organs, as evidenced by the complex breathing action of the engineered lung. This breathing action was key to providing new insight into the etiology of pulmonary edema” – Dr. James M. Anderson, M.D. ● ● ● ● ● ● ● ● ● NEXT STEPS/PROBLEMS/APPLICATIONS Limitations: ○ “organoids are highly variable in size and shape, and it is difficult to maintain cells in consistent positions in these structures for extended analysis.” ○ miscalculations during experimentation can lead inaccurate levels of fluid shear stress, tension, and compression on the cells. Which effect organ development and function ○ Most models can only contain one or several cells at a time. Due to the high variability in shape and size, cells do not maintain consistent positions in chips for extended analysis Miscalculations during experimentation can lead inaccurate levels of fluid shear stress, tension, and compression on the cells. Which affect organ development and function Current chip models are small and can only contain one-several cells at a time Balijepalli, Aarathi and Vaibhav Sivaramakrishan. "Organs-On-Chips: Research and Commercial Perspectives." Drug Discovery Today, vol. 22, no. 2, Feb. 2017, pp. 397-403. EBSCOhost, doi:10.1016/j.drudis.2016.11.009. Kusek, Kristien. “Wyss Institute Models a Human Disease in an Organ-on-a-Chip.” Wyss Institute, President and Fellows of Harvard College, 7 Nov. 2012, wyss.harvard.edu/wyss-institute-models-a-human-disease-in-an-organ-on-a-chip/. Dongeun, Huh, et al. "Reconstituting Organ-Level Lung Functions on a Chip." Science, vol. 328, no. 5986, 25 June 2010, pp. 1662-1668. EBSCOhost,.
