|| Focused Investigation Project
This project will implement a novel “organs on a chip” platform to investigate the effects, mechanisms, and protective measures related to cosmic radiation. Human tissues will be bioengineered from induced pluripotent stem cells (iPS cells), matured, physiologically connected by vascular perfusion containing immune cells, and subjected to space radiation and simulated microgravity, separately or simultaneously.
|Research Impact/Earth Benefits:
|| The significance of our project is that we have made advances in: (1) developing a predictive organs-on-a chip human multi-organ platform for studying effects of radiation damage, (2) tissue engineered organ models for the bone marrow, cardiac muscle, and sensory neurons, and (3) preliminary data on the effects of radioprotective agents on irradiated tissues.
Radiation exposure poses significant risks to human health and is associated with a host of both acute and chronic sequelae. Most notorious of the short-term effects of radiation exposure is acute radiation sickness (ARS), which is caused by acute exposures to >1 Gy of radiation and can be broken down into three subtypes: hematopoietic, gastrointestinal, and cerebrovascular. Chronic effects of low-dose, protracted radiation exposure include cataracts, cardiovascular disease, cognitive impairment, reproductive issues, and, most notably, cancer. The types of radiation exposure can be broken down into two categories: low-linear energy transfer (LET) radiation and high-LET radiation. Low-LET radiation consists of x-rays and gamma radiation (from 60-Co or 37-Cs sources, for example). Generally speaking, low-LET radiation causes damage within the cell indirectly through the formation of free radicals. High-LET radiation consists of protons, alpha particles, neutrons, and various high-charge and energy ions called HZE particles. HZE particles are small (<1%) but highly damaging components of galactic cosmic radiation (GCR). They include carbon, silicon, iron, oxygen, neon, magnesium, and calcium ions. High-LET radiation causes direct damage to the cell, including complex DNA damage and alterations to DNA repair pathways.
Space radiation consists primarily of protons, followed by alpha particles, and then HZE particles. Neutron radiation is a secondary type of radiation produced when primary components of Galactic Cosmic Rays (GCR) interact with target material, such as spacecraft or human tissue. While HZE particles are a small fraction of GCR, they are the most damaging components to human tissues, forming wide tracks of damage when passing through cells and are of greatest risk for potential deep-space missions. Studies on the effects of high-LET radiation, including those in space and as a result of nuclear warfare, have largely been limited due to the complex logistics and high costs associated with conducting experiments in space. NASA's Brookhaven National Laboratory has developed a terrestrial galactic cosmic ray simulator (GCRSim) comprising of seven different ion types at several energies for a series of 33 separate beams over the course of a single exposure. Simpler radiation source systems, comprising of one or two high-LET radiation types (i.e., mixed neutron, Fe-ion, etc.), are more commonly used by researchers to simulate space radiation given accessibility and experimental constraints. Nevertheless, most of these studies are limited to small animal and 2D human cell culture models. Since human tissue often responds differently to radiation damage than animal tissue, especially in response to injury and repair, experimental data in mice and other small animals have had limited translational use.
Human tissue platforms for in vitro studies of integrated human physiology in health and disease are becoming increasingly predictive of clinical data. However, there are no human tissue-based models of the effects of high-LET, mixed neutron radiation exposure that enable predictive studies of the risks associated with spaceflight and the mitigation of these risks. This project was conducted to address this critical gap, through a highly innovative design and validation of a human organs on a chip model of radiation exposure and the use of this model for assessing radiation damage and radiation protective medicines.