TY - JOUR
KW - body-on-a-chip
KW - Drug development
KW - microphysiological systems
KW - multi-organ
KW - Off-target toxicity
KW - Opioid overdose
AU - Aakash Patel
AU - Suruchi Poddar
AU - Daniel Nierenberg
AU - Stephanie Lang
AU - Hao Wang
AU - Camilly Pestana Pires DeMello
AU - Julio Gamarra
AU - Alisha Colon
AU - Paula Kennedy
AU - Jeffry Roles
AU - Jules Klion
AU - Will Bogen
AU - Christopher Long
AU - Xiufang Guo
AU - Patrick Tighe
AU - Stephan Schmidt
AU - Michael L. Shuler
AU - James J. Hickman
AB - Opioids have been the primary method used to manage pain for hundreds of years, however the increasing prescription rate of these drugs in the modern world has led to a public health crisis of overdose related deaths. Naloxone is the current standard treatment for opioid overdose rescue, but it has not been fully investigated for potential off-target toxicity effects. The current methods for pharmaceutical development do not correlate well with pre-clinical animal studies compared to clinical results, creating a need for improved methods for therapeutic evaluation. Microphysiological systems (MPS) are a rapidly growing field, and the FDA has accepted this area of research to address this concern, offering a promising alternative to traditional animal models. This study establishes a novel multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids. By integrating primary human and human induced pluripotent stem cell (hiPSC)-derived cells, including preBötzinger complex neurons, liver, cardiac, and skeletal muscle components, this study establishes a novel functional multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids, with clinically relevant functional readouts of organ function. The system was able to successfully exhibit opioid overdose using methadone, as well as rescue using naloxone evidenced by the neuronal component activity. In addition to efficacy, the multi-organ platform was able to characterize potential off-target toxicity effects of naloxone, specifically in the cardiac component.
BT - Current Research in Toxicology
DA - 2025-01-01
DO - 10.1016/j.crtox.2024.100209
N2 - Opioids have been the primary method used to manage pain for hundreds of years, however the increasing prescription rate of these drugs in the modern world has led to a public health crisis of overdose related deaths. Naloxone is the current standard treatment for opioid overdose rescue, but it has not been fully investigated for potential off-target toxicity effects. The current methods for pharmaceutical development do not correlate well with pre-clinical animal studies compared to clinical results, creating a need for improved methods for therapeutic evaluation. Microphysiological systems (MPS) are a rapidly growing field, and the FDA has accepted this area of research to address this concern, offering a promising alternative to traditional animal models. This study establishes a novel multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids. By integrating primary human and human induced pluripotent stem cell (hiPSC)-derived cells, including preBötzinger complex neurons, liver, cardiac, and skeletal muscle components, this study establishes a novel functional multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids, with clinically relevant functional readouts of organ function. The system was able to successfully exhibit opioid overdose using methadone, as well as rescue using naloxone evidenced by the neuronal component activity. In addition to efficacy, the multi-organ platform was able to characterize potential off-target toxicity effects of naloxone, specifically in the cardiac component.
PY - 2025
EP - 100209
ST - Microphysiological system to address the opioid crisis
T2 - Current Research in Toxicology
TI - Microphysiological system to address the opioid crisis: A novel multi-organ model of acute opioid overdose and recovery
UR - https://www.sciencedirect.com/science/article/pii/S2666027X24000628
VL - 8
Y2 - 2025-01-21
SN - 2666-027X
ER -