Researchers in Germany report the development of a retina-on-a-chip which combines living human cells with an artificial tissue-like system. The scientists, who describe their work (“Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human Retina-on-a-Chip platform”) in eLife, think their cutting-edge tool may provide a useful alternative to existing models for studying eye disease and allow scientists to test the effects of drugs on the retina more efficiently.
“The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration, or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of utmost importance,” the investigators wrote.
“The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell-types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro.
“We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.”
“It is extremely challenging, if not almost impossible, to recapitulate the complex tissue architecture of the human retina solely using engineering approaches,” explained Christopher Probst, PhD, postdoctoral researcher at the Fraunhofer Institute for Interfacial Engineering and Biotechnology in Stuttgart, Germany, and co-lead author of the current study.
To overcome these challenges, the scientists coaxed human pluripotent stem cells to develop into several different types of retina cells on artificial tissue. This tissue recreates the environment that cells would experience in the body and delivers nutrients and drugs to the cells through a system that mimics human blood vessels.
“This combination of approaches enabled us to successfully create a complex multi-layer structure that includes all cell types and layers present in retinal organoids, connected to a retinal pigment epithelium layer,” said co-lead author Kevin Achberger, PhD, postdoctoral researcher at the department of neuroanatomy & developmental biology at the Eberhard Karls University of Tübingen, Germany. “It is the first demonstration of a 3D retinal model that recreates many of the structural characteristics of the human retina and behaves in a similar way.”
The team treated their retina-on-the-chip with the anti-malaria drug chloroquine and the antibiotic gentamicin, which are toxic to the retina. They found that the drugs had a toxic effect on the retinal cells in the model, suggesting that it could be a useful tool for testing for harmful drug effects.
“One advantage of this tiny model is that it could be used as part of an automated system to test hundreds of drugs for harmful effects on the retina very quickly,” noted Achberger. “Also, it may enable scientists to take stem cells from a specific patient and study both the disease and potential treatments in that individual’s own cells.”
“This new approach combines two promising technologies—organoids and organ-on-a-chip—and has the potential to revolutionize drug development and usher in a new era of personalized medicine,” added senior author Peter Loskill, PhD, assistant professor for experimental regenerative medicine at Eberhard Karls University.
Loskill is head of the Fraunhofer Attract group Organ-on-a-Chip at the Fraunhofer Institute for Interfacial Engineering and Biotechnology. His laboratory, which spans the two universities, is developing similar organ-on-a-chip technology for other organs.