Optogenetic Modeling of Arrhythmias Using Holographic Light Stimulation
The pumping function of the heart is based on the contraction of heart muscle cells (cardiomyocytes) triggered by electrical signals. These form a three-dimensional, electrically coupled, functional network that enables the propagation of macroscopic action potential waves. These spatio-temporal patterns are essential for the synchronization of the contraction of the heart and thus for the perpetuation of the normal heart function. Cardiac arrhythmias are mainly due to disturbances in this propagation. For example, a spiral excitation wavefront can arise, which can lead to a greatly increased heart rate (tachycardia) and potentially fatal ventricular fibrillation. The emergence and termination of such disorders are not yet fully understood.
At this point, the discipline of optogenetics has initiated a paradigm shift. The discovery of so-called rhodopsins, which react to light and can be expressed in specific cells and cell types, made it possible to control the activity of such cells in a defined way with light. By means of in vitro experiments on artificial cardiomyocyte networks, certain cardiac arrhythmias can be simulated and investigated. Disturbances in excitation conduction can be specifically induced, observed, controlled and approaches for their termination can be derived. Thus, spiral waves can be better investigated and phenomenologically understood by a fundamentally new approach. Cell cultures from human heart muscle cells obtained from human induced pluripotent stem cells can be used for the experiments. These offer the advantage that they can be carried out in addition to the common animal experiments, reducing the problem of transferability from animals to humans.
For such experiments with optogenetic cell cultures, optical system technology plays a key role as an enabling technology. Individual cells or entire cell groups have to be activated by light stimulation in a cell-specific manner with millisecond time resolution and cellular spatial resolution. To stimulate spiral excitation waves, spatially and temporally variable light patterns have to be applied to stimulate the cellular networks.
Researchers at TUD Dresden University of Technology in the group of Prof. Juergen Czarske solved this problem by using a special programmable ferroelectric light modulator as the key component. Computer-generated holograms are displayed on the modulator to generate complex light patterns in three dimensions. The induced contractions of the heart muscle cells and their propagation are recorded and analyzed using video microscopy. Dr. Felix Schmieder and Dr. Lars Buettner have pointed out that the use of light modulators with a high resolution of three megapixels offers further advantages in the experiments: For example, optical distortions caused by the cell sample or lens aberrations in the optical system can be corrected by the modulator concurrently, so that a sub-cellular resolution is achieved. In the future, the optical system will be developed to real-time and full 3D operation in order to mimic defibrillation and pacemaker functions.
The work is funded by the German Research Foundation and the Berthold Leibinger Foundation. Medical project partner is the Department of Pharmacology and Toxicology of the University Medical Center Göttingen around the group of Dr. Olaf Bergmann. Partial results of the work have already been published in international scientific journals and been presented at international conferences.
Conclusion: Optogenetics on human cells makes it possible to model and investigate certain heart diseases in in vitro cell cultures and to develop novel therapeutic approaches. Optical system technology based on spatial light modulators with a high pixel count and real-time capability is the key technology for enabling experiments with maximum complexity and flexibility at the same time.
Contact:
Faculty of Electrical and Computer Engineering
Laboratory for Measurement and Sensor System Techniques (MST),
TUD Dresden University of Technology
Chair: Prof. Dr.-Ing. habil. Jürgen Czarske
Helmholtzstraße 18, 01069 Dresden