Nongenetic Optical Modulation of Pluripotent Stem Cells Derived Cardiomyocytes Function in the Red Spectral Range

Abstract

Optical stimulation in the red/near infrared range recently gained increasing interest, as a not‐invasive tool to control cardiac cell activity and repair in disease conditions. Translation of this approach to therapy is hampered by scarce efficacy and selectivity. The use of smart biocompatible materials, capable to act as local, NIR‐sensitive interfaces with cardiac cells, may represent a valuable solution, capable to overcome these limitations. In this work, a far red‐responsive conjugated polymer, namely poly[2,1,3‐benzothiadiazole‐4,7‐diyl[4,4‐bis(2‐ethylhexyl)−4H‐cyclopenta[2,1‐b:3,4‐b’]dithiophene‐2,6‐diyl]] (PCPDTBT) is proposed for the realization of photoactive interfaces with cardiomyocytes derived from pluripotent stem cells (hPSC‐CMs). Optical excitation of the polymer turns into effective ionic and electrical modulation of hPSC‐CMs, in particular by fastening Ca2+ dynamics, inducing action potential shortening, accelerating the spontaneous beating frequency. The involvement in the phototransduction pathway of Sarco‐Endoplasmic Reticulum Calcium ATPase (SERCA) and Na+/Ca2+ exchanger (NCX) is proven by pharmacological assays and is correlated with physical/chemical processes occurring at the polymer surface upon photoexcitation. Very interestingly, an antiarrhythmogenic effect, unequivocally triggered by polymer photoexcitation, is also observed. Overall, red‐light excitation of conjugated polymers may represent an unprecedented opportunity for fine control of hPSC‐CMs functionality and can be considered as a perspective, noninvasive approach to treat arrhythmias.

Enhancing the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes with an n-Type Organic Semiconductor Coating

“…Light-based pacing technologies offer a wireless alternative for delivering stimulation to cells. 9,10 Materials such as graphene, 11 silicon nanowires, 12 gold nanoparticles, 13 and conjugated polymers 14,15 have shown the ability to optically pace CMs when exposed to light. The absorption of light by these materials generates effects such as photovoltage, heat increase, or reactive oxygen species (ROS) production, which can modulate CM pacing through various mechanisms.…”

“…16,17 For example, one study has shown that when human induced pluripotent stem cell-derived CMs (hiPSC-CMs) were grown on a p-type (hole conducting) organic semiconductor (i.e., poly-3-hexylthiophene, P3HT), exposure to 550 nm light for (PCPDTBT) films, which generated a temperature rise on their surface when illuminated. 15 Alongside the heating effect upon light exposure, ROS were detected in the media near the PCPDTBT-cell interface. The authors inferred that the combination of temperature changes and ROS generation induced by polymer photoexcitation affected calcium handling proteins and, ultimately, CM beating frequency.…”

“…The authors inferred that the combination of temperature changes and ROS generation induced by polymer photoexcitation affected calcium handling proteins and, ultimately, CM beating frequency. 15 These successful examples of light-based pacing technology can ideally be applied for long-term stimulation to induce maturation, similar to electrical stimulation. However, a significant challenge lies in determining safe light exposure conditions to prevent cell damage.…”

“…For example, P3HT exhibits no adverse effects on cells over multiple days of culture, 14 while PCPDTBT not only demonstrates a lack of cytotoxicity but also enhances cell growth and function compared to inert substrates such as glass. 15 Thus, organic semiconductor coatings may offer additional benefits by altering surface stiffness, topography, or physicochemical properties known to impact cell maturation. 19 Understanding both the passive and active effects of these photoactive biomaterials will guide future optimization of CM tissue engineering constructs and optical pacing devices.…”

“…Light-based pacing technologies offer a wireless alternative for delivering stimulation to cells. , Materials such as graphene, silicon nanowires, gold nanoparticles, and conjugated polymers , have shown the ability to optically pace CMs when exposed to light. The absorption of light by these materials generates effects such as photovoltage, heat increase, or reactive oxygen species (ROS) production, which can modulate CM pacing through various mechanisms. , For example, one study has shown that when human induced pluripotent stem cell-derived CMs (hiPSC-CMs) were grown on a p-type (hole conducting) organic semiconductor (i.e., poly-3-hexylthiophene, P3HT), exposure to 550 nm light for 30 s resulted in an increase in their beating frequency .…”