Jokubas Ausra

Monitoring and control of cardiac function are critical for investigation of cardiovascular pathophysiology and developing life-saving therapies. However, chronic stimulation of the heart in freely moving small animal subjects, which offer a variety of genotypes and phenotypes, is currently difficult. Specifically, real-time control of cardiac function with high spatial and temporal resolution is currently not possible. Here, we introduce a wireless battery-free device with on-board computation for real-time cardiac control with multisite stimulation enabling optogenetic modulation of the entire rodent heart. Seamless integration of the biointerface with the heart is enabled by machine learning–guided design of ultrathin arrays. Long-term pacing, recording, and on-board computation are demonstrated in freely moving animals. This device class enables new heart failure models and offers a platform to test real-time therapeutic paradigms over chronic time scales by providing means to control cardiac function continuously over the lifetime of the subject.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require large animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to combine the advantages of molecular tools and implantable devices. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. This protocol describes how to perform an open thoracic surgical technique for epicardial implantation of novel wireless cardiac bioelectronic devices in adult rats and has significantly lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes about 40 minutes to complete for an experienced operator, and up to 8 surgeries can be completed in one day. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

Wireless, battery-free, and fully subdermally implantable optogenetic tools are poised to transform neurobiological research in freely moving animals. Current-generation wireless devices are sufficiently small, thin, and light for subdermal implantation, offering some advantages over tethered methods for naturalistic behavior. Yet current devices using wireless power delivery require invasive stimulus delivery, penetrating the skull and disrupting the blood–brain barrier. This can cause tissue displacement, neuronal damage, and scarring. Power delivery constraints also sharply curtail operational arena size. Here, we implement highly miniaturized, capacitive power storage on the platform of wireless subdermal implants. With approaches to digitally manage power delivery to optoelectronic components, we enable two classes of applications: transcranial optogenetic activation millimeters into the brain (validated using motor cortex stimulation to induce turning behaviors) and wireless optogenetics in arenas of more than 1 m² in size. This methodology allows for previously impossible behavioral experiments leveraging the modern optogenetic toolkit. Significance Delivery of light for optogenetic stimulation of the brain is challenging, especially in small animals, because of behavioral constraints associated with physical tethering by fiber optic cables. This limitation interferes with some classes of in vivo behavioral experiments and makes others impossible. Additionally, the penetrating probes associated with these and related technologies cause damage to targeted regions of neural tissues, thereby complicating experimental evaluation. Here, we introduce a wireless, battery-free system that interfaces to the animal as a minimally invasive, subdermal implant capable of delivering high-intensity optogenetic light stimulation directly through the skull, without penetrating the brain. This approach avoids damage to brain tissue, facilitates simple surgical implantation, and enables new, ethologically grounded neuroscience experiments, applicable over large experimental arenas.

Wireless battery free and fully implantable tools for the interrogation of the central and peripheral nervous system have quantitatively expanded the capabilities to study mechanistic and circuit level behavior in freely moving rodents. The light weight and small footprint of such devices enables full subdermal implantation that results in the capability to perform studies with minimal impact on subject behavior and yields broad application in a range of experimental paradigms. While these advantages have been successfully proven in rodents that move predominantly in 2D, the full potential of a wireless and battery free device can be harnessed with flying species, where interrogation with tethered devices is very difficult or impossible. Here we report on a wireless, battery free and multimodal platform that enables optogenetic stimulation and physiological temperature recording in a highly miniaturized form factor for use in songbirds. The systems are enabled by behavior guided primary antenna design and advanced energy management to ensure stable optogenetic stimulation and thermography throughout 3D experimental arenas. Collectively, these design approaches quantitatively expand the use of wireless subdermally implantable neuromodulation and sensing tools to species previously excluded from in vivo real time experiments.

Wireless battery free and fully implantable tools for the interrogation of the central and peripheral nervous system have quantitively expanded the capabilities to study mechanistic and circuit level behavior in freely moving rodents. The light weight and small footprint of such devices enables fully subdermal implantation that results in the capability to perform studies with minimal impact on subject behavior and yields broad application in a range of experimental paradigms. While these advantages have been successfully proven in rodents that move predominantly in 2D the full potential of a wireless and battery free device can be harnessed with species that move in 3D, where interrogation with tethered devices is very difficult or impossible. Here we report on a wireless, battery free and multimodal platform that enables optogenetic stimulation and physiological recording in a highly miniaturized form factor for use in songbirds. The systems are enabled by behavior guided primary antenna design and advanced energy management to ensure stable optogenetic stimulation and physiological recording throughout 3D experimental arenas. Collectively, these design approaches quantitatively expand the use of wireless subdermally implantable neuromodulation and sensing tools to species previously excluded from in vivo real time experiments.

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.