Biohybrid printing approaches for cardiac pathophysiological studies.

Bioengineered hearts, which include single cardiomyocytes, engineered heart tissue, and chamber-like models, generate various biosignals, such as contractility, electrophysiological, and volume-pressure dynamic signals. Monitoring changes in these signals is crucial for understanding the mechanisms of disease progression and developing potential treatments. However, current methodologies face challenges in the continuous monitoring of bioengineered hearts over extended periods and typically require sacrificing the sample post-experiment, thereby limiting in-depth analysis. Thus, a biohybrid system consisting of living and nonliving components was developed. This system primarily features heart tissue alongside nonliving elements designed to support or comprehend its functionality. Biohybrid printing technology has simplified the creation of such systems and facilitated the development of various functional biohybrid systems capable of measuring or even regulating multiple functions, such as pacemakers, which demonstrates its versatility and potential applications. The future of biohybrid printing appears promising, with the ongoing exploration of its capabilities and potential directions for advancement.

Bioprinting-Assisted Tissue Assembly for Structural and Functional Modulation of Engineered Heart Tissue Mimicking Left Ventricular Myocardial Fiber Orientation.

Left ventricular twist is influenced by the unique oriented structure of myocardial fibers. Replicating this intricate structural-functional relationship in an in vitro heart model remains challenging, mainly due to the difficulties in achieving a complex structure with synchrony between layers. This study introduces a novel approach through the utilization of bioprinting-assisted tissue assembly (BATA)-a synergistic integration of bioprinting and tissue assembly strategies. By flexibly manufacturing tissue modules and assembly platforms, BATA can create structures that traditional methods find difficult to achieve. This approach integrates engineered heart tissue (EHT) modules, each with intrinsic functional and structural characteristics, into a layered, multi-oriented tissue in a controlled manner. EHTs assembled in different orientations exhibit various contractile forces and electrical signal patterns. The BATA is capable of constructing complex myocardial fiber orientations within a chamber-like structure (MoCha). MoCha replicates the native cardiac architecture by exhibiting three layers and three alignment directions, and it reproduces the left ventricular twist by exhibiting synchronized contraction between layers and mimicking the native cardiac architecture. The potential of BATA extends to engineering tissues capable of constructing and functioning as complete organs on a large scale. This advancement holds the promise of realizing future organ-on-demand technology.

Fully Implantable Neurostimulation System for Long-Term Behavioral Animal Study.

Spinal cord stimulation (SCS) is an emerging therapeutic option for patients with neuropathic pain due to spinal cord injury (SCI). Numerous studies on pain relief effects with SCS have been conducted and demonstrated promising results while the mechanisms of analgesic effect during SCS remain unclear. However, an experimental system that enables large-scale long-term animal studies is still an unmet need for those mechanistic studies. This study proposed a fully wireless neurostimulation system that can efficiently support a long-term animal study for neuropathic pain relief. The developed system consists of an implantable stimulator, an animal cage with an external charging coil, and a wireless communication interface. The proposed device has the feature of remotely controlling stimulation parameters via radio-frequency (RF) communication and wirelessly charging via magnetic induction in freely moving rats. Users can program stimulation parameters such as pulse width, intensity, and duration through an interface on a computer. The stimulator was packaged with biocompatible epoxy to ensure long-term durability under in vivo conditions. Animal experiments using SCI rats were conducted to demonstrate the functionality of the device, including long-term usability and therapeutic effects. The developed system can be tailored to individual user needs with commercially available components, thus providing a cost-effective solution for large-scale long-term animal studies on neuropathic pain relief.

Closed-loop direct control of seizure focus in a rodent model of temporal lobe epilepsy via localized electric fields applied sequentially.

Direct electrical stimulation of the seizure focus can achieve the early termination of epileptic oscillations. However, direct intervention of the hippocampus, the most prevalent seizure focus in temporal lobe epilepsy is thought to be not practicable due to its large size and elongated shape. Here, in a rat model, we report a sequential narrow-field stimulation method for terminating seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. The effects and regional specificity of this method were demonstrated via electrophysiological and biological responses. Our proposed modality demonstrates spatiotemporal preciseness and selectiveness for modulating the pathological target region which may have potential for further investigation as a therapeutic approach.

An Efficient Noninvasive Neuromodulation Modality for Overactive Bladder Using Time Interfering Current Method.

OBJECTIVE: The present study aimed to evaluate a new tibial nerve stimulation (TNS) modality, which uses interferential currents, in terms of the stimulation electric field penetration efficiency into the body and physiological effectiveness. METHODS: In silico experiments were performed to analyze the penetration efficiency of proposed interferential current therapy (ICT). Based on this, we performed in vivo experiments to measure excitation threshold of ICT for the tibial nerve, which is related to stimulation field near the nerve. Regarding analysis of the physiological effectiveness, in vivo ICT-TNS was performed, and changes in bladder contraction frequency and voiding volume were measured. The penetration efficiency and physiological effectiveness of ICT were evaluated by comparison with those of conventional TNS using transcutaneous electrical nerve stimulation (TENS). RESULTS: Simulation results showed that ICT has high penetration efficiency, thereby generating stronger field than TENS. These results are consistent with the in vivo results that nerve excitation threshold of ICT is lower than that of TENS. Moreover, ICT-TNS decreased contraction frequency and increased voiding volume, and its performance was profound compared with that of TENS-TNS. CONCLUSION: The proposed ICT is more efficient in inducing the stimulation field near the tibial nerve placed deep inside the body compared with conventional TENS and shows a good clinical effectiveness for TNS. SIGNIFICANCE: The high efficiency of ICT increases the safety of noninvasive neurostimulation; therefore, it has clinical potential to become a promising modality for TNS to treat OAB and other peripheral neurostimulations.

Long-term Non-Anesthetic Preclinical Study Available Extra-Cranial Brain Activator (ECBA) System for the Future Minimally-Invasive Human Neuro-Modulation.

Long-term preclinical study available extracranial brain activator (ECBA) system, ECBAv2, is proposed for the non-anesthetic canine models. The titanium-packaged module shows enhanced durability, even after a year of implantation in the scalp. In addition, the wearable helmet type base station provides a stable experimental environment without anesthesia. In this work, HFS stimulation is induced to six canine models for 30 minutes every day over 4 weeks (10Hz, 40Hz and no stimulation for each pair of subjects). Pre- and post-HFS stimulation PET-CT image shows remarkable increases of glucose metabolism in the temporal and parietal lobes. Moreover, both the 40-Hz and 10-Hz groups shows noticeable increase and the former group has more increments than the latter. Our results establish that HFS stimulation definitely worked as facilitating brain activity which may affect memory and sensory skills, respectively.

Long-Term Non Anesthetic Preclinical Study Available Extra-Cranial Brain Activator (ECBA) System for the Future Minimally Invasive Human Neuro Modulation.

In recent years, electroceuticals have been spotlighted as an emerging treatment for various severe chronic brain diseases, owing to their intrinsic advantage of electrical interaction with the brain, which is the most electrically active organ. However, the majority of research has verified only the short-term efficacy through acute studies in laboratory tests owing to the lack of a reliable miniaturized platform for long-term animal studies. The construction of a sufficient integrated system for such a platform is extremely difficult because it requires multi-disciplinary work using state-of-the-art technologies in a wide range of fields. In this study, we propose a complete system of an implantable platform for long-term preclinical brain studies. Our proposed system, the extra-cranial brain activator (ECBA), consists of a titanium-packaged implantable module and a helmet-type base station that powers the module wirelessly. The ECBA can also be controlled by a remote handheld device. Using the ECBA, we performed a long-term non-anesthetic study with multiple canine subjects, and the resulting PET-CT scans demonstrated remarkable enhancement in brain activity relating to memory and sensory skills. Furthermore, the histological analysis and high-temperature aging test confirmed the reliability of the system for up to 31 months. Hence, the proposed ECBA system is expected to lead a new paradigm of human neuromodulation studies in the near future.

Analyzing the advantages of subcutaneous over transcutaneous electrical stimulation for activating brainwaves.

Transcranial electrical stimulation (TES) is a widely accepted neuromodulation modality for treating brain disorders. However, its clinical efficacy is fundamentally limited due to the current shunting effect of the scalp and safety issues. A newer electrical stimulation technique called subcutaneous electrical stimulation (SES) promises to overcome the limitations of TES by applying currents directly at the site of the disorder through the skull. While SES seems promising, the electrophysiological effect of SES compared to TES is still unknown, thus limiting its broader application. Here we comprehensively analyze the SES and TES to demonstrate the effectiveness and advantages of SES. Beagles were bilaterally implanted with subdural strips for intracranial electroencephalography and electric field recording. For the intracerebral electric field prediction, we designed a 3D electromagnetic simulation framework and simulated TES and SES. In the beagle model, SES induces three to four-fold larger cerebral electric fields compared to TES, and significant changes in power ratio of brainwaves were observed only in SES. Our prediction framework suggests that the field penetration of SES would be several-fold larger than TES in human brains. These results demonstrate that the SES would significantly enhance the neuromodulatory effects compared to conventional TES and overcome the TES limitations.

Development of wirelessly-powered, extracranial brain activator (ECBA) in a large animal model for the future non-invasive human neuromodulation.

As transcranial electrical stimulation (tES) is an emerging and promising technique for neuromodulation, we developed a novel device; wirelessly-powered, extracranial brain activator (ECBA), which is mounted subcutaneously, and its neuromodulation effect was investigated. The oscillatory changes in electrocorticography (EcoG) were analyzed from two types of stimulation. Two weeks prior to the recording experiment, we underwent surgery for implantation of subdural strips and ECBA module over centroparietal regions of anesthetized beagles. Low-frequency stimulation (LFS) and subsequent high-frequency stimulation (HFS) protocols (600 pulses respectively) were applied. Then, the power changes before and after each stimulation in five different bands were compared. A significantly larger voltage difference with subcutaneous than transcutaneous stimulation measured at EcoG channels indicated a substantial current attenuation between the skin and skull. Compared with the baseline, all subjects showed consistently decreased delta power and increased gamma power after HFS. LFS also induced a similar, but opposite, pattern of power change in four beagles. The results from this study indicate that LFS and HFS with our novel ECBA can consistently and effectively modulate neural activity of the cortex, inducing neural inhibition and facilitation functions, respectively. Future studies are necessary to further ensuring a consistent efficacy and long-term safety.