Acrylated adhesive proteinic microneedle patch for local drug delivery and stable device implantation.

Microneedle patches have been developed as favorable platforms for delivery systems, such as the locoregional application of therapeutic drugs, and implantation systems, such as electronic devices on visceral tissue surfaces. However, the challenge lies in finding materials that can achieve both biocompatibility and stable fixation on the target tissue. To address this issue, utilizing a biocompatible adhesive biomaterial allows the flat part of the patch to adhere as well, enabling double-sided adhesion for greater versatility. In this work, we propose an adhesive microneedle patch based on mussel adhesive protein (MAP) with enhanced mechanical strength via ultraviolet-induced polyacrylate crosslinking and Coomassie brilliant blue molecules. The strong wet tissue adhesive and biocompatible nature of engineered acrylated-MAP resulted in the development of a versatile wet adhesive microneedle patch system for in vivo usage. In a mouse tumor model, this microneedle patch effectively delivered anticancer drugs while simultaneously sealing the skin wound. Additionally, in an application of rat subcutaneous implantation, an electronic circuit was stably anchored using a double-sided wet adhesive microneedle patch, and its signal location underneath the skin did not change over time. Thus, the proposed acrylated-MAP-based wet adhesive microneedle patch system holds great promise for biomedical applications, paving the way for advancements in drug delivery therapeutics, tissue engineering, and implantable electronic medical devices.

Flexible Peripheral Nerve Interfacing Electrode for Joint Position Control in Closed-Loop Neuromuscular Stimulation.

Addressing peripheral nerve disorders with electronic medicine poses significant challenges, especially in replicating the dynamic mechanical properties of nerves and understanding their functionality. In the field of electronic medicine, it is crucial to design a system that thoroughly understands the functions of the nervous system and ensures a stable interface with nervous tissue, facilitating autonomous neural adaptation. Herein, we present a novel neural interface platform that modulates the peripheral nervous system using flexible nerve electrodes and advanced neuromodulation techniques. Specifically, we have developed a surface-based inverse recruitment model for effective joint position control via direct electrical nerve stimulation. Utilizing barycentric coordinates, this model constructs a three-dimensional framework that accurately interpolates inverse isometric recruitment values across various joint positions, thereby enhancing control stability during stimulation. Experimental results from rabbit ankle joint control trials demonstrate our model's effectiveness. In combination with a proportional-integral-derivative (PID) controller, it shows superior performance by achieving reduced settling time (less than 1.63 s), faster rising time (less than 0.39 s), and smaller steady-state error (less than 3 degrees) compared to the legacy model. Moreover, the model's compatibility with recent advances in flexible interfacing technologies and its integration into a closed-loop controlled functional neuromuscular stimulation (FNS) system highlight its potential for precise neuroprosthetic applications in joint position control. This approach marks a significant advancement in the management of neurological disorders with advanced neuroprosthetic solutions.

A Customizable Proteinic Bioadhesive Patch with Water-Switchable Underwater Adhesiveness, Adjustable Biodegradability, and Modifiable Stretchability for Healing Diverse Internal Wounds.

Customizable bioadhesives for individual organ requirements, including tissue type and motion, are essential, especially given the rise in implantable medical device applications demanding adequate underwater adhesion. While synthetic bioadhesives are widely used, their toxicity upon degradation shifts focus to biocompatible natural biomaterials. However, enhancing the adhesive strengths of these biomaterials presents ongoing challenges while accommodating the unique properties of specific organs. To address these issues, three types of customized underwater bioadhesive patches (CUBAPs) with strong, water-responsive adhesion and controllable biodegradability and stretchability based on bioengineered mussel adhesive proteins conjugated with acrylic acid and/or methacrylic acid are proposed. The CUBAP system, although initially nonadhesive, shows strong underwater adhesion upon hydration, adjustable biodegradation, and adequate physical properties by adjusting the ratio of poly(acrylic acid) and poly(methacrylic acid). Through ex vivo and in vivo evaluations using defective organs and the implantation of electronic devices, the suitability of using CUBAPs for effective wound healing in diverse internal organs is demonstrated. Thus, this innovative CUBAP system offers strong underwater adhesiveness with tailored biodegradation timing and physical properties, giving it great potential in various biomedical applications.

Electroconductive, Adhesive, Non-Swelling, and Viscoelastic Hydrogels for Bioelectronics.

As a new class of materials, implantable flexible electrical conductors have recently been developed and applied to bioelectronics. An ideal electrical conductor requires high conductivity, tissue-like mechanical properties, low toxicity, reliable adhesion to biological tissues, and the ability to maintain its shape in wet physiological environments. Despite significant advances, electrical conductors that satisfy all these requirements are insufficient. Herein, a facile method for manufacturing a new conductive hydrogels through the simultaneous exfoliation of graphite and polymerization of zwitterionic monomers triggered by microwave irradiation is introduced. The mechanical properties of the obtained conductive hydrogel are similar to those of living tissue, which is ideal as a bionic adhesive for minimizing contact damage due to mechanical mismatches between hard electronics and soft tissues. Furthermore, it exhibits excellent adhesion performance, electrical conductivity, non-swelling, and high conformability in water. Excellent biocompatibility of the hydrogel is confirmed through a cytotoxicity test using C2C12 cells, a biocompatibility test on rat tissues, and their histological analysis. The hydrogel is then implanted into the sciatic nerve of a rat and neuromodulation is demonstrated through low-current electrical stimulation. This hydrogel demonstrates a tissue-like extraneuronal electrode, which possesses high conformability to improve the tissue-electronics interfaces, promising next-generation bioelectronics applications.

Electrostatic-Mechanical Synergistic In Situ Multiscale Tissue Adhesion for Sustainable Residue-Free Bioelectronics Interfaces.

Recent studies on soft adhesives have sought to deeply understand how their chemical or mechanical structures interact strongly with living tissues. The aim is to optimally address the unmet needs of patients with acute or chronic diseases. Synergistic adhesion involving both electrostatic (hydrogen bonds) and mechanical interactions (capillarity-assisted suction stress) seems to be effective in overcoming the challenges associated with long-term unstable coupling to tissues. Here, an electrostatically and mechanically synergistic mechanism of residue-free, sustainable, in situ tissue adhesion by implementing hybrid multiscale architectonics. To deduce the mechanism, a thermodynamic model based on a tailored multiscale combinatory adhesive is proposed. The model supports the experimental results that the thermodynamically controlled swelling of the nanoporous hydrogel embedded in the hierarchical elastomeric structure enhances biofluid-insensitive, sustainable, in situ adhesion to diverse soft, slippery, and wet organ surfaces, as well as clean detachment in the peeling direction. Based on the robust tissue adhesion capability, universal reliable measurements of electrophysiological signals generated by various tissues, ranging from rodent sciatic nerve, the muscle, brain, and human skin, are successfully demonstrated.

Durable and Fatigue-Resistant Soft Peripheral Neuroprosthetics for In Vivo Bidirectional Signaling.

Soft neuroprosthetics that monitor signals from sensory neurons and deliver motor information can potentially replace damaged nerves. However, achieving long-term stability of devices interfacing peripheral nerves is challenging, since dynamic mechanical deformations in peripheral nerves cause material degradation in devices. Here, a durable and fatigue-resistant soft neuroprosthetic device is reported for bidirectional signaling on peripheral nerves. The neuroprosthetic device is made of a nanocomposite of gold nanoshell (AuNS)-coated silver (Ag) flakes dispersed in a tough, stretchable, and self-healing polymer (SHP). The dynamic self-healing property of the nanocomposite allows the percolation network of AuNS-coated flakes to rebuild after degradation. Therefore, its degraded electrical and mechanical performance by repetitive, irregular, and intense deformations at the device-nerve interface can be spontaneously self-recovered. When the device is implanted on a rat sciatic nerve, stable bidirectional signaling is obtained for over 5 weeks. Neural signals collected from a live walking rat using these neuroprosthetics are analyzed by a deep neural network to predict the joint position precisely. This result demonstrates that durable soft neuroprosthetics can facilitate collection and analysis of large-sized in vivo data for solving challenges in neurological disorders.

Adaptive self-healing electronic epineurium for chronic bidirectional neural interfaces.

Realizing a clinical-grade electronic medicine for peripheral nerve disorders is challenging owing to the lack of rational material design that mimics the dynamic mechanical nature of peripheral nerves. Electronic medicine should be soft and stretchable, to feasibly allow autonomous mechanical nerve adaptation. Herein, we report a new type of neural interface platform, an adaptive self-healing electronic epineurium (A-SEE), which can form compressive stress-free and strain-insensitive electronics-nerve interfaces and enable facile biofluid-resistant self-locking owing to dynamic stress relaxation and water-proof self-bonding properties of intrinsically stretchable and self-healable insulating/conducting materials, respectively. Specifically, the A-SEE does not need to be sutured or glued when implanted, thereby significantly reducing complexity and the operation time of microneurosurgery. In addition, the autonomous mechanical adaptability of the A-SEE to peripheral nerves can significantly reduce the mechanical mismatch at electronics-nerve interfaces, which minimizes nerve compression-induced immune responses and device failure. Though a small amount of Ag leaked from the A-SEE is observed in vivo (17.03 ppm after 32 weeks of implantation), we successfully achieved a bidirectional neural signal recording and stimulation in a rat sciatic nerve model for 14 weeks. In view of our materials strategy and in vivo feasibility, the mechanically adaptive self-healing neural interface would be considered a new implantable platform for a wide range application of electronic medicine for neurological disorders in the human nervous system.

Hemodynamic correlation imaging of the mouse brain for application in unilateral neurodegenerative diseases.

We developed a single-camera two-channel hemodynamic imaging system that uses near-infrared light to monitor the mouse brain in vivo with an exposed, un-thinned, and intact skull to explore the effect of Parkinson's disease on the resting state functional connectivity of the brain. To demonstrate our system's ability to monitor cerebral hemodynamics, we first performed direct electrical stimulation of an anesthetized healthy mouse brain and detected hemodynamic changes localized to the stimulated area. Subsequently, we developed a unilaterally lesioned 6-hydroxydopamine (hemi-parkinsonian) mouse model and detected the differences in functional connectivity between the normal and hemi-parkinsonian mouse brains by comparing the hemispheric hemodynamic correlations during the resting state. Seed-based correlation for the oxy-hemoglobin channel from the left and right hemispheres of healthy mice was much higher and more symmetric than in hemi-parkinsonian mice. Through a k-means clustering of the hemodynamic signals, the healthy mouse brains were segmented according to brain region, but the hemi-parkinsonian mice did not show a similar segmentation. Overall, this study highlights the development of a spatial multiplexing hemodynamic imaging system that reveals the resting state hemodynamic connectivity in healthy and hemi-parkinsonian mice.

Compact Neural Interface Using a Single Multichannel Cuff Electrode for a Functional Neuromuscular Stimulation System.

Cuff electrodes have been introduced into functional neuromuscular stimulation systems to either obtain neural signals or elicit limb movements. Multiple electrodes must be implanted to construct a feedback control loop, including one electrode for acquisition and another for stimulation. Existing approaches require too much space inside the body and a complicated surgical procedure. This paper proposes a novel neural interface method that uses a single cuff electrode with multichannel capability to simultaneously acquire multichannel recordings and induce electrical stimulation at the proximal nerve trunk of the sciatic nerve. Recordings and stimulation are conducted in a time-shared manner using a path controller. Using the proposed method, joint positions are estimated from multichannel recorded neural signals during electrical stimulation as neural signals are continuously recorded. In addition, the proposed system is shown to be suitable for controlling joint position. The proposed neural interface method overcomes the spatial limitations of electrode implantation and thus offers a new approach to developing compact neural interface systems.

Compact Optical Nerve Cuff Electrode for Simultaneous Neural Activity Monitoring and Optogenetic Stimulation of Peripheral Nerves.

Optogenetic stimulation of the peripheral nervous system is a novel approach to motor control, somatosensory transduction, and pain processing. Various optical stimulation tools have been developed for optogenetic stimulation using optical fibers and light-emitting diodes positioned on the peripheral nerve. However, these tools require additional sensors to monitor the limb or muscle status. We present herein a novel optical nerve cuff electrode that uses a single cuff electrode to conduct to simultaneously monitor neural activity and optogenetic stimulation of the peripheral nerve. The proposed optical nerve cuff electrode is designed with a polydimethylsiloxane substrate, on which electrodes can be positioned to record neural activity. We confirm that the illumination intensity and the electrical properties of the optical nerve cuff electrode are suitable for optical stimulation with simultaneous neural activity monitoring in Thy1::ChR2 transgenic mice. With the proposed electrode, the limb status is monitored with continuous streaming signals during the optical stimulation of anesthetized and moving animals. In conclusion, this optical nerve cuff electrode provides a new optical modulation tool for peripheral nervous system studies.

Graded 6-OHDA-induced dopamine depletion in the nigrostriatal pathway evokes progressive pathological neuronal activities in the subthalamic nucleus of a hemi-parkinsonian mouse.

Recent studies have established methods for establishing a rodent model that mimics progressive stages of human Parkinson's disease (PD), via injection of graded doses of 6-hydroxydopamine (6-OHDA) into regions within the nigrostriatal pathway. However, the electrophysiological characteristics of the subthalamic nucleus (STN) in this model have not been fully elucidated in this model. This study aimed to investigate changes in the neuronal activity of the STN in a graded mouse model of PD. Increasing doses of 6-OHDA were unilaterally injected into the medial forebrain bundle (MFB) to produce a hemi-parkinsonian mouse model, mimicking early, moderate, advanced, and severe stages of human PD. Mice treated with higher doses of 6-OHDA demonstrated significantly lower rates of use of the impaired (contralateral) forelimb during wall contact, relative to sham mice. The STN firing rate was significantly increased in groups with >75% dopaminergic cell loss in the substantia nigra pars compacta (SNc), whereas little increase was observed in groups with partial lesions of the SNc, relative to the sham group. In addition, firing patterns of the STN in groups treated with higher doses of 6-OHDA became more irregular and exhibited burst-like patterns of activity, with dominant slow wave oscillations in the frequency range of 0.3-2.5 Hz. Our results demonstrated a strong correlation between neuronal activities in the STN and dopamine depletion in the nigrostriatal pathway, which can be manipulated by variation of 6-OHDA doses.

Differential heart rate variability and physiological responses associated with accumulated short- and long-term stress in rodents.

In this study, we tested the hypothesis that chronic stress has cumulative effects over time on heart rate variability (HRV) and physiological responses in a rodent model of chronic mild stress. Rats were exposed to either short-term (2weeks) or long-term (4weeks) stress, followed by a 1-week recovery period. Controls were normally housed rats that did not undergo the stress procedure. For electrocardiogram recordings, transmitters were implanted in all rats 10days before the onset of the experiment to allow recovery from surgery. To investigate physiological responses, body weight, temperature, sucrose preference, and serum corticosterone levels were measured weekly. Rats exposed to both short- and long-term stress showed significant reductions in body weight, which did not normalize after the recovery period. A significant difference was observed between short- and long-term stress groups in serum corticosterone levels, with long-term stress significantly increasing serum corticosterone levels, which remained elevated after the recovery period (P<0.05). HRV analysis indicated that long-term stress significantly decreased time-domain indexes, whereas significantly increased frequency-domain indexes were observed in the low-frequency range (0.1-1Hz). These results may represent dysfunction in parasympathetic/vagal modulation with hyperactivation of the sympathetic nervous system after long-term exposures to stress. In addition, prolonged Q-to-T wave (QT) intervals were observed in rats exposed to long-term stress, which did not return to baseline levels after the recovery period. These findings are consistent with the view that chronic stress is associated with cardiac autonomic disorders and emphasize the importance of monitoring stress in our daily life since the effects of even mild stress may be cumulative.

Ankle-Angle Estimation from Blind Source Separated Afferent Activity in the Sciatic Nerve for Closed-Loop Functional Neuromuscular Stimulation System.

Cuff electrode recording has been proposed as a solution to obtain robust feedback signals for closed-loop controlled functional neuromuscular stimulation (FNS) systems. However, single-channel cuff electrode recording requires several electrodes to obtain the feedback signal related to each muscle. In this study, we propose an ankle-angle estimation method in which recording is conducted from the proximal nerve trunk with a multichannel cuff electrode to minimize cuff electrode usage. In experiments, muscle afferent signals were recorded from a rabbit's proximal sciatic nerve trunk using a multichannel cuff electrode, and blind source separation and ankle-angle estimation were performed using fast independent component analysis (PP/FastICA) combined with dynamically driven recurrent neural network (DDRNN). The experimental results indicate that the proposed method has high ankle-angle estimation accuracy for both situations when the ankle motion is generated by position servo system or neuromuscular stimulation. Furthermore, the results confirm that the proposed method is applicable to closed-loop FNS systems to control limb motion.

A time-course study of behavioral and electrophysiological characteristics in a mouse model of different stages of Parkinson's disease using 6-hydroxydopamine.

Parkinson's disease (PD) is characterized by abnormal motor symptoms and increased neuronal activity in the subthalamic nucleus (STN) as the disease progresses. We investigated the behavioral and electrophysiological characteristics in a mouse model mimicking the progressive stages of human PD (early, moderate, and advanced) by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB) at three different concentrations (2, 4, and 6 µg/2 µl). Significant changes in motor symptoms were demonstrated between groups in association with relative TH-positive cell loss in the substantia nigra pars compacta (SNc). Moreover, electrophysiologically assessed changes in the mean neuronal firing rate in the STN neurons were comparable to those in the early to advanced stages of human PD. Thus, the mouse model presented herein replicates the unique characteristics of each progressive stage of PD, in both motor and neurophysiological aspects, and therefore can be useful for further investigations of PD pathology.

Characteristics of the neuronal firing patterns in the subthalamic nucleus with graded dopaminergic cell loss in the nigrostriatal pathway.

The aim of this study was to evaluate the neuronal firing changes in the subthalamic nucleus (STN) in a graded mouse model of Parkinson's disease. Unilateral graded dopaminergic cell loss in the substantia nigra pars compacta was achieved by injecting different concentrations of 6-hydroxydopamine (6-OHDA) in the right medial forebrain bundle. Electrophysiological analysis of neuronal firing patterns in the STN revealed an increased firing rate, burst index, and interspike interval coefficient of variation in groups treated with higher 6-OHDA concentrations. The results of this study suggest the detailed pathophysiological characteristics of Parkinson's disease in a mouse model.

Fabrication and characterization of stimulus nerve cuff electrode with highly roughened surface for chronic implant.

Nerve cuff electrodes for peripheral nerve prostheses are required chronically implanted electrodes which simultaneously stimulate and record nerve activity. It is inevitable challenge to investigate electrode material with low interfacial impedance and enhanced charge transfer capacity. In this study, stimulus nerve cuff electrodes on polyimide with Pt, conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT), black Pt, and IrOx were fabricated and characterized. The electrochemical properties were investigated using cyclic voltammetry, electrochemical impedance spectroscopy, and voltage transient measurements. From th experimental results, stimulus nerve cuff electrodes with black Pt showed the highest charge delivery capacity (80 times higher than Pt), charge injection capacity (6 times higher than Pt), and lowest interfacial impedance (3.8 times lower than Pt).

An implantable wireless system for muscle afferent recording from the sciatic nerve during functional electrical stimulation.

An implantable wireless system was developed for recording muscle afferent activity and stimulating peripheral nerves with cuff electrodes. The proposed system was fabricated into the nerve cuff electrode, neural amplifier, neural stimulator, and wireless communication system with battery power. The nerve cuff electrode and neural amplifier were designed to improve the signal-to-interference ratio and signal-to-noise ratio. The wireless communication system was designed based on the medical implant communication service regulations to be suitable for implantation. The main function of this system was to extract muscle afferent activity from peripheral nerve during functional electrical stimulation. The cuff electrodes were chronically implanted on the sciatic nerve for recording and on the tibial and peroneal nerves for stimulation. When the extension and flexion movements of ankle joint were elicited from alternative electrical stimuli, the corresponding neural signals and ankle angles were recorded simultaneously. The muscle afferent activity was then extracted from the recorded neural signal through a simple blanking process. The experimental results showed that the ankle movements could be detected from the extracted muscle afferent activity.

Feedback control of electrode offset voltage during functional electrical stimulation.

Control of the electrode offset voltage is an important issue related to the processes of functional electrical stimulation because excess charge accumulation over time damages both the tissue and the electrodes. This paper proposes a new feedback control scheme to regulate the electrode offset voltage to a predetermined reference value. The electrode offset voltage was continuously monitored using a sample-and-hold (S/H) circuit during stimulation and non-stimulation periods. The stimulation current was subsequently adjusted using a proportional-integral (PI) controller to minimise the error between the reference value and the electrode offset voltage. During the stimulation period, the electrode offset voltage was maintained through the S/H circuit, and the PI controller did not affect the amplitude of the stimulation current. In contrast, during the non-stimulation period, the electrode offset voltage was sampled through the S/H circuit and rapidly regulated through the PI controller. The experimental results obtained using a nerve cuff electrode showed that the electrode offset voltage was successfully controlled in terms of the performance specifications, such as the steady- and transient-state responses and the constraint of the controller output. Therefore, the proposed control scheme can potentially be used in various nerve stimulation devices and applications requiring control of the electrode offset voltage.

Gait phase detection from sciatic nerve recordings in functional electrical stimulation systems for foot drop correction.

Cutaneous afferent activities recorded by a nerve cuff electrode have been used to detect the stance phase in a functional electrical stimulation system for foot drop correction. However, the implantation procedure was difficult, as the cuff electrode had to be located on the distal branches of a multi-fascicular nerve to exclude muscle afferent and efferent activities. This paper proposes a new gait phase detection scheme that can be applied to a proximal nerve root that includes cutaneous afferent fibers as well as muscle afferent and efferent fibers. To test the feasibility of this scheme, electroneurogram (ENG) signals were measured from the rat sciatic nerve during treadmill walking at several speeds, and the signal properties of the sciatic nerve were analyzed for a comparison with kinematic data from the ankle joint. On the basis of these experiments, a wavelet packet transform was tested to define a feature vector from the sciatic ENG signals according to the gait phases. We also propose a Gaussian mixture model (GMM) classifier and investigate whether it could be used successfully to discriminate feature vectors into the stance and swing phases. In spite of no significant differences in the rectified bin-integrated values between the stance and swing phases, the sciatic ENG signals could be reliably classified using the proposed wavelet packet transform and GMM classification methods.

Improvement of signal-to-interference ratio and signal-to-noise ratio in nerve cuff electrode systems.

Cuff electrodes are effective for chronic electroneurogram (ENG) recording while minimizing nerve damage. However, the ENG signals are usually contaminated by electromyogram (EMG) activity from the surrounding muscles, stimulus artifacts produced by the electrical stimulation and noise generated in the first stage of the neural signal amplifier. This paper proposed a new cuff electrode to reduce the interference from EMG signals and stimulus artifacts. As a result, when an additional middle electrode was placed at the center of the cuff electrode, a significant improvement in the signal-to-interference ratio was achieved at 11% for the EMG signals and 12% for the stimulus artifacts when compared to a conventional tripolar cuff. Furthermore, a new low-noise amplifier was proposed to improve the signal-to-noise ratio. The circuit was designed based on a noise analysis to minimize the noise, and the results show that the total noise of the amplifier was below 1 µV for a cuff impedance of 1 kΩ and a frequency bandwidth of 300 to 5000 Hz.