Flexible, Biodegradable, and Wireless Magnetoelectric Paper for Simple In Situ Personalization of Bioelectric Implants.

Bioelectronic implants delivering electrical stimulation offer an attractive alternative to traditional pharmaceuticals in electrotherapy. However, achieving simple, rapid, and cost-effective personalization of these implants for customized treatment in unique clinical and physical scenarios presents a substantial challenge. This challenge is further compounded by the need to ensure safety and minimal invasiveness, requiring essential attributes such as flexibility, biocompatibility, lightness, biodegradability, and wireless stimulation capability. Here, a flexible, biodegradable bioelectronic paper with homogeneously distributed wireless stimulation functionality for simple personalization of bioelectronic implants is introduced. The bioelectronic paper synergistically combines i) lead-free magnetoelectric nanoparticles (MENs) that facilitate electrical stimulation in response to external magnetic field and ii) flexible and biodegradable nanofibers (NFs) that enable localization of MENs for high-selectivity stimulation, oxygen/nutrient permeation, cell orientation modulation, and biodegradation rate control. The effectiveness of wireless electrical stimulation in vitro through enhanced neuronal differentiation of neuron-like PC12 cells and the controllability of their microstructural orientation are shown. Also, scalability, design flexibility, and rapid customizability of the bioelectronic paper are shown by creating various 3D macrostructures using simple paper crafting techniques such as cutting and folding. This platform holds promise for simple and rapid personalization of temporary bioelectronic implants for minimally invasive wireless stimulation therapies.

Technical note: High-efficient and wireless transcranial ultrasound excitation based on electromagnetic acoustic transducer.

BACKGROUND: The generation of transcranial ultrasound is usually based on the piezoelectric effect, so it is necessary to attach transducers around the skull. However, the skull will cause serious attenuation and scattering of ultrasound, which makes it particularly difficult for transcranial ultrasound imaging and modulation. PURPOSE: In transcranial ultrasound imaging, there is significant attenuation and scattering of ultrasound waves by the skull bone. To mitigate this influence and enable precise imaging and high-efficient transcranial ultrasound for specific patients (such as stroke patients who already require craniotomy as part of their surgical care), this paper proposes to use EMAT to excite metal plates placed inside the skull based on the excellent penetration characteristics of EM waves into the skull, generating ultrasound signals, which can completely avoid the influence of skull on ultrasound transmission. METHODS: Based on an efficient wireless transcranial ultrasound experimental platform, we first verified that the skull would not affect the propagation of electromagnetic waves generated by EMAT. In addition, the distribution of the transcranial sound field generated by EMAT was measured. RESULTS: EMAT can generate 1.0 MHz ultrasound by wireless excitation of a 0.1 mm thick copper plate through an adult skull with a thickness of ∼1 cm, and the frequency and amplitude of the generated ultrasound are not affected by the skull. The results indicated that the electromagnetic waves successfully penetrated the skull, with a recorded strength of approximately 2 mV. We also found that the ultrasound signals generated by the EMAT probe through the skull remained unaffected, measuring around 2 mV. In addition, the measurement of the transcranial sound field distribution (80*50 mm2 ) generated by EMAT shows that compared with the traditional extracranial ultrasound generation method, the sound field distribution generated by the wireless excitation of the intracranial copper plate based on EAMT is no longer affected by the uneven and irregular skull. CONCLUSION: Our experiments involved validating the penetration capabilities of electromagnetic waves utilizing the EMAT probe through a 7 (5+2) mm thick organic glass plate and a real human skull ranging from 8 to 15 mm in thickness. The efficient and wireless transcranial ultrasound excitation proposed in this paper may be possible for transcranial ultrasound imaging and therapy.

Magnetoelectric nanoparticles shape modulates their electrical output.

Core-shell magnetoelectric nanoparticles (MENPs) have recently gained popularity thanks to their capability in inducing a local electric polarization upon an applied magnetic field and vice versa. This work estimates the magnetoelectrical behavior, in terms of magnetoelectric coupling coefficient (αME), via finite element analysis of MENPs with different shapes under either static (DC bias) and time-variant (AC bias) external magnetic fields. With this approach, the dependence of the magnetoelectrical performance on the MENPs geometrical features can be directly derived. Results show that MENPs with a more elongated morphology exhibits a superior αME if compared with spherical nanoparticles of similar volume, under both stimulation conditions analyzed. This response is due to the presence of a larger surface area at the interface between the magnetostrictive core and piezoelectric shell, and to the MENP geometrical orientation along the direction of the magnetic field. These findings pave a new way for the design of novel high-aspect ratio magnetic nanostructures with an improved magnetoelectric behaviour.

Photoactive Nanomaterials for Wireless Neural Biomimetics, Stimulation, and Regeneration.

Nanomaterials at the neural interface can provide the bridge between bioelectronic devices and native neural tissues and achieve bidirectional transmission of signals with our brain. Photoactive nanomaterials, such as inorganic and polymeric nanoparticles, nanotubes, nanowires, nanorods, nanosheets or related, are being explored to mimic, modulate, control, or even substitute the functions of neural cells or tissues. They show great promise in next generation technologies for the neural interface with excellent spatial and temporal accuracy. In this review, we highlight the discovery and understanding of these nanomaterials in precise control of an individual neuron, biomimetic retinal prosthetics for vision restoration, repair or regeneration of central or peripheral neural tissues, and wireless deep brain stimulation for treatment of movement or mental disorders. The most intriguing feature is that the photoactive materials fit within a minimally invasive and wireless strategy to trigger the flux of neurologically active molecules and thus influences the cell membrane potential or key signaling molecule related to gene expression. In particular, we focus on worthy pathways of photosignal transduction at the nanomaterial-neural interface and the behavior of the biological system. Finally, we describe the challenges on how to design photoactive nanomaterials specific to neurological disorders. There are also some open issues such as long-term interface stability and signal transduction efficiency to further explore for clinical practice.

Injectable Black Phosphorus Nanosheets for Wireless Nongenetic Neural Stimulation.

Neurons can be modified to express light-sensitive proteins for enabling stimulation with a high spatial and temporal resolution, but such techniques require gene transfection and systematical implantation. Here, a black phosphorus nanosheet-based injectable strategy is described for wireless neural stimulation both in vitro and in vivo without cell modifications. These nanosheets, with minimal invasiveness, high biocompatibility, and biodegradability, are anchored on cell membranes as miniature near-infrared (NIR) light transducers to create local heating for neural activity excitation. Based on cultured multielectrode-array recording, in vivo electrophysiology analysis, and open field behavioral tests, it is demonstrated that remotely applied NIR illumination can reliably trigger spiking activity in cultured neurons and rat brains. Excitingly, reliable regulation of brain function to control animal behaviors is also described. Moreover, this approach has shown its potential for future clinical use by successful high-frequency stimulation in cells and animals in this proof-of-concept study. It is believed that this new method will offer a powerful alternative to other neural stimulation solutions and potentially be of independent value to the healthcare system.

A Versatile Hermetically Sealed Microelectronic Implant for Peripheral Nerve Stimulation Applications.

This article presents a versatile neurostimulation platform featuring a fully implantable multi-channel neural stimulator for chronic experimental studies with freely moving large animal models involving peripheral nerves. The implant is hermetically sealed in a ceramic enclosure and encapsulated in medical grade silicone rubber, and then underwent active tests at accelerated aging conditions at 100°C for 15 consecutive days. The stimulator microelectronics are implemented in a 0.6-µm CMOS technology, with a crosstalk reduction scheme to minimize cross-channel interference, and high-speed power and data telemetry for battery-less operation. A wearable transmitter equipped with a Bluetooth Low Energy radio link, and a custom graphical user interface provide real-time, remotely controlled stimulation. Three parallel stimulators provide independent stimulation on three channels, where each stimulator supports six stimulating sites and two return sites through multiplexing, hence the implant can facilitate stimulation at up to 36 different electrode pairs. The design of the electronics, method of hermetic packaging and electrical performance as well as in vitro testing with electrodes in saline are presented.

Wireless Subcutaneous Trigeminal Nerve Field Stimulation for Refractory Trigeminal Pain: A Single Center Experience.

INTRODUCTION: Subcutaneous trigeminal nerve field stimulation (sTNFS) is a neuromodulatory treatment for neuropathic trigeminal pain with the ability to reduce the intensity and frequency of pain attacks. However, hardware issues including lead migration, skin erosion, infection, so-called pocket pain at the site of the implanted neurostimulator are reported. Implantable wireless neurostimulation technology promises not only an even less invasive sTNFS treatment and thinner and more flexible electrodes better suited for facial implants, but also provides further advantages such as lack of an implantable neurostimulator and 3T magnetic resonance imaging compatibility. MATERIAL AND METHODS: All patients who had received trial stimulation with a partially implantable sTNFS system were analyzed for ICHD-3 (3rd edition of the International Classification of Headache Disorders) diagnosis, success of trial stimulation, pre- and postoperative pain intensity, frequency of attacks, complications, and side-effects of sTNFS. RESULTS: All patients (N = 3) responded to sTNFS (≥50% pain reduction) during the trial period. According to ICHD-3, N = 2 of the patients were classified with trigeminal neuralgia (TN) with concomitant persistent facial pain and N = 1 patient with multiple sclerosis associated TN. The time of the test period was 44 ± 31.24 days (mean ± SD). The average daily duration of stimulation per patient amounted 2.5 ± 2.2 hours (range 1-5). The pain intensity (defined on a visual analog scale) was reduced by 80% ± 17% (mean ± SD). Reduction or cessation in pain medication was observed in all patients. No surgical complications occurred in the long-term follow-up period of 18.84 ± 6 (mean ± SD) months. CONCLUSION: The partially implantable sTNFS device seems to be safe, effective, and reliable. Compared to conventional devices, the equipment is not limited to the length of trial stimulation. Furthermore, the daily stimulation duration was much shorter compared to previous reports.

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

BACKGROUND: Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates. METHODS: The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35 days, patients will be treated consecutively with three different SCS paradigms ("burst," "1 kHz," and "1.499 kHz") and placebo stimulation. Each SCS paradigm will be applied for 5 days with a washout period of 70 h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5 days of SCS. Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life (as determined by Quality of Life EQ-5D-5L questionnaire), anxiety perception (as determined by the Hospital Anxiety and Depression Scale), and physical restriction (as determined by the Oswestry Disability Index). DISCUSSION: Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00018929 . Registered on 14 January 2020.

Wireless Spinal Cord Stimulation Technology for the Treatment of Neuropathic Pain: A Single-Center Experience.

OBJECTIVES: A new wireless spinal cord stimulation (SCS) technology, which was introduced in recent years, promises minimal invasive SCS as well as additional advantages such as a wide range of stimulation paradigms and 3-T magnetic resonance imaging (MRI) conditionality. MATERIALS AND METHODS: We prospectively evaluated 12 patients suffering from therapy-resistant neuropathic pain, who were implanted with a wireless SCS system from 2017 to 2019. Potential issues pertaining to handling and usability of the SCS device were evaluated from a patients' as well as from a surgeon's perspective. RESULTS: Mean follow-up was 228.0 days (95% CI, 20.0-518.0 days). We did not record any handling issues nor did we record any relevant local discomfort associated with the implanted SCS device. N = 3/12 patients reported discomfort from wearing the SCS antenna and one patient complained about a short battery life of the controller device. There were no reported incidents during 3-T MRI studies. After an average test period of 51.7 days (95% CI, 11.0-104.0 days), N = 9/12 patients (75%) had reached pain relief of 50% or more with an average pain relief (responders and partial responders) of 67.4% (95% CI, 50.0%-85.0%). On average, patients tested 2.2 different stimulation paradigms, with frequencies ranging from 60 Hz to 10 kHz, but there was no preferred stimulation paradigm. CONCLUSIONS: Minimal invasive implantation of wireless SCS systems was feasible and safe. The device offered a broader range of stimulation paradigms compared to conventional SCS devices, an allowed for a prolonged testing phase and continuous adjustment of SCS programs.

Redefining Spinal Cord Stimulation "Trials": A Randomized Controlled Trial Using Single-Stage Wireless Permanent Implantable Devices.

BACKGROUND: "Traditional" spinal cord stimulation (SCS) trials with percutaneous electrodes externalized to a pulse generator (PG) are typically limited in duration due to risk of infection. Newer miniaturized wireless SCS technology eliminates the percutaneous extension (as well as PGs implanted for chronic use), thus facilitating a single-stage implantation after which the device can remain indefinitely. OBJECTIVE: To evaluate fully implanted wireless SCS devices during a 30-day screening trial in subjects with chronic low back pain and leg pain and a history of lumbosacral spine surgery. METHODS: In a randomized controlled trial of single-stage wireless SCS using a wireless percutaneous system, 99 subjects received either 10 kHz high frequency stimulation (HFS) or lower frequency stimulation (LFS) below 1500 Hz (Bolash R, Creamer M, Rauck R, et al. Wireless high frequency spinal cord stimulation (10 kHz) compared to multi-waveform low frequency spinal cord stimulation in the management of chronic pain in failed back surgery syndrome subjects: preliminary results of a multicenter, prospective, randomized controlled study. Pain Med 2019, https://doi.org/10.1093/pm/pnz019). In this report, we assess the 30-day trial success rate (≥50% pain relief from baseline) and complications. RESULTS: The overall trial success rate was 88% (87/99): 92% (46/50) for HFS and 84% (41/49) for LFS (NS). The trial success rate in the 64 subjects with predominant low back pain was 92% (59/64) vs. 80% (28/35) in those with leg pain ≥ low back pain (NS). During the screening trial, one infection occurred (1%) and one subject withdrew and was explanted (1%). Electrode migrations were seen on routine follow-up x-rays in 10 cases (10%). CONCLUSION: Using wireless SCS devices that allow for an extended trial period and evaluation of various waveforms, we observed a high rate trial success rate with both HFS and LFS waveforms, with minimal incidence of infection. Long-term follow-up will address the cost-effectiveness and morbidity associated with this technology, which facilitates single-stage treatment.

A case report of wireless peripheral nerve stimulation for complex regional pain syndrome type-I of the upper extremity: 1 year follow up.

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic disabling painful disorder with limited options to achieve therapeutic relief. CRPS type I which follows trauma, may not show obvious damage to the nervous structures and remains dubious in its pathophysiology and also its response to conservative treatment or interventional pain management is elusive. Spinal cord and dorsal root ganglion stimulation (SCS, DRGS) provide good relief, mainly for causalgia or CRPS I of lower extremities but not very encouraging for upper extremity CRPS I. we reported earlier, a case of CRPS I of right arm treated successfully by wireless peripheral nerve stimulation (WPNS) with short term follow up. Here we present 1-year follow-up of this patient. OBJECTIVE: To present the first case of WPNS for CRPS I with a year follow up. The patient had minimally invasive peripheral nerve stimulation (PNS), without implantable pulse generator (IPG) or its accessories. CASE REPORT: This was a case of refractory CRPS I after blunt trauma to the right forearm of a young female. She underwent placement of two Stimwave electrodes (Leads: FR4A-RCV-A0 with tines, Generation 1 and FR4A-RCV-B0 with tines, Generation 1) in her forearm under intraoperative electrophysiological and ultrasound guidance along radial and median nerves. This WPNS required no IPG. At high frequency (HF) stimulation (HF 10 kHz/32 µs, 2.0 mA), patient had shown remarkable relief in pain, allodynia and temperature impairment. At 5 months she started driving without opioid consumption, while allodynia disappeared. At 1 year follow up she was relieved of pain [visual analogue scale (VAS) score of 4 from 7] and Kapanji Index (Score) improved to 7-8. Both hands look similar in color and temperature. She never made unscheduled visits to the clinic or visited emergency room for any complications related to the WPNS. CONCLUSIONS: CRPS I involving upper extremity remain difficult to manage with conventional SCS or DRGS because of equipment related adverse events. Minimally invasive WPNS in this case had shown consistent relief without any complications or side effects related to the wireless technology or the technique at the end of 1 year. IMPLICATIONS: This is the first case illustration of WPNS for CRPS I, successfully treated and followed up for 1 year.

Piezoelectric barium titanate nanostimulators for the treatment of glioblastoma multiforme.

Major obstacles to the successful treatment of gliolastoma multiforme are mostly related to the acquired resistance to chemotherapy drugs and, after surgery, to the cancer recurrence in correspondence of residual microscopic foci. As innovative anticancer approach, low-intensity electric stimulation represents a physical treatment able to reduce multidrug resistance of cancer and to induce remarkable anti-proliferative effects by interfering with Ca2+ and K+ homeostasis and by affecting the organization of the mitotic spindles. However, to preserve healthy cells, it is utterly important to direct the electric stimuli only to malignant cells. In this work, we propose a nanotechnological approach based on ultrasound-sensitive piezoelectric nanoparticles to remotely deliver electric stimulations to glioblastoma cells. Barium titanate nanoparticles (BTNPs) have been functionalized with an antibody against the transferrin receptor (TfR) in order to obtain the dual targeting of blood-brain barrier and of glioblastoma cells. The remote ultrasound-mediated piezo-stimulation allowed to significantly reduce in vitro the proliferation of glioblastoma cells and, when combined with a sub-toxic concentration of temozolomide, induced an increased sensitivity to the chemotherapy treatment and remarkable anti-proliferative and pro-apoptotic effects.

Piezoelectric Effects of Materials on Bio-Interfaces.

Electrical stimulation of cells and tissues is an important approach of interaction with living matter, which has been traditionally exploited in the clinical practice for a wide range of pathological conditions, in particular, related to excitable tissues. Standard methods of stimulation are, however, often invasive, being based on electrodes and wires used to carry current to the intended site. The possibility to achieve an indirect electrical stimulation, by means of piezoelectric materials, is therefore of outstanding interest for all the biomedical research, and it emerged in the latest decade as a most promising tool in many bioapplications. In this paper, we summarize the most recent achievements obtained by our group and by others in the exploitation of piezoelectric nanoparticles and nanocomposites for cell stimulation, describing the important implications that these studies present in nanomedicine and tissue engineering. A particular attention will be also dedicated to the physical modeling, which can be extremely useful in the description of the complex mechanisms involved in the mechanical/electrical transduction, yet also to gain new insights at the base of the observed phenomena.

Serial assessment of functional recovery following nerve injury using implantable thin-film wireless nerve stimulators.

INTRODUCTION: Comprehensive assessment of the time course of functional recovery following peripheral nerve repair is critical for surgical management of peripheral nerve injuries. This study describes the design and implementation of a novel implantable wireless nerve stimulator capable of repeatedly interfacing peripheral nerve tissue and providing serial evaluation of functional recovery postoperatively. METHODS: Thin-film wireless implants were fabricated and subcutaneously implanted into Lewis rats. Wireless implants were used to serially stimulate rat sciatic nerve and assess functional recovery over 3 months following various nerve injuries. RESULTS: Wireless stimulators demonstrated consistent performances over 3 months in vivo and successfully facilitated serial assessment of nerve and muscle function following nerve crush and nerve transection injuries. CONCLUSIONS: This study highlights the ability of implantable wireless nerve stimulators to provide a unique view into the time course of functional recovery in multiple motor targets. Muscle Nerve 54: 1114-1119, 2016.