Multiple sessions of therapeutic electrical stimulation using implantable thin-film wireless nerve stimulators improve functional recovery after sciatic nerve isograft repair.

INTRODUCTION/AIMS: Although therapeutic electrical stimulation (TES) of injured peripheral nerve promotes axon regeneration and functional recovery, clinical applications of this therapy are limited to the intraoperative timeframe. Implantable, thin-film wireless nerve stimulators offer a potential solution to this problem by enabling delivery of electrical stimuli to an injured nerve over a period of several days post-surgery. The aim of this study was to determine the optimal time course of stimulation for maximizing functional recovery in a rat sciatic nerve isograft repair model. METHODS: Adult male Lewis rats underwent thin-film wireless nerve stimulator implantation following sciatic nerve transection and 40 mm nerve isograft repair. Immediately after surgery, animals began a daily regimen of TES for up to 12 consecutive days. Functional recovery was assessed by compound muscle action potential (CMAP), evoked muscle force, wet muscle mass, and axon counting. RESULTS: Serial CMAP measurements increased in amplitude over the course of the study, yet no significant difference between cohorts for serial or terminal CMAPs was observed. Axon counts and wet muscle mass measurements were greatest in the 6-day stimulation group, which correlated with a significant increase in evoked muscle force for the 6-day stimulation group at the terminal time point. DISCUSSION: Six daily sessions of TES were found to be most effective for augmenting functional recovery compared to other time courses of stimulation. Future studies should incorporate additional subjects and track axonal sprouting or measure neurotrophin levels during the therapeutic window to further elucidate the mechanisms behind, and ideal amount of, TES.

Intramuscular Microvascular Flow Sensing for Flap Monitoring in a Porcine Model of Arterial and Venous Occlusion.

BACKGROUND: Commercially available near infrared spectroscopy devices for continuous free flap tissue oxygenation (StO2) monitoring can only be used on flaps with a cutaneous component. Additionally, differences in skin quality and pigmentation may alter StO2 measurements. Here, we present a novel implantable heat convection probe that measures microvascular blood flow for peripheral monitoring of free flaps, and is not subject to the same issues that limit the clinical utility of near-infrared spectroscopy. METHODS: The intratissue microvascular flow-sensing device includes a resistive heater, 4 thermistors, a small battery, and a Bluetooth chip, which allows connection to a smart device. Convection of applied heat is measured and mathematically transformed into a measurement of blood flow velocity. This was tested alongside Vioptix T.Ox in a porcine rectus abdominis myocutaneous flap model of arterial and venous occlusion. After flap elevation, the thermal device was deployed intramuscularly, and the cutaneous T.Ox device was applied. Acland clamps were alternately applied to the flap artery and veins to achieve 15 minutes periods of flap ischemia and congestion with a 15 minutes intervening recovery period. In total, five devices were tested in three flaps in three separate pigs over 16 vaso-occlusive events. RESULTS: Flow measurements were responsive to both ischemia and congestion, and returned to baseline during recovery periods. Flow measurements corresponded closely with measured StO2. Cross-correlation at zero lag showed agreement between these two sensing modalities. Two novel devices tested simultaneously on the same flap showed only minor variations in flow measurements. CONCLUSION: This novel probe is capable of detecting changes in tissue microcirculatory blood flow. This device performed well in a swine model of flap ischemia and congestion, and shows promise as a potentially useful clinical tool. Future studies will investigate performance in fasciocutaneous flaps and characterize longevity of the device over a period of several days.

Intramuscular Near-Infrared Spectroscopy for Muscle Flap Monitoring in a Porcine Model.

BACKGROUND: Current near-infrared spectroscopy (NIRS)-based systems for continuous flap monitoring are limited to flaps which carry a cutaneous paddle. As such, this useful and reliable technology has not previously been applicable to muscle-only free flaps where other modalities with substantial limitations continue to be utilized. METHODS: We present the first NIRS probe which allows continuous monitoring of local tissue oxygen saturation (StO2) directly within the substance of muscle tissue. This probe is flexible, subcentimeter in scale, waterproof, biocompatible, and is fitted with resorbable barbs which facilitate temporary autostabilization followed by easy atraumatic removal. This novel device was compared with a ViOptix T.Ox monitor in a porcine rectus abdominus myocutaneous flap model of arterial and venous occlusions. During these experiments, the T.Ox device was affixed to the skin paddle, while the novel probe was within the muscle component of the same flap. RESULTS: The intramuscular NIRS device and skin-mounted ViOptix T.Ox devices produced very similar StO2 tracings throughout the vascular clamping events, with obvious and parallel changes occurring upon vascular clamping and release. The normalized cross-correlation at zero lag describing correspondence between the novel intramuscular NIRS and T.Ox devices was >0.99. CONCLUSION: This novel intramuscular NIRS probe offers continuous monitoring of oxygen saturation within muscle flaps. This experiment demonstrates the potential suitability of this intramuscular NIRS probe for the task of muscle-only free flap monitoring, where NIRS has not previously been applicable. Testing in the clinical environment is necessary to assess durability and reliability.

A Wireless Near-Infrared Spectroscopy Device for Flap Monitoring: Proof of Concept in a Porcine Musculocutaneous Flap Model.

BACKGROUND: Current near-infrared spectroscopy (NIRS)-based systems for continuous flap monitoring are highly sensitive for detecting malperfusion. However, the clinical utility and user experience are limited by the wired connection between the sensor and bedside console. This wire leads to instability of the flap-sensor interface and may cause false alarms. METHODS: We present a novel wearable wireless NIRS sensor for continuous fasciocutaneous free flap monitoring. This waterproof silicone-encapsulated Bluetooth-enabled device contains two light-emitting diodes and two photodetectors in addition to a battery sufficient for 5 days of uninterrupted function. This novel device was compared with a ViOptix T.Ox monitor in a porcine rectus abdominus myocutaneous flap model of arterial and venous occlusions. RESULTS: Devices were tested in four flaps using three animals. Both devices produced very similar tissue oxygen saturation (StO2) tracings throughout the vascular clamping events, with obvious and parallel changes occurring on arterial clamping, arterial release, venous clamping, and venous release. Small interdevice variations in absolute StO2 value readings and magnitude of change were observed. The normalized cross-correlation at zero lag describing correspondence between the novel NIRS and T.Ox devices was >0.99 in each trial. CONCLUSION: The wireless NIRS flap monitor is capable of detecting StO2 changes resultant from arterial vascular occlusive events. In this porcine flap model, the functionality of this novel sensor closely mirrored that of the T.Ox wired platform. This device is waterproof, highly adhesive, skin conforming, and has sufficient battery life to function for 5 days. Clinical testing is necessary to determine if this wireless functionality translates into fewer false-positive alarms and a better user experience.

Schwann cells seeded in acellular nerve grafts improve functional recovery.

INTRODUCTION: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared with nerve isografts. METHODS: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regeneration, and functional recovery were evaluated in a 14-mm rat sciatic injury model and compared with isografts. RESULTS: At 14 days, motor or sensory-derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, histomorphometric analysis found CP-ANGs with SCs and isografts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation. CONCLUSIONS: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect.

Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis.

Monitoring homeostasis is an essential aspect of obtaining pathophysiological insights for treating patients. Accurate, timely assessments of homeostatic dysregulation in deep tissues typically require expensive imaging techniques or invasive biopsies. We introduce a bioresorbable shape-adaptive materials structure that enables real-time monitoring of deep-tissue homeostasis using conventional ultrasound instruments. Collections of small bioresorbable metal disks distributed within thin, pH-responsive hydrogels, deployed by surgical implantation or syringe injection, allow ultrasound-based measurements of spatiotemporal changes in pH for early assessments of anastomotic leaks after gastrointestinal surgeries, and their bioresorption after a recovery period eliminates the need for surgical extraction. Demonstrations in small and large animal models illustrate capabilities in monitoring leakage from the small intestine, the stomach, and the pancreas.

Bioresorbable, wireless, passive sensors for continuous pH measurements and early detection of gastric leakage.

Continuous monitoring of biomarkers at locations adjacent to targeted internal organs can provide actionable information about postoperative status beyond conventional diagnostic methods. As an example, changes in pH in the intra-abdominal space after gastric surgeries can serve as direct indicators of potentially life-threatening leakage events, in contrast to symptomatic reactions that may delay treatment. Here, we report a bioresorbable, wireless, passive sensor that addresses this clinical need, designed to locally monitor pH for early detection of gastric leakage. A pH-responsive hydrogel serves as a transducer that couples to a mechanically optimized inductor-capacitor circuit for wireless readout. This platform enables real-time monitoring of pH with fast response time (within 1 hour) over a clinically relevant period (up to 7 days) and timely detection of simulated gastric leaks in animal models. These concepts have broad potential applications for temporary sensing of relevant biomarkers during critical risk periods following diverse types of surgeries.

Antimicrobial Effectiveness Testing of Resorbable Electrospun Fiber Matrix per United States Pharmacopeia (USP) <51>.

Contamination of surgical, traumatic, and chronic wounds with microorganisms presents a challenge to successful wound healing. In the present in vitro study, a synthetic electrospun fiber matrix (SEFM) cleared for use in the management of chronic, surgical, and traumatic wounds underwent USP (United States Pharmacopeia) <51> Antimicrobial Effectiveness Testing to determine its in vitro effectiveness against various microorganisms commonly found in non-healing wounds. The SEFM was tested in both sheet (s-SEFM) and micronized form (m-SEFM) against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus brasiliensis, Candida albicans, Proteus mirabilis, and Enterococcus faecalis. Testing was performed per the USP <51> standard on days 7, 14, and 28. Both the s-SEFM and m-SEFM met the USP <51> acceptance criteria for all microorganisms. The results obtained for s-SEFM demonstrated >1-log10 reduction against E. coli, S. aureus, P. aeruginosa, P. mirabilis, E. faecalis, and C. albicans at day 7; >3-log10 reduction with no detection of these microbes at days 14 and 28, and no increase from initial inoculum at days 7, 14, and 28 against A. brasiliensis. The results obtained for m-SEFM demonstrated >3-log10 reduction with no detectable microorganisms at day 7. The results observed in this study indicate that the SEFM is effective in vitro at inhibiting bacterial and fungal growth and colonization per USP <51> testing.

Electroactive Spinal Instrumentation for Targeted Osteogenesis and Spine Fusion: A Computational Study.

BACKGROUND: Direct current electrical stimulation may serve as a promising nonpharmacological adjunct promoting osteogenesis and fusion. The aim of this study was to evaluate the utility of electroactive spine instrumentation in the focal delivery of therapeutic electrical stimulation to enhance lumbar bone formation and interbody fusion. METHODS: A finite element model of adult human lumbar spine (L4-L5) instrumented with single-level electroactive pedicle screws was simulated. Direct current electrical stimulation was routed through anodized electroactive pedicle screws to target regions of fusion. The electrical fields generated by electroactive pedicle screws were evaluated in various tissue compartments including isotropic tissue volumes, cortical, and trabecular bone. Electrical field distributions at various stimulation amplitudes (20-100 µA) and pedicle screw anodization patterns were analyzed in target regions of fusion (eg, intervertebral disc space, vertebral body, and pedicles). RESULTS: Electrical stimulation with electroactive pedicle screws at various stimulation amplitudes and anodization patterns enabled modulation of spatial distribution and intensity of electric fields within the target regions of lumbar spine. Anodized screws (50%) vs unanodized screws (0%) induced high-amplitude electric fields within the intervertebral disc space and vertebral body but negligible electric fields in spinal canal. Direct current electrical stimulation via anodized screws induced electrical fields, at therapeutic threshold of >1 mV/cm, sufficient for osteoinduction within the target interbody region. CONCLUSIONS: Selective anodization of electroactive pedicle screws may enable focal delivery of therapeutic electrical stimulation in the target regions in human lumbar spine. This study warrants preclinical and clinical testing of integrated electroactive system in inducing target lumbar fusion in vivo. CLINICAL RELEVANCE: The findings of this study provide a foundation for clinically investigating electroactive intrumentation to enhance spine fusion.

Percutaneously introduced wireless intramuscular near-infrared spectroscopy device detects muscle oxygenation changes in porcine model of lower extremity compartment syndrome.

Serial examination and direct measurement of intracompartmental pressure (ICP) are suboptimal strategies for the detection of acute compartment syndrome (CS) because they are operator-dependent and yield information that only indirectly reflects intracompartmental muscle perfusion. As a result, instances of unnecessary fasciotomy and unrecognized CS are relatively common. Recently, near-infrared spectroscopy (NIRS)-based systems for compartment monitoring have generated interest as an adjunct tool. Under ideal conditions, NIRS directly measures the oxygenation of intracompartmental muscle (StO2 ), thereby obviating the challenges of interpreting equivocal clinical examination or ICP data. Despite these potential advantages, existing NIRS sensors are plagued by technical difficulties that limit clinical utility. Most of these limitations relate to their transcutaneous design that makes them susceptible to both interference from intervening skin/subcutaneous tissue, underlying hematoma, and instability of the skin-sensor interface. Here, we present a flexible, wireless, Bluetooth-enabled, percutaneously introducible intramuscular NIRS device that directly and continuously measures the StO2 of intracompartmental muscle. Proof of concept for this device is demonstrated in a swine lower extremity balloon compression model of acute CS, wherein we simultaneously track muscle oxygenation, ICP, and compartment perfusion pressure (PP). The observed StO2 decreased with increasing ICP and decreasing PP and then recovered following pressure reduction. The mean change in StO2 as the PP was decreased from baseline to 30 mmHg was -7.6%. The mean difference between baseline and nadir StO2 was -17.4%. Cross-correlations (absolute value) describing the correspondence between StO2 and ICP were >0.73. This novel intramuscular NIRS device identifies decreased muscle perfusion in the setting of evolving CS.

Development of novel electrospun absorbable polycaprolactone (PCL) scaffolds for hernia repair applications.

INTRODUCTION: Permanent/nonresorbable hernia repair materials rely on profibrotic wound healing, and repair sites are commonly composed of disorganized tissue with inferior mechanical strength and risk of reherniation. Resorbable electrospun scaffolds represent a novel class of biomaterials, which may provide a unique platform for the design of advanced soft tissue repair materials. These materials are simple, inexpensive, nonwoven materials composed of polymer fibers that readily mimic the natural extracellular matrix. The primary goal of the present study was to evaluate the physiomechanical properties of novel electrospun scaffolds to determine their suitability for hernia repair. Based on previous experimentation, scaffolds possessing ≥ 20 N suture retention strength, ≥ 20 N tear resistance, and ≥ 50 N/cm tensile strength are appropriate for hernia repair. METHODS: Six novel electrospun scaffolds were fabricated by varying combinations of polymer concentration (10-12 %) and flow rate (3.5-10 mL/h). Briefly, poly(ε-caprolactone) (PCL) was dissolved in a solvent mixture and electrospun onto a planar metal collector, yielding sheets with randomly oriented fibers. Physiomechanical properties were evaluated through scanning electron microscopy, laser micrometry, and mechanical testing. RESULTS: Scanning electron micrographs demonstrated fiber diameters ranging from 1.0 ± 0.1 µm (10 % PCL, 3.5 mL/h) to 1.5 ± 0.2 µm (12 % PCL, 4 mL/h). Laser micrometry demonstrated thicknesses ranging from 0.72 ± 0.07 mm (12 % PCL, 10 mL/h) to 0.91 ± 0.05 mm (10 % PCL, 3.5 mL/h). Mechanical testing identified two scaffolds possessing suture retention strengths ≥ 20 N (12 % PCL, 10 mL/h and 12 % PCL, 6 mL/h), and no scaffolds possessing tear resistance values ≥ 20 N (range, 4.7 ± 0.9 N to 10.6 ± 1.8 N). Tensile strengths ranged from 35.27 ± 2.08 N/cm (10 % PCL, 3.5 mL/h) to 81.76 ± 15.85 N/cm (12 % PCL, 4 mL/h), with three scaffolds possessing strengths ≥ 50 N/cm (12 % PCL, 10 mL/h; 12 % PCL, 6 mL/h; 12 % PCL, 4 mL/h). CONCLUSIONS: Two electrospun scaffolds (12 % PCL, 10 mL/h and 12 % PCL, 6 mL/h) possessed suture retention and tensile strengths appropriate for hernia repair, justifying evaluation in a large animal model. Additional studies examining advanced methods of fabrication may further improve the unique properties of these scaffolds, propelling them into applications in a variety of clinical settings.

GDNF overexpression fails to provoke muscle recovery from botulinum toxin poisoning: a preliminary study.

Glial cell line-derived neurotrophic factor (GDNF) has potent axonal growth and survival effects on motoneurons. This study used transgenic Myo-GDNF mice to assess the effects of targeted GDNF overexpression on functional recovery after botulinum toxin type A (BTxA) chemodenervation. BTxA (0.1 U) was injected into the tibialis anterior (TA) muscle of wild-type CF1 and transgenic Myo-GDNF mice. On days 1, 7, 14, and 21 after injection, evoked muscle force production and muscle mass were measured (n = 6, for each group at each time point). Greater maximal tetanic force and calculated specific force were evoked in Myo-GDNF animals when compared with control CF1 animals at days 1, 7, and 21. However, the differences were not statistically significant. Similarly, modest reductions in muscle atrophy in the Myo-GDNF group at all time points were not statistically significant. Targeted overexpression of GDNF in the muscles of Myo-GDNF mice did not improve motor recovery in the first 21 days after BTxA chemodenervation.

A custom interface for the joint operation of Med Associates and Tucker-Davis Technologies hardware in a rodent behavioral model.

BACKGROUND: Rodent behavioral models with an electrophysiological component may require the joint operation of hardware from Med Associates, Inc. (St. Albans, VT) and Tucker-Davis Technologies (TDT; Alachua, FL). Although these manufacturers do produce supplemental hardware for interfacing with each other, investing in such hardware may be untenable for research groups with limited funds who wish to use equipment already in their possession. NEW METHOD: We designed a printed circuit board (PCB) in KiCad and had it fabricated by Advanced Circuits (Aurora, CO), with components sourced from Digi-Key (Thief River Falls, MN). The PCB provided 8 channels of bidirectional communication for the transmission of signals between Med Associates' SG-716B SmartCtrl connection panel and TDT's RZ5D base station. This setup enabled the coordinated operation of programs running separately on each set of hardware. RESULTS: The custom-built PCB facilitated the joint operation of Med Associates and TDT hardware in a go/no-go detection task involving rats with electrical implants in their sciatic nerves. COMPARISON WITH EXISTING METHODS: Conventional methods for interfacing Med Associates and Tucker-Davis Technologies rely on the purchase of pre-built hardware whose costs can add up to thousands of dollars. The present method offers a viable alternative that is easily implemented and considerably less expensive (below $200). CONCLUSION: The present approach provides an inexpensive yet effective alternative to far more costly interfacing solutions offered by Med Associates and Tucker-Davis Technologies.

Implantable, wireless, self-fixing thermal sensors for continuous measurements of microvascular blood flow in flaps and organ grafts.

Vascular pedicle thrombosis after free flap transfer or solid organ transplantation surgeries can lead to flap necrosis, organ loss requiring re-transplantation, or even death. Although implantable flow sensors can provide early warning of malperfusion and facilitate operative salvage, measurements performed with existing technologies often depend on extrinsic conditions such as mounting methods and environmental fluctuations. Furthermore, the mechanisms for fixing such probes to vascular or skeletal structures may disrupt the normal blood flow or cause unnecessary tissue damage. Requirements for wired connections to benchtop readout systems also increase costs, complicate clinical care and constrain movements of the patient. Here, we report a wireless, miniaturized flow sensing system that exploits sub-millimeter scale, multi-nodal thermal probes, with biodegradable barbs that secure the probes to the surrounding tissues in a manner that facilitates removal after a period of use. These smartphone-readable devices, together with experimentally validated analytical models of the thermal transport physics, enable reliable, accurate flow sensing in ways that are largely immune to variations in temperature and mechanical perturbations. In vivo demonstrations of this technology in porcine myocutaneous flap and kidney malperfusion models highlight the essential capabilities in microsurgical and transplantation-related biomedical application scenarios.

Soft, bioresorbable coolers for reversible conduction block of peripheral nerves.

Implantable devices capable of targeted and reversible blocking of peripheral nerve activity may provide alternatives to opioids for treating pain. Local cooling represents an attractive means for on-demand elimination of pain signals, but traditional technologies are limited by rigid, bulky form factors; imprecise cooling; and requirements for extraction surgeries. Here, we introduce soft, bioresorbable, microfluidic devices that enable delivery of focused, minimally invasive cooling power at arbitrary depths in living tissues with real-time temperature feedback control. Construction with water-soluble, biocompatible materials leads to dissolution and bioresorption as a mechanism to eliminate unnecessary device load and risk to the patient without additional surgeries. Multiweek in vivo trials demonstrate the ability to rapidly and precisely cool peripheral nerves to provide local, on-demand analgesia in rat models for neuropathic pain.

A bioresorbable peripheral nerve stimulator for electronic pain block.

Local electrical stimulation of peripheral nerves can block the propagation of action potentials, as an attractive alternative to pharmacological agents for the treatment of acute pain. Traditional hardware for such purposes, however, involves interfaces that can damage nerve tissue and, when used for temporary pain relief, that impose costs and risks due to requirements for surgical extraction after a period of need. Here, we introduce a bioresorbable nerve stimulator that enables electrical nerve block and associated pain mitigation without these drawbacks. This platform combines a collection of bioresorbable materials in architectures that support stable blocking with minimal adverse mechanical, electrical, or biochemical effects. Optimized designs ensure that the device disappears harmlessly in the body after a desired period of use. Studies in live animal models illustrate capabilities for complete nerve block and other key features of the technology. In certain clinically relevant scenarios, such approaches may reduce or eliminate the need for use of highly addictive drugs such as opioids.

Wireless implantable optical probe for continuous monitoring of oxygen saturation in flaps and organ grafts.

Continuous, real-time monitoring of perfusion after microsurgical free tissue transfer or solid organ allotransplantation procedures can facilitate early diagnosis of and intervention for anastomotic thrombosis. Current technologies including Doppler systems, cutaneous O2-sensing probes, and fluorine magnetic resonance imaging methods are limited by their intermittent measurements, requirements for skilled personnel, indirect interfaces, and/or their tethered connections. This paper reports a wireless, miniaturized, minimally invasive near-infrared spectroscopic system designed for uninterrupted monitoring of local-tissue oxygenation. A bioresorbable barbed structure anchors the probe stably at implantation sites for a time period matched to the clinical need, with the ability for facile removal afterward. The probe connects to a skin-interfaced electronic module for wireless access to essential physiological parameters, including local tissue oxygenation, pulse oxygenation, and heart rate. In vitro tests and in vivo studies in porcine flap and kidney models demonstrate the ability of the system to continuously measure oxygenation with high accuracy and sensitivity.

High-speed, scanned laser structuring of multi-layered eco/bioresorbable materials for advanced electronic systems.

Physically transient forms of electronics enable unique classes of technologies, ranging from biomedical implants that disappear through processes of bioresorption after serving a clinical need to internet-of-things devices that harmlessly dissolve into the environment following a relevant period of use. Here, we develop a sustainable manufacturing pathway, based on ultrafast pulsed laser ablation, that can support high-volume, cost-effective manipulation of a diverse collection of organic and inorganic materials, each designed to degrade by hydrolysis or enzymatic activity, into patterned, multi-layered architectures with high resolution and accurate overlay registration. The technology can operate in patterning, thinning and/or cutting modes with (ultra)thin eco/bioresorbable materials of different types of semiconductors, dielectrics, and conductors on flexible substrates. Component-level demonstrations span passive and active devices, including diodes and field-effect transistors. Patterning these devices into interconnected layouts yields functional systems, as illustrated in examples that range from wireless implants as monitors of neural and cardiac activity, to thermal probes of microvascular flow, and multi-electrode arrays for biopotential sensing. These advances create important processing options for eco/bioresorbable materials and associated electronic systems, with immediate applicability across nearly all types of bioelectronic studies.

High-Frequency Alternating Current Block Using Macro-Sieve Electrodes: A Pilot Study.

Background and objective High-frequency alternating current (HFAC) can yield a rapid-acting and reversible nerve conduction block. The present study aimed to demonstrate the successful implementation of HFAC block delivery via regenerative macro-sieve electrodes (MSEs). Methods Dual-electrode assemblies in two configurations [dual macro-sieve electrode-1 (DMSE-I), DMSE-II] were fabricated from pairs of MSEs and implanted in the transected and subsequently repaired sciatic nerves of two male Lewis rats. After four months of postoperative nerve regeneration through the MSEs' transit zones, the efficacy of acute HFAC block was tested for both configurations. Frequencies ranging from 10 kHz to 42 kHz, and stimulus amplitudes with peak-to-peak voltages ranging from 2 V to 20 V were tested. Evoked muscle force measurement was used to quantify the nerve conduction block. Results HFAC stimulation delivered via DMSE assemblies obtained a complete block at frequencies of 14 to 26 kHz and stimulus amplitudes of 12 to 20 V p-p. The threshold voltage for the complete block showed an approximately linear dependence on frequency. The threshold voltage for the partial conduction block was also approximately linear. For those frequencies that displayed both partial and complete block, the partial block thresholds were consistently lower. Conclusion This study provides a proof of concept that regenerative MSEs can achieve complete and reversible conduction block via HFAC stimulation of regenerated nerve tissue. A chronically interfaced DMSE assembly may thereby facilitate the inactivation of targeted nerves in cases wherein pathologic neuronal hyperactivity is involved.

Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes.

BACKGROUND/AIMS: Bioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes. METHODS: To address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals. RESULTS: Rats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD. CONCLUSION: Overall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk.