Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation noninvasively without surgically implanted devices is enabling for fundamental research and clinical translation. Here we demonstrate how relatively high frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. We validate this principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, we demonstrate how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve. Our method is simple, relying on repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

3D printed composite model of pelvic osteochondroma and nerve roots

Background 3D-printing has become increasingly utilized in the preoperative planning of clinical orthopaedics. Surgical treatment of bone tumours within the pelvis is challenging due to the complex 3D bone structure geometry, as well as the proximity of vital structures. We present a unique case where a composite bone and nerve model of the lower lumbar spine, pelvis and accompanying nerve roots was created using 3D-printing. The 3D-printed model created an accurate reconstruction of the pelvic tumour and traversing nerves for preoperative planning and allowed for efficient and safe surgery. Case presentation We present a unique case where a composite bone and nerve model of the lower lumbar spine, pelvis and accompanying nerve roots was created using 3D-printing. The bony pelvis and spine model was created using the CT, whereas the nerve roots were derived from the MRI and printed in an elastic material. 3D-printed model created an accurate reconstruction of the pelvic tumour and traversing nerves for preoperative planning and allowed for efficient and safe surgery. Pelvic tumour surgery is inherently dangerous due to the delicate nature of the surrounding anatomy. The composite model enabled the surgeon to very carefully navigate the anatomy with a focused resection and extreme care knowing the exact proximity of the L3 and L4 nerve roots. Conclusion The patient had complete resection of this tumour, no neurological complication and full resolution of his symptoms due to careful, preoperative planning with the use of the composite 3D model.

Opening injection pressure monitoring using an in-line device does not prevent intraneural injection in an isolated nerve model

BackgroundInjection pressure monitoring using in-line devices is affordable and easy to implement into a regional anesthesia practice. However, solid evidence regarding their performance is lacking. We aimed to evaluate if opening injection pressure (OIP), measured with a disposable in-line pressure monitor, can prevent intraneural (subepineural) injection using 15 pound per square inch (PSI) as the reference safety threshold.MethodsAn isolated nerve model with six tibial and six common peroneal nerves from three unembalmed fresh cadavers was used for this observational study. A mixture of 0.5% ropivacaine with methylene blue was injected intraneurally at a rate of 10 mL/min, to a maximum of 3 mL. OIP was recorded for each injection as well as evidence of intraneural contrast. Injected volume at 15 and 20 PSI was recorded, and when it leaked out the epineurium, if it occurred.ResultsIn all cases, OIP was<15 PSI and intraneural contrast was evident before the safety threshold. The 15–20 PSI mark was attained in 5 of 12 injections (41%), with a median injected volume of 0.9 mL (range 0.4–2.3 mL). Peak pressure of >20 PSI was reached in two injections (at 0.6 mL and 2.7 mL). Contrast leaked out the epineurium in 11 of 12 injections (91%) with a median injected volume of 0.6 mL (range 0.1–1.3 mL).ConclusionsOur results suggest that in-line pressure monitoring may not prevent intraneural injection using an injection pressure of 15 PSI as reference threshold. Due to the preliminary nature of our study, further evidence is needed to demonstrate clinical relevance.

Neuroma Prevention and Implantation Effects of NEUROCAP in Rat Sciatic Nerve Model

Introduction Symptomatic neuroma with neuropathic pain can develop following peripheral nerve injury. Current interventions for symptomatic neuroma have unpredictable results. NEUROCAP (Polyganics, Groningen, The Netherlands) is a bioresorbable nerve capping device intended to protect a peripheral nerve end and separate the nerve from the surrounding environment, to prevent the recurrence of a symptomatic neuroma. Materials and Methods This study aims to assess the implantation effects of the NEUROCAP device in a rat sciatic nerve model during 12 months (±2 days). Forty-one adult male Sprague-Dawley rats were used in this study. They were randomly divided into a capping or test group, or a noncapping or control group for different time points of survival (12 weeks, 6 months, and 12 months). The objective of this study was evaluated regarding procedural data, adverse events, clinical observations, and histopathology. Results The overall general health of the animals was adequate throughout the study, with the exception of autotomy during the first 4 months of survival. Eight animals were euthanized early due to autotomy, excluded from the study and seven of them have been replaced. Autotomy was an expected outcome and a known limitation of the animal model, particularly as this was a full sciatic nerve transection model. Neuroma formation was observed in the control group while there was no neuroma formation present in the test group. The control group showed increased nerve outgrowth and more chaotic fascicles in comparison with the test group. The test group also had a higher percentage of myelinated fibers compared to the control group. These results indicate a preventive mode of action of the NEUROCAP with regard to neuroma formation after nerve transection in a rat sciatic nerve model. Conclusion The results indicate that NEUROCAP is safe and effective in preventing the recurrence of neuroma formation and inhibiting nerve outgrowth.

3D culture platform of human iPSCs-derived nociceptors for peripheral nerve modelling and tissue innervation

Functional humanized in vitro nerve models are coveted as an alternative to animal models due to their ease of access, lower cost, clinical relevance and no need for recurrent animal sacrifice. To this end, we developed a sensory nerve model using induced pluripotent stem cells (iPSCs)-derived nociceptors that are electrically active and exhibit a functional response to noxious stimuli. The differentiated neurons were co-cultured with primary Schwann cells on an aligned microfibrous scaffold to produce biomimetic peripheral nerve tissue. Compared to glass coverslips, our scaffold enhances tissue development and stabilization. Using this model, we demonstrate that myelin damage can be induced from hyperglycemia exposure (glucose at 45 mM) and mitigated by epalrestat (1µM) supplementation. Through fibrin embedding of the platform, we were able to create 3D anisotropic myelinated tissue, reaching over 6.5 mm in length. Finally, as a proof-of-concept, we incorporated pancreatic pseudoislets and endometrial organoids into our nerve platform, to build nociceptor innervation models. In summary, we propose here an improved tool for neurobiology research that permits pathology modelling, drug screening and target tissue innervation.