Silicone nerve cuff electrodes are commonly implanted on relatively large and accessible somatic nerves as peripheral neural interfaces. While these cuff electrodes are soft (1–50 MPa), their self-closing mechanism requires of thick walls (200–600 µm), which in turn contribute to fibrotic tissue growth around and inside the device, compromising the neural interface. We report the use of thiol-ene/acrylate shape memory polymer (SMP) for the fabrication of thin film multi-electrode softening cuffs (MSC). We fabricated multi-size MSC with eight titanium nitride (TiN) electrodes ranging from 1.35 to 13.95 × 10⁻⁴ cm² (1–3 kΩ) and eight smaller gold (Au) electrodes (3.3 × 10⁻⁵ cm²; 750 kΩ), that soften at physiological conditions to a modulus of 550 MPa. While the SMP material is not as soft as silicone, the flexural forces of the SMP cuff are about 70–700 times lower in the MSC devices due to the 30 μm thick film compared to the 600 μm thick walls of the silicone cuffs. We demonstrated the efficacy of the MSC to record neural signals from rat sciatic and pelvic nerves (1000 µm and 200 µm diameter, respectively), and the selective fascicular stimulation by current steering. When implanted side-by-side and histologically compared 30 days thereafter, the MSC devices showed significantly less inflammation, indicated by a 70–80% reduction in ED1 positive macrophages, and 54–56% less fibrotic vimentin immunoreactivity. Together, the data supports the use of MSC as compliant and adaptable technology for the interfacing of somatic and autonomic peripheral nerves.

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

While intracortical microelectrode arrays (MEAs) may be useful in a variety of basic and clinical scenarios, their implementation is hindered by a variety of factors, many of which are related to the stiff material composition of the device. MEAs are often fabricated from high modulus materials such as silicon, leaving devices vulnerable to brittle fracture and thus complicating device fabrication and handling. For this reason, polymer-based devices are being heavily investigated; however, their implementation is often difficult due to mechanical instability that requires insertion aids during implantation. In this study, we design and fabricate intracortical MEAs from a shape memory polymer (SMP) substrate that remains stiff at room temperature but softens to 20 MPa after implantation, therefore allowing the device to be implanted without aids. We demonstrate chronic recordings and electrochemical measurements for 16 weeks in rat cortex and show that the devices are robust to physical deformation, therefore making them advantageous for surgical implementation.

Significance: Early postnatal development of the cerebellum involves a number of events that require signaling via the neurotransmitter GABA, which acts on specific receptors anchored in the plasma membrane. GABAergic transmission regulates the proliferation and migration of neuronal precursors of astrocytic lineage. Glial cells are known to express GABA-A receptors that include GABAρ subunits, but their expression pattern, functional properties, and trafficking dynamics remain unknown. This study found that a large number of glial cells express GABAρ in the cerebellum. Functional properties and intracellular trafficking of GABA-A receptors in glial cells grown in vitro suggest a different mechanism of GABAergic control of extrasynaptic transmission.

Objective . Neural interfaces designed to stimulate or record electrical activity from peripheral nerves have applications ranging from the electrical modulation of nerve activity as a therapeutic option (e.g. epilepsy and depression) to the design of prosthetics. Currently, most peripheral nerve interfaces are either cuff-style devices that wrap around the target nerve or intraneural devices that are implanted within the nerve. While the latter option offers higher specificity and signal-to-noise ratio, penetrating devices can cause significant damage to the nerve due to the high degree of mechanical mismatch. Because of this, there is interest in developing penetrating devices fabricated from soft or softening materials (materials having a low elastic modulus). However, there is currently a lack of understanding regarding implantation forces required for successful insertion, which is a constraint for soft device design. Softer devices require robust designs to achieve a critical buckling force that is larger than forces experienced during device insertion. Approach . This study comprehensively assesses insertion force under different implantation conditions, with three variations for implantation speed, angle, and device tip angle, during insertion of silicon shanks in rat sciatic nerve. Additionally, we report compression moduli for rat sciatic nerve at different compression rates to inform computational modeling. Main results . We found that insertion speed and angle had significant effects on peak insertion force. We observed lower insertion forces (10–60 mN) when the device was implanted at higher angles relative to perpendicular insertion (80–125 mN). We also demonstrate the use of a nerve-stabilizing device to keep the nerve immobile during implantation. Additionally, we found that compression moduli were significantly different in small and large strain regions of the stress–strain curve with values between 1500–4500 Pa depending on compression rate. Significance . This study provides information imperative to the design and successful implementation of soft penetrating peripheral nerve interfaces.