Dermal Sensory Regenerative Peripheral Nerve Interface for Reestablishing Sensory Nerve Feedback in Peripheral Afferents in the Rat

Background: Without meaningful, intuitive sensory feedback, even the most advanced myoelectric devices require significant cognitive demand to control. The dermal sensory regenerative peripheral nerve interface (DS-RPNI) is a biological interface designed to establish high-fidelity sensory feedback from prosthetic limbs. Methods: DS-RPNIs were constructed in rats by securing fascicles of residual sensory peripheral nerves into autologous dermal grafts, with the objectives of confirming regeneration of sensory afferents within DS-RPNIs and establishing the reliability of afferent neural response generation with either mechanical or electrical stimulation. Results: Two months after implantation, DS-RPNIs were healthy and displayed well-vascularized dermis with organized axonal collaterals throughout and no evidence of neuroma. Electrophysiologic signals were recorded proximal from DS-RPNI's sural nerve in response to both mechanical and electrical stimuli and compared with (1) full-thickness skin, (2) deepithelialized skin, and (3) transected sural nerves without DS-RPNI. Mechanical indentation of DS-RPNIs evoked compound sensory nerve action potentials (CSNAPs) that were like those evoked during indentation of full-thickness skin. CSNAP firing rates and waveform amplitudes increased in a graded fashion with increased mechanical indentation. Electrical stimuli delivered to DS-RPNIs reliably elicited CSNAPs at low current thresholds, and CSNAPs gradually increased in amplitude with increasing stimulation current. Conclusions: These findings suggest that afferent nerve fibers successfully reinnervate DS-RPNIs, and that graded stimuli applied to DS-RPNIs produce proximal sensory afferent responses similar to those evoked from normal skin. This confirmation of graded afferent signal transduction through DS-RPNI neural interfaces validate DS-RPNI's potential role of facilitating sensation in human-machine interfacing. Clinical Relevance Statement: The DS-RPNI is a novel biotic-abiotic neural interface that allows for transduction of sensory stimuli into neural signals. It is expected to advance the restoration of natural sensation and development of sensorimotor control in prosthetics.</p

Effects of light intensity on depression-like behavioral responses.

<p>Bar graphs on the left side show the duration for immobility, climbing and swimming during FST on the test day for cohort 1 (A) and cohort 2 (A′). The changes in preference for SSP are shown over two days for cohort 1 (B) and over 3 days for cohort 2 (B′). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057115#s3" target="_blank">Results</a> are displayed as mean ± SEM. Numbers on each column indicate the sample size. * indicates p<0.05.</p

Effects of light intensity on 5-HT expression in midbrain and forebrain regions related to the regulation of mood or circadian rhythms.

<p>The histograms and representative photomicrographs depict 5-HT staining in each condition in the PAG (A), Cgc (B), and SCN (C). Each set of histograms show the density of 5-HT-ir fibers in each area. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057115#s3" target="_blank">Results</a> are displayed as mean ± SEM (n = 6). * indicates p<0.05. Scale bar, 250 µm. aq, aqueduct; CC, corpus callosum; OC, optic chiasm; V, third ventricle.</p

Effects of light intensity on circadian rhythms.

<p>The actograms (A) depict representative daily activity from one animal for each condition over two weeks. The line graph (B) shows the average activity for each condition over the course of a day. The daily activity was averaged over the last 14 days of recording, and normalized by dividing by the total daily activity and is displayed as a percentage of total activity for each individual animal. The normalized activity was then averaged within each condition and shown in the line graph. The error bars represent the SEM between individuals within each condition. The bar graphs show the average values from each condition for each of the circadian parameters observed: daily activity (C), day/night activity ratio (D), duration of the active phase (E), activity onset (F) and offset (G) times, and entrainment stability of both onset (H) and offset (I). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057115#s3" target="_blank">Results</a> are displayed as mean ± SEM (n = 6). * indicates p<0.007 (with Bonferroni correction for multiple comparisons).</p

Effects of daytime light intensity on anxiety-like behaviors assessed by open field (A) and light/dark box test (B).

<p>The results are presented as mean±sem (n = 7).</p

Effects of light intensity on 5-HT signals in the DRN.

<p>(A), representative photomicrographs of 5-HT staining in the DRN across the rostral-caudal extent in BLD and DLD group. Histograms show the number of 5-HT neurons (B) and the density of 5-HT-ir (C) in the rostral and middle portion of the DRN of animals from the BLD and DLD groups. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057115#s3" target="_blank">Results</a> are displayed as mean ± SEM (n = 6). * indicates p<0.05. Scale bar, 250 µm. aq, aqueduct; mlf, medial longitudinal fasciculus.</p

Sensory nerve regeneration and reinnervation in muscle following peripheral nerve injury

Sensory afferent fibers are an important component of motor nerves and compose the majority of axons in many nerves traditionally thought of as “pure” motor nerves. These sensory afferent fibers innervate special sensory end organs in muscle, including muscle spindles that respond to changes in muscle length and Golgi tendons that detect muscle tension. Both play a major role in proprioception, sensorimotor extremity control feedback, and force regulation. After peripheral nerve injury, there is histological and electrophysiological evidence that sensory afferents can reinnervate muscle, including muscle that was not the nerve’s original target. Reinnervation can occur after different nerve injury and muscle models, including muscle graft, crush, and transection injuries, and occurs in a nonspecific manner, allowing for cross-innervation to occur. Evidence of cross-innervation includes the following: muscle spindle and Golgi tendon afferent-receptor mismatch, vagal sensory fiber reinnervation of muscle, and cutaneous afferent reinnervation of muscle spindle or Golgi tendons. There are several notable clinical applications of sensory reinnervation and cross-reinnervation of muscle, including restoration of optimal motor control after peripheral nerve repair, flap sensation, sensory protection of denervated muscle, neuroma treatment and prevention, and facilitation of prosthetic sensorimotor control. This review focuses on sensory nerve regeneration and reinnervation in muscle, and the clinical applications of this phenomena. Understanding the physiology and limitations of sensory nerve regeneration and reinnervation in muscle may ultimately facilitate improvement of its clinical applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/174928/1/mus27661_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/174928/2/mus27661.pd