Stem‐cell–based therapies to enhance peripheral nerve regeneration

Peripheral nerve injury remains a major cause of morbidity in trauma patients. Despite advances in microsurgical techniques and improved understanding of nerve regeneration, obtaining satisfactory outcomes after peripheral nerve injury remains a difficult clinical problem. There is a growing body of evidence in preclinical animal studies demonstrating the supportive role of stem cells in peripheral nerve regeneration after injury. The characteristics of both mesoderm‐derived and ectoderm‐derived stem cell types and their role in peripheral nerve regeneration are discussed, specifically focusing on the presentation of both foundational laboratory studies and translational applications. The current state of clinical translation is presented, with an emphasis on both ethical considerations of using stems cells in humans and current governmental regulatory policies. Current advancements in cell‐based therapies represent a promising future with regard to supporting nerve regeneration and achieving significant functional recovery after debilitating nerve injuries.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154610/1/mus26760.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154610/2/mus26760_am.pd

Elisa Chimenti, Marra. Choix de poèmes

Traducción al castellano de una selección de 10 poemas del poemario inédito Marra de Elisa Chimenti.THALIM, Sorbonne Nouvelle et ILLE, Université Haute-Alsac

In Situ Polymerization of a Conductive Polymer in Acellular Muscle Tissue Constructs

We present a method to chemically deposit a conductive polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), on acellularized muscle tissue constructs. Morphology and structure of the deposition was characterized using optical and scanning electron microscopies (SEM). The micrographs showed elongated, smooth, tubular PEDOT structures completely penetrating and surrounding the tissue fibers. The chemical polymerization was performed using iron chloride, a mild oxidizer. Remaining iron and chlorine in the tissue constructs were reduced to acceptable metabolic levels, while preserving the structural integrity of the tissue. We expect that these acellular, polymerized tissue implants will remain essentially unmodified in cellular environments in vitro and in vivo because of the chemical and thermal stability of the PEDOT polymer depositions. Our results indicate that in situ polymerization occurs throughout the tissue, converting it into an extensive acellular, non-antigenic substrate of interest for in vivo experiments related to nerve repair and bioartificial prosthesis. We expect these conducting polymer scaffolds to be useful for direct integration with electronically and ionically active tissues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63276/1/tea.2007.0123.pd

The future of upper extremity rehabilitation robotics: research and practice

The loss of upper limb motor function can have a devastating effect on people’s lives. To restore upper limb control and functionality, researchers and clinicians have developed interfaces to interact directly with the human body’s motor system. In this invited review, we aim to provide details on the peripheral nerve interfaces and brain‐machine interfaces that have been developed in the past 30 years for upper extremity control, and we highlight the challenges that still remain to transition the technology into the clinical market. The findings show that peripheral nerve interfaces and brain‐machine interfaces have many similar characteristics that enable them to be concurrently developed. Decoding neural information from both interfaces may lead to novel physiological models that may one day fully restore upper limb motor function for a growing patient population.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155489/1/mus26860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155489/2/mus26860.pd

Electrical stimulation of renal nerves for modulating urine glucose excretion in rats

Abstract Background The role of the kidney in glucose homeostasis has gained global interest. Kidneys are innervated by renal nerves, and renal denervation animal models have shown improved glucose regulation. We hypothesized that stimulation of renal nerves at kilohertz frequencies, which can block propagation of action potentials, would increase urine glucose excretion. Conversely, we hypothesized that low frequency stimulation, which has been shown to increase renal nerve activity, would decrease urine glucose excretion. Methods We performed non-survival experiments on male rats under thiobutabarbital anesthesia. A cuff electrode was placed around the left renal artery, encircling the renal nerves. Ureters were cannulated bilaterally to obtain urine samples from each kidney independently for comparison. Renal nerves were stimulated at kilohertz frequencies (1–50 kHz) or low frequencies (2–5 Hz), with intravenous administration of a glucose bolus shortly into the 25–40-min stimulation period. Urine samples were collected at 5–10-min intervals, and colorimetric assays were used to quantify glucose excretion and concentration between stimulated and non-stimulated kidneys. A Kruskal-Wallis test was performed across all stimulation frequencies (α = 0.05), followed by a post-hoc Wilcoxon rank sum test with Bonferroni correction (α = 0.005). Results For kilohertz frequency trials, the stimulated kidney yielded a higher average total urine glucose excretion at 33 kHz (+ 24.5%; n = 9) than 1 kHz (− 5.9%; n = 6) and 50 kHz (+ 2.3%; n = 14). In low frequency stimulation trials, 5 Hz stimulation led to a lower average total urine glucose excretion (− 40.4%; n = 6) than 2 Hz (− 27.2%; n = 5). The average total urine glucose excretion between 33 kHz and 5 Hz was statistically significant (p < 0.005). Similar outcomes were observed for urine flow rate, which may suggest an associated response. No trends or statistical significance were observed for urine glucose concentrations. Conclusion To our knowledge, this is the first study to investigate electrical stimulation of renal nerves to modulate urine glucose excretion. Our experimental results show that stimulation of renal nerves may modulate urine glucose excretion, however, this response may be associated with urine flow rate. Future work is needed to examine the underlying mechanisms and identify approaches for enhancing regulation of glucose excretion.https://deepblue.lib.umich.edu/bitstream/2027.42/143868/1/42234_2018_Article_8.pd

Treatment of peroneal nerve injuries with simultaneous tendon transfer and nerve exploration

Abstract Background Common peroneal nerve palsy leading to foot drop is difficult to manage and has historically been treated with extended bracing with expectant waiting for return of nerve function. Peroneal nerve exploration has traditionally been avoided except in cases of known traumatic or iatrogenic injury, with tendon transfers being performed in a delayed fashion after exhausting conservative treatment. We present a new strategy for management of foot drop with nerve exploration and concomitant tendon transfer. Method We retrospectively reviewed a series of 12 patients with peroneal nerve palsies that were treated with tendon transfer from 2005 to 2011. Of these patients, seven were treated with simultaneous peroneal nerve exploration and repair at the time of tendon transfer. Results Patients with both nerve repair and tendon transfer had superior functional results with active dorsiflexion in all patients, compared to dorsiflexion in 40% of patients treated with tendon transfers alone. Additionally, 57% of patients treated with nerve repair and tendon transfer were able to achieve enough function to return to running, compared to 20% in patients with tendon transfer alone. No patient had full return of native motor function resulting in excessive dorsiflexion strength. Conclusion The results of our limited case series for this rare condition indicate that simultaneous nerve repair and tendon transfer showed no detrimental results and may provide improved function over tendon transfer alone.http://deepblue.lib.umich.edu/bitstream/2027.42/109530/1/13018_2014_Article_67.pd

Experimental testing of bionic peripheral nerve and muscle interfaces: animal model considerations

Introduction: Man-machine interfacing remains the main challenge for accurate and reliable control of bionic prostheses. Implantable electrodes in nerves and muscles may overcome some of the limitations by significantly increasing the interface's reliability and bandwidth. Before human application, experimental preclinical testing is essential to assess chronic in-vivo biocompatibility and functionality. Here, we analyze available animal models, their costs and ethical challenges in special regards to simulating a potentially life-long application in a short period of time and in non-biped animals. Methods: We performed a literature analysis following the PRISMA guidelines including all animal models used to record neural or muscular activity via implantable electrodes, evaluating animal models, group size, duration, origin of publication as well as type of interface. Furthermore, behavioral, ethical, and economic considerations of these models were analyzed. Additionally, we discuss experience and surgical approaches with rat, sheep, and primate models and an approach for international standardized testing. Results: Overall, 343 studies matched the search terms, dominantly originating from the US (55%) and Europe (34%), using mainly small animal models (rat: 40%). Electrode placement was dominantly neural (77%) compared to muscular (23%). Large animal models had a mean duration of 135 ± 87.2 days, with a mean of 5.3 ± 3.4 animals per trial. Small animal models had a mean duration of 85 ± 11.2 days, with a mean of 12.4 ± 1.7 animals. Discussion: Only 37% animal models were by definition chronic tests (>3 months) and thus potentially provide information on long-term performance. Costs for large animals were up to 45 times higher than small animals. However, costs are relatively small compared to complication costs in human long-term applications. Overall, we believe a combination of small animals for preliminary primary electrode testing and large animals to investigate long-term biocompatibility, impedance, and tissue regeneration parameters provides sufficient data to ensure long-term human applications

Stimulated grip strength measurement: Validation of a novel method for functional assessment

BackgroundReliable measurement of functional recovery is critical in translational peripheral nerve regeneration research. Behavioral functional assessments such as volitional grip strength testing (vGST) are limited by inherent behavioral variability. Isometric tetanic force testing (ITFT) is highly reliable but precludes serial measurements. Combining elements of vGST and ITFT, stimulated grip strength testing (sGST) involves percutaneous median nerve stimulation to elicit maximal tetanic contraction of digital flexors, thereby allowing for consistent measurement of maximal grip strength.MethodsWe measured side‐to‐side equivalence of force using sGST, vGST, and ITFT to determine relative reliability and repeatability. We also performed weekly force measurements following median nerve repair.ResultssGST demonstrated greater reliability and inter‐trial repeatability than vGST and similar reliability to ITFT, with the added benefit of serial measurements.ConclusionssGST is a valid method for assessing functional recovery that addresses the limitations of the currently available modalities used in translational peripheral nerve regeneration research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151883/1/mus26646.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151883/2/mus26646_am.pd

Hair follicle specific ACVR1/ALK2 critically affects skin morphogenesis and attenuates wound healing

The bone morphogenic protein signaling (BMP) is intricately involved in the quiescence and regulation of stem cells through activation of BMP receptors. Hair follicle stem cells play a critical role in cutaneous homeostasis and regeneration. Here, we utilize a novel mouse model with targeted overexpression of the BMP receptor ALK2/ACVR1 in hair follicle stem cells, to characterize its role in skin development and postnatal wound healing. Initial histologic evaluation demonstrated significant dysregulation in hair follicle morphogenesis in mutant mice. These demonstrated increased numbers of individual hair follicles with altered morphology and localization. Mutant follicles were found to exhibit elevated proliferative activity as well as increased prevalence of CD34 and ITGA6 positive follicle stem cells. Interestingly, constitutive overexpression of ALK2 resulted in attenuation of cutaneous wound healing. These findings demonstrate that hair follicle specific ALK2 is intricately involved in maintenance of the stem cell niche and wound healing.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138367/1/wrr12549_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138367/2/wrr12549.pd