Jaret L. Olson

Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model

Mesenchymal stem cells (MSCs) support axon regeneration across artificial nerve bridges but their differentiative capacity and ability to promote nerve regeneration remains unclear. In this study, MSCs isolated from bone marrow of Sprague-Dawley rats were characterized by plastic adherence and pluripotency towards mesodermal lineages. Isolated undifferentiated MSCs (uMSCs) were stimulated towards a Schwann cell (SC) phenotype using specific growth factors, and cell marker analysis was performed to verify SC phenotype in vitro. Differentiation resulted in temporally dependent positive immunocytochemical staining for the SC markers, glial fibrillary acidic protein (GFAP), S100, and nerve growth factor receptor (NGFR), with maximal marker expression achieved after 6days of treatment with differentiation media. Quantitative analysis demonstrated that ~50% of differentiated MSCs (dMSCs) have a SC phenotype. Using an indirect co-culture system, we compared the ability of dorsal root ganglion (DRG) cells to extend neurites in indirect contact with uMSCs and dMSCs as compared to SCs. The mean values of the longest length of the DRG neurites were the same for the dMSCs and SCs and significantly higher than the uMSC and DRG mono-culture systems (p < 0.05). In vivo, compared to an empty conduit, dMSC seeded collagen nerve conduits resulted in a greater number of sciatic motoneurons regenerating axons through the conduit into the distal nerve stump. We conclude that bone marrow-derived MSCs differentiate into a SC-phenotype that expresses SC markers transiently and sufficiently to support limited neurite outgrowth in vitro and axonal regeneration equivalent to that of SCs in vitro and in vivo. The nerve autograft remains the most effective conduit for supporting regeneration across nerve gaps.

Novel targeted sensory reinnervation technique to restore functional hand sensation after transhumeral amputation.

We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation.

Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats

Functional recovery after peripheral nerve injury and surgical repair declines with time and distance because the injured neurons without target contacts (chronic axotomy) progressively lose their regenerative capacity and chronically denervated Schwann cells (SCs) atrophy and fail to support axon regeneration. Findings that brief low frequency electrical stimulation (ES) accelerates axon outgrowth and muscle reinnervation after immediate nerve surgery in rats and human patients suggest that ES might improve regeneration after delayed nerve repair. To test this hypothesis, common peroneal (CP) neurons were chronically axotomized and/or tibial (TIB) SCs and ankle extensor muscles were chronically denervated by transection and ligation in rats. The CP and TIB nerves were cross-sutured after three months and subjected to either sham or one hour 20Hz ES. Using retrograde tracing, we found that ES significantly increased the numbers of both motor and sensory neurons that regenerated their axons after a three month period of chronic CP axotomy and/or chronic TIB SC denervation. Muscle and motor unit forces recorded to determine the numbers of neurons that reinnervated gastrocnemius muscle demonstrated that ES significantly increased the numbers of motoneurons that reinnervated chronically denervated muscles. We conclude that electrical stimulation of chronically axotomized motor and sensory neurons is effective in accelerating axon outgrowth into chronically denervated nerve stumps and improving target reinnervation after delayed nerve repair. Possible mechanisms for the efficacy of ES in promoting axon regeneration and target reinnervation after delayed nerve repair include the upregulation of neurotrophic factors.

Validity and reliability of the Purdue Pegboard Test in carpal tunnel syndrome.

There is a paucity of validated tests to quantify hand function impairment due to carpal tunnel syndrome (CTS). The aim of this study was to test the validity and reliability of the Purdue Pegboard Test (PPT) in CTS patients. We compared 190 CTS patients with 122 healthy, age‐matched controls. CTS severity was determined based on electrophysiologic parameters and the Levine Self‐Assessment Questionnaire. The time to complete the PPT and the test–retest reliability were tested. The test–retest reliability was high with an intraclass correlation coefficient of 0.91. Compared to healthy controls, the CTS patients were significantly slower. Although the functional performance generally declined with increasing severity of electrophysiologic abnormalities, the correlation between hand function decline and symptom severity in the young and middle‐aged groups was low. We conclude that the PPT is a valid and reliable tool to quantify functional impairment caused by CTS. It can be a useful outcome measure in young and middle‐aged patients. Muscle Nerve , 2011

Electrical stimulation enhances sensory recovery: A randomized controlled trial

Brief postsurgical electrical stimulation (ES) has been shown to enhance peripheral nerve regeneration in animal models following axotomy and crush injury. However, whether this treatment is beneficial in humans with sensory nerve injury has not been tested. The goal of this study was to test the hypothesis that ES would enhance sensory nerve regeneration following digital nerve transection compared to surgery alone.

Side-to-side nerve grafts sustain chronically denervated peripheral nerve pathways during axon regeneration and result in improved functional reinnervation.

BACKGROUND:Progressive atrophy of Schwann cells in denervated nerve stumps is a major reason for progressive failure of functional recovery after peripheral nerve injury and surgical repair. OBJECTIVE:To examine whether side-to-side nerve bridges between an intact donor nerve and a recipient denervated distal nerve stump promote nerve growth and in turn, protect distal nerve stumps to improve axon regeneration after delayed surgical repair. METHODS:In Sprague-Dawley rats, 1 or 3 side-to-side common peroneal (CP) nerve bridges were used to bridge between the donor intact tibial (TIB) nerve and a recipient denervated CP distal nerve stump in the contralateral hind limb. No bridges were placed in control animals. After 4 months, either a fluorescent retrograde dye was applied to back-label TIB motoneurons with axons that had grown into the CP nerve stump or the proximal and distal CP nerve stumps were resutured in experimental and control animals to encourage CP nerve regeneration for 5 months. Retrograde dyes were again applied to count CP motoneurons that regenerated their axons through protected and unprotected nerve stumps. RESULTS:Significantly more donor TIB motoneurons regenerated axons into the recipient denervated CP nerve stump through 3 side-to-side CP nerve bridges compared with 1 bridge. This TIB nerve protection significantly increased the number of CP motoneurons regenerating axons through the denervated CP nerve stumps, the number of regenerated axons, and the weight of the reinnervated muscles. CONCLUSION:Multiple side-to-side nerve bridges protect chronically denervated nerve stumps to improve axon regeneration and target reinnervation after delayed nerve repair.

Distal nerve transfers are effective in treating patients with upper trunk obstetrical brachial plexus injuries: an early experience.

Background: Current surgical management of obstetrical brachial plexus injury is primary reconstruction with sural nerve grafts. Recently, the nerve-to-nerve transfer technique has been used to treat brachial plexus injury in adults, affording the benefit of distal coaptations that minimize regenerative distance. The purpose of this study was to test the hypothesis that nerve transfers are effective in reconstructing isolated upper trunk obstetrical brachial plexus injuries. Methods: Ten patients aged 10 to 18 months were treated with three nerve transfers: spinal accessory nerve to the suprascapular nerve for shoulder abduction and external rotation; a radial to axillary nerve for shoulder abduction; and ulnar or median nerve transfer to the musculocutaneous nerve for elbow flexion. Patients were assessed preoperatively and postoperatively using the Active Movement Scale. All patients were followed regularly for up to 2 years. Results: Improvement in elbow and shoulder function was observed between 6 and 24 months. By 6 months, all patients passed the cookie test. At 24 months, shoulder abduction improved from 3.7 ± 0.6 to 5.0 ± 0.5, shoulder external rotation from 1.8 ± 0.4 to 4.3 ± 0.6, shoulder flexion from 3.7 ± 0.5 to 5.4 ± 0.5, elbow flexion from 3.7 ± 0.6 to 6.3 ± 0.2, and forearm supination from 2.1 ± 0.4 to 5.9 ± 0.2. There was no clinically appreciable donor-site morbidity. Conclusions: Nerve transfers reduced operative times compared with traditional nerve grafting procedures. Those patients showed significant gains in Active Movement Scale score by 24 months postoperatively, comparable to results achieved by nerve grafting. These findings support nerve transfers as a potential alternative treatment option for upper trunk obstetrical brachial plexus injuries. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

First Permanent Implant of Nerve Stimulation Leads Activated by Surface Electrodes, Enabling Hand Grasp and Release The Stimulus Router Neuroprosthesis

Background. More than 150 000 neuroprostheses (NPs) have been implanted in people to restore bodily function in a variety of neural disorders. The authors developed a novel NP, the Stimulus Router System (SRS), in which only passive leads are implanted. Each lead picks up a portion of the current delivered through the skin by an external stimulator. Objective. The authors report on the first human implant of an SRS. Methods. The recipient was a tetraplegic man with bilateral hand paralysis. Three SRS leads were implanted in his right forearm to activate the finger extensors, finger flexors, and thumb flexor. A wristlet containing a surface stimulator and electrodes was used to pass trains of electrical pulses through the skin to each lead. Hand opening and grasp were controlled via a wireless earpiece that sensed small tooth-clicks and transmitted signals to the wristlet. Results. The current required to activate the muscles was less than half that required prior to implantation and below perceptual threshold. Maximal grip force and hand opening aperture were both larger using the SRS. The implanted leads have remained functional for 3 years. The recipient reported various tasks of daily life that improved during SRS usage. An electronic counter revealed mean monthly usage of 18.5 hours, equivalent to 55 hours of continuous manual activity. Conclusions. This first implant of the SRS indicates that it can be effective and reliable and has potential to provide an alternative to existing NPs.

Modified Von Langenbeck Cleft Palate Repair Using an Anterior Triangular Flap: Decreased Incidence of Anterior Oronasal Fistulas

Objective: A complication following cleft palate surgery is the development of oronasal fistulas. Despite recent advances aimed at addressing this concern, rates of postoperative fistulas have remained unchanged and are reported at between 3% and 60%. Oronasal fistulas commonly occur between the hard and soft palate and at the anterior portion of the cleft. These fistulas lead to functional problems with nasal emission, hypernasal speech, and food regurgitation through the nose. For clefts of the secondary palate, we developed a modification of the Von Langenbeck technique in which an anterior triangular flap is used to decrease the incidence of postoperative fistulas. Method: A triangular flap composed of oromucosa was designed for isolated clefts of the secondary palate only. It is based at the anterior margin of the cleft and is used as a turnover flap to allow closure of the often very tight anterior nasal side. A retrospective chart analysis was performed from 2000 to 2007. All patients who had isolated clefts of the secondary palate and had undergone a modified Von Langenbeck procedure were included in the study. Patients were evaluated 4 to 8 weeks postoperatively for the presence of oronasal fistulas. Results: With the introduction of the anterior triangular flap, we show that 0 of 182 patients developed a postoperative oronasal fistula. Conclusions: This modification of the standard Von Langenbeck uses an anterior triangular flap and confers the advantage of assisting in nasal side closure of the anterior margin of the cleft; in doing so, it reduces the rate of fistula formation.

Updates in Targeted Sensory Reinnervation for Upper Limb Amputation

Advanced robotic devices capable of simulating the dexterous ability of the upper limb with an array of internal sensors have raised the enticing prospect of replacing the lost intricate functions of the arm following upper limb amputation. However, a large gap still exists in the application of this technology to the human user. In particular, the ability to provide physiologically relevant sensory feedback—to have the amputee feel the prosthetic hand as their own—has not yet been achieved. Although a number of different approaches are being investigated, targeted sensory reinnervation, a refinement of the original targeted muscle reinnervation procedure, is the most recent and promising development in the effort to create a functional human–machine interface with a closed loop sensory feedback system. This technique aims to re-establish hand sensation on the skin so that it can be readily accessed non-invasively during functional tasks. Recent efforts are being directed towards distributing hand maps widely on the stump without interference of sensations from the native area. In this article, we will review the surgical approaches that have been used for sensory reinnervation in upper arm amputation and compare the resultant outcomes and potential functional utility of the techniques.