Prespinal Versus Conventional Hemicontralateral C7 Nerve Transfer in the Treatment of Total Brachial Plexus Roots Avulsion Injuries: A Retrospective Study With a Minimum Follow-Up Period of 4 Years.

PURPOSE: Contralateral C7 (CC7)-to-median nerve transfer has been commonly used to restore hand function in brachial plexus injury. To shorten the nerve graft, the prespinal route was described and achieved direct coaptation when combined with humeral shortening osteotomy. The limb was positioned at 0° shoulder abduction and neutral head position. Given our concern about donor-site morbidity when harvesting the whole CC7 nerve and tension across the neurorrhaphy site after mobilization, we aimed to describe our modified prespinal route and compare its outcomes and complications with the conventional hemi-CC7 transfer. METHODS: From 2004 to 2014, 39 patients with preganglionic total brachial plexus root avulsion injuries, with a minimum of 4 years of follow-up, were included. Overall, 20 and 19 patients underwent the conventional hemi-CC7-to-median nerve and hemi-CC7-to-lower trunk (LT) transfer through the modified prespinal route, respectively. The modified prespinal route was combined with bilateral clavicle shortening osteotomy to achieve direct coaptation to the LT at 45° shoulder abduction. RESULTS: The modified prespinal route showed the median period to achieve ≥M3 hand grip assessed in clinical follow-up was shorter (26.5 months vs 45.5 months), and a higher proportion of patients achieved ≥M3 hand grip recovery (63% vs 30%). One patient experienced symptomatic phrenic nerve injury; however, the hemidiaphragm fully recovered after 6 months. The long-term donor-site complication rate was 2.6%, including one sensory abnormality, and no permanent donor-site weakness after hemi-CC7 harvesting was observed. CONCLUSIONS: The modified prespinal route combined with clavicle osteotomy allowed direct coaptation to the LT and did not require head immobilization. It may allow a higher proportion of patients to achieve ≥M3 hand grip more quickly than conventional hemi-CC7 transfer. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Does an Internal Joint Stabilizer and Standardized Protocol Prevent Recurrent Instability in Complex Persistent Elbow Instability?

BACKGROUND: The treatment of complex persistent elbow instability after trauma is challenging. Previous studies on treatments have reported varied surgical techniques, which makes it difficult to establish a therapeutic algorithm. Furthermore, the surgical procedures may not sufficiently restore elbow stability, even with an additional device, and a noted high rate of arthritis progression.While a recently developed internal joint stabilizer effectively treats elbow instability, its clinical application for complex persistent elbow instability is limited and the standardized protocol is not well described. Additionally, we want to know whether the arthritis progression will cause a negative impact on the functional outcomes of complex persistent elbow instability. QUESTIONS/PURPOSES: (1) Does treatment of complex persistent elbow instability with a hinged internal joint stabilizer and a standardized protocol prevent recurrent instability and other complications? (2) What are the pre- to postoperative improvements in pain, disability, elbow performance, and ROM? (3) Is the development of post-traumatic arthritis associated with worse pain, disability, elbow performance, and ROM? METHODS: Between September 2014 and October 2019, we treated 22 patients for persistent dislocation or subluxation after initial treatment of traumatic elbow fracture-dislocations. Of those, we considered patients who were at least 20 years of age, with an interval of 6 weeks or more between the injury (initial treatment) and the index reconstructive procedure, which had been performed at our institute, as potentially eligible. During that time, we used an internal joint stabilizer with a standardized protocol for posttraumatic complex persistent elbow instability. We performed total elbow replacements in patients older than 50 years who had advanced elbow arthritis. Based on that, 82% (18 of 22) of patients were eligible; 14% (3 of 22) were excluded because total elbow replacements was undertaken, and another 5% (1 of 22) were lost before the minimum study follow-up of 1 year (median 24 months [range 12 to 63]), leaving 64% (14 of 22) for analysis in this retrospective study. We treated 14 patients (14 elbows) with posttraumatic complex persistent elbow instability with an internal joint stabilizer and a standardized protocol that comprised debridement arthroplasty with ulnar neurolysis, restoration of bony and ligamentous (reattachment) structures, application of an internal joint stabilizer, and early rehabilitation. There were eight men and six women in this study, with a median (range) age of 44 years (21 to 68). The initial elbow fracture-dislocation injury pattern was a terrible triad injury in seven patients, a posterolateral rotatory injury in four patients, and a posterior Monteggia fracture in three patients. Preoperative and follow-up radiographs were reviewed for evidence of recurrent instability and arthritis. Complications such as wound infection, seroma, neurovascular injury, and hardware complications were ascertained through chart review. Preoperative and postoperative VAS score for pain, DASH, and Mayo Elbow Performance Scores (MEPS) were collected and compared. Furthermore, extension-flexion and supination-pronation arcs were collected by chart review. We divided the patients into two groups according to whether or not they developed posttraumatic arthritis. We then presented the differences between pain, disability, elbow performance, and ROM. The hinged internal joint stabilizer was removed using another open procedure under general anesthesia 6 to 8 weeks after surgery. RESULTS: There were no recurrent instability during and after device removal. Seven patients developed complications, including wound infection, seroma, neurovascular injury, hardware complications, and heterotopic ossification. Two patients had complications related to internal joint stabilizers and three had complications linked to radial head prostheses. Median (range) preoperative to postoperative changes included decreased pain (VAS 5 [2 to 9] to 0 [0 to 3], difference of medians -5; p < 0.001), decreased disability (DASH 41 [16 to 66] to 7 [0 to 46], difference of medians -34; p < 0.001), improved function (MEPS 60 [25 to 70] to 95 [65 to 100], difference of medians 35; p < 0.001), improved extension-flexion arc (40° [10° to 70°] to 113° [75° to 140°], difference of medians 73°; p < 0.001), and supination-pronation arc (78° [30° to 165°] to 148° [70° to 175°], difference of medians 70°; p < 0.001). Between patients with and without development of post-traumatic arthritis, there were no differences in postoperative pain (VAS 0 [0 to 3] to 0 [0 to 1], difference of medians 0; p = 0.17), disability (DASH 7 [0 to 46] to 7 [0 to 18], difference of medians 0; p = 0.40), function (MEPS 80 [65 to 100] to 95 [75 to 100], difference of medians 15; p = 0.79), extension-flexion arc (105° [75° to 140°] to 115° [80° to 125°], difference of medians 10°; p = 0.40), and supination-pronation arc (155° [125° to 175°] to 135° [70° to 160°], difference of medians -20°; p < 0.18). CONCLUSION: In this small, retrospective study, we found that an internal joint stabilizer with a standardized treatment protocol could maintain concentric reduction while allowing early functional motion, and that it could improve clinical outcomes for patients with complex persistent elbow instability. However, patients must be counseled that the complications related to the radial head prostheses may occur, and that the benefits of early motion must compensate for an additional removal procedure and the risk of seroma formation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Surgical reconstructions for adult brachial plexus injuries. Part II: Treatments for total arm type.

Brachial plexus injuries (BPI) contribute not only to physical dysfunction but also to socioeconomic aspects and psychological disability. Patients with total arm-type BPI will lose not only the shoulder and elbow function but also the hand function, making reconstruction particularly challenging. Reconstructive procedures commonly include nerve repair, grafting, neurotization (nerve transfer), tendon transfer and free functional muscle transfer (FFMT). Although it is difficult to achieve prehensile hand function, most of patients with total arm-type BPI can be treated with satisfied outcomes. In addition to surgical techniques, comprehensive rehabilitation is another important factor for successful outcomes, and efficient communication can help to boost patient morale and eliminate uncertainty.

Nerve Bypass Surgery for Spinal Cord Reconstruction.

OBJECTIVE: Spinal cord injury (SCI) is a devastating condition that significantly decreases the patient's quality of life. Therefore, treatments that can facilitate nerve regeneration, reduce complications, and increase quality of life are valuable for these patients. In this study, we aimed to assess nerve bypass surgery's feasibility and clinical outcomes by transferring the intercostal nerves into the spinal cord. METHODS: Eight patients with complete thoracic SCI and delayed presentation more than a year after the injury were analyzed retrospectively. All patients underwent nerve bypass surgery with the transfer of 2 pairs of intercostal nerves from proximal to the injury site to the anterolateral spinal cord, followed by duraplasty with fascia grafting to close the dura. RESULTS: Six of the 8 (75%) patients demonstrated motor and sensory improvements, based on the American SCI Association score. Three patients demonstrated a limited recovery of motor function that could be independently triggered without ICN initiation. Five patients demonstrated evidence of cerebrospinal fluid leakage after surgery; however, only 1 patient complained of a headache. CONCLUSIONS: Spinal cord bypass surgery is a potential reconstruction method to treat chronic complete thoracic SCI with functional improvements, and is worth further investigation.

Improving iPSC Differentiation Using a Nanodot Platform.

Differentiation of induced pluripotent stem cells (iPSCs) is an extremely complex process that has proven difficult to study. In this research, we utilized nanotopography to elucidate details regarding iPSC differentiation by developing a nanodot platform consisting of nanodot arrays of increasing diameter. Subjecting iPSCs cultured on the nanodot platform to a cardiomyocyte (CM) differentiation protocol revealed several significant gene expression profiles that were associated with poor differentiation. The observed expression trends were used to select existing small-molecule drugs capable of modulating differentiation efficiency. BRD K98 was repurposed to inhibit CM differentiation, while iPSCs treated with NSC-663284, carmofur, and KPT-330 all exhibited significant increases in not only CM marker expression but also spontaneous beating, suggesting improved CM differentiation. In addition, quantitative polymerase chain reaction was performed to determine the gene regulation responsible for modulating differentiation efficiency. Multiple genes involved in extracellular matrix remodeling were correlated with a CM differentiation efficiency, while genes involved in the cell cycle exhibited contrasting expression trends that warrant further studies. The results suggest that expression profiles determined via short time-series expression miner analysis of nanodot-cultured iPSC differentiation can not only reveal drugs capable of enhancing differentiation efficiency but also highlight crucial sets of genes related to processes such as extracellular matrix remodeling and the cell cycle that can be targeted for further investigation. Our findings confirm that the nanodot platform can be used to reveal complex mechanisms behind iPSC differentiation and could be an indispensable tool for optimizing iPSC technology for clinical applications.

Comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury in the rat.

Cervical spinal cord injury interrupts supraspinal pathways innervating thoracic sympathetic preganglionic neurons and results in cardiovascular dysfunction. Both respiratory and locomotor functions were also impaired due to damages of motoneuron pools controlling respiratory and forelimb muscles, respectively. However, no study has investigated autonomic and somatic motor functions in the same animal model. The present study aimed to establish a cervical spinal cord injury model to evaluate cardiorespiratory response and locomotor activity in unanesthetized rats. Cardiovascular response and respiratory behavior following laminectomy or cervical spinal contusion were measured using noninvasive blood pressure analyzer and plethysmography systems, respectively. Locomotor activity was evaluated by an open-field test and a locomotor rating scale. The results demonstrated that mean arterial blood pressure and heart rate were significantly reduced in contused rats compared with uninjured rats at the acute injured stage. Tidal volume was also significantly reduced during the acute and subchronic stages. Moreover, locomotor function was severely impaired, evidenced by decreasing moving ability and locomotor rating scores from the acute to chronic injured stages. Retrograde neurotracer results revealed that cervical spinal cord injury caused a reduction in number of phrenic and triceps motoneurons. Immunofluorescence staining revealed a significant attenuation of serotonergic, noradrenergic, glutamatergic, and GABAergic fibers innervating the thoracic sympathetic preganglionic neurons in chronically contused rats. These results revealed the pathological mechanism underlying the comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury. We proposed that this animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.NEW & NOTEWORTHY The present study establishes a preclinical rodent model to comprehensively investigate physiological functions under unanesthetized condition following cervical spinal cord contusion. The results demonstrated that cervical spinal cord contusion is associated with impairments in cardiovascular, respiratory, and locomotor function. Respiratory and forelimb motoneurons and neurochemical innervations of sympathetic preganglionic neurons were damaged following injury. This animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.

Therapeutic effect of induced pluripotent stem cell -derived extracellular vesicles in an in vitro and in vivo osteoarthritis model.

Background/Objective: Osteoarthritis (OA) is a multifactorial joint disease associated with the deterioration of chondrocytes and inflammation. Treatment of OA is only aimed at reducing pain and improving joint function. Recently, extracellular vesicles (EVs) secreted from stem cells have emerged as a cell regenerative tool in several degenerative diseases, including OA. We hypothesised that induced pluripotent stem cell (iPSC)-derived EVs would be beneficial for regenerating chondrocytes and OA therapy. Therefore, we aimed to investigate iPSC-EVs' effects on chondrocyte behaviour in an interleukin 1 beta (IL-1ß)-induced in vitro OA model and anterior cruciate ligament transection (ACLT)-induced in vivo OA model of rabbit articular cartilage. Methods: The iPSC-EVs were isolated by sequential ultracentrifugation from a 48-h-incubated conditional medium of iPSC. The isolated iPSC-EVs were characterised by transmission electron microscopy, western blot analyses, and dynamic light scatter. The effects of iPSC-EVs on the viability of human primary chondrocytes and cell senescence were analysed. Premature senescence of cells was induced by long-term incubation with low doses of hydrogen peroxide. To investigate the therapeutic effect of iPSC-EVs on OA chondrocytes in vitro, IL-1ß was used to induce chondrocyte damage. Inflammatory macrophages were activated from THP-1 monocytes to observe the impact of iPSC-EV on macrophage polarisation. The phenotypes of the macrophages exposed to iPSC-EVs were evaluated by ELISA and western blot analyses. The primary chondrocytes were co-cultured with different phenotypes of macrophages to observe the expression of collagen II and catabolic enzymes in chondrocytes. iPSC-EVs were injected intraarticularly into the rabbit with an ACLT-induced OA model. The progression of lesions was assessed through macroscopic and histopathological studies. Results: We showed that iPSC-EVs significantly stimulated the proliferation of primary human chondrocytes and suppressed cell senescence by regulating the expression of p21 and collagen II. iPSC-EVs reduced matrix degradation enzymes and IL-6 expression and attenuated IL-1ß-mediated cell death of chondrocytes. Furthermore, iPSC-EVs modulated macrophage polarisation, resulting in the rescue of damaged chondrocytes in an inflammatory microenvironment. In the rabbit ACLT model, the OA-like lesions, including inflammation, subchondral bone protrusion, and articular cartilage destruction, were ameliorated by iPSC-EV. A histopathological study consistently revealed that iPSC-EVs attenuated ACLT-mediated alteration of MMP13 and ADAMTS5 and collagen II expression. Conclusion: iPSC-EVs protected chondrocytes by enhancing cell proliferation, suppressing premature senescence, and maintaining homeostasis of collagen II synthesis and matrix degradation enzymes such as matrix metalloproteinases (MMPs) and ADAMTS5. iPSC-EVs also reduced cell death in IL-1ß-mediated chondrocyte cell damage. In the rabbit ACLT-induced OA model, iPSC-EV injection reduced cartilage destruction, as indicated by the upregulation of collagen II and down-regulation of MMP13 and ADAMTS5. Overall, our results suggest that iPSC-EVs possess therapeutic potential and may be used as an OA treatment option. The translational potential of this article: This study highlights the potential of iPSC-EVs as a therapeutic option for chondrocyte regeneration and OA treatment.

Human Olfactory Ensheathing Cell-derived Extracellular Cesicles: miRNA Profile and Neuroprotective Effect.

BACKGROUND: Extracellular Vesicle (EV)-based therapy has been identified as a leading alternative approach in several disease models. EV derived from the Olfactory Ensheathing Cell (OEC) has been documented for its strong neuro-regenerative capacity. However, no information on its cargo that may contribute to its therapeutic effect has been available. OBJECTIVE: To report the first miRNA profile of human OEC (hOEC) -EV, and investigate the neuroprotective effects. METHODS: hOEC-EV was isolated and sequenced. We established in vitro experiments to assess the therapeutic potential of hOEC-EVs with respect to insulted neural progenitor cells (NPCs), and the angiogenesis effect. Secondary post-injury insults were imitated using t-BHP-mediated oxidative stress. RESULTS: We noted a strong abundance of hOEC-EV-miRNAs, including hsa-miR148a-3p, hasmiR151a- 3p and several members of let-7 family. The common targets of 15 miRNAs among the top 20 miRNAs were thrombospondin 1 and cyclin dependent kinase 6. We demonstrated that hOEC-EVs promote normal NPC proliferation and differentiation to neuron-like morphologies with prolonged axons. hOEC-EVs protect cells from t-BHP mediated apoptosis. We also found that the migration rate of either NPCs or endothelial cells significantly improved with hOEC-EVs. Furthermore, in vitro tube formation assays indicated that angiogenesis, an important process for tissue repair, was significantly enhanced in human umbilical vein endothelial cells exposed to hOEC-EVs. CONCLUSION: Our results revealed that hOEC-EVs exert neuroprotective effects by protecting cells from apoptosis and promoting in vitro biological processes that are important to neural tissue repair, including neural cell proliferation, axonal growth, and cell migration, in addition to enhancing angiogenesis.

Extracellular vesicles isolated from human olfactory ensheathing cells enhance the viability of neural progenitor cells.

OBJECTIVE: Acquired neurological diseases such as severe traumatic brain or spinal cord injury (SCI) cause irreversible disability. Olfactory ensheathing cell (OEC) transplantation has been trialed as a promising SCI treatment. Extracellular vesicles (EVs), which regulate cell-cell interactions, have recently garnered extensive research interests and emerged as a non-cell-based therapy in neurological disorders, including in SCI animal models. However, there have been no reports of human OEC-EVs and their beneficial effects on neuron regeneration. Here, we investigated the effects of EVs isolated from human OEC on the viability of neuronal cells. METHODS: EVs were isolated from primary human OECs (hOECs) by serial ultracentrifugation. The hOEC-EVs were characterized by transmission electron microscopy, western blotting, and nanoparticle tracking analyses. We conducted CCK8 and lactate dehydrogenase assays to assess the cell proliferation and cytotoxicity of neural progenitor cells (NPCs) exposed to hOEC-EVs. Tert-butyl hydroperoxide (t-BHP) was utilized to mimic oxidative stress-induced cytotoxicity in NPCs. RESULTS: The modal diameter of hOEC-derived EVs was 113.2 nm. Expressions of EV markers such as CD9, CD63, and CD81 were detected by western blotting. hOEC-derived EVs enhanced the proliferation of NPCs and ameliorated cell cytotoxicity mediated by t-BHP. DISCUSSION: Our findings reveal a role for hOEC-derived EVs in NPC proliferation and oxidative stress-induced neuronal toxicity model. These results may be useful for developing non-cell therapy OEC-EV-based treatment in acquired nervous system disease.

Surgical reconstructions for adult brachial plexus injuries. Part I: Treatments for combined C5 and C6 injuries, with or without C7 injuries.

Brachial plexus injuries will cause a significantly decreased quality of life. Patients with upper arm type brachial plexus injuries, which means C5 and C6 roots injury, will lose their shoulder elevation/abduction/external rotation, and elbow flexion function. Additional elbow, wrist, and hand extension function deficit will occur in patients with C7 root injury. With the advances of reconstructive procedures, the upper arm brachial plexus injuries can be successfully restored through nerve repair, nerve grafting, nerve transfer, muscle / tendon transfer and free functioning muscle transfer. In this review article, we summarized the various reconstructive procedures to restore the function of shoulder and elbow. Nowadays, the upper arm type BPI can be treat with satisfied outcomes (80-90% successful rate).