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      Early sacral neuromodulation ameliorates urinary bladder function and structure in complete spinal cord injury minipigs

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          Abstract

          Aims

          To determine the effects of early sacral neuromodulation (SNM) and pudendal neuromodulation (PNM) on lower urinary tract (LUT) function, minipigs with complete spinal cord injury (cSCI) were analyzed. SNM and PNM have been proposed as therapeutic approaches to improve bladder function, for example after cSCI. However, further evidence on efficacy is required before these methods can become clinical practice.

          Methods

          Eleven adults, female Göttingen minipigs with cSCI at vertebral level T11‐T12 were included: SNM (n = 4), PNM (n = 4), and SCI control (SCIC: n = 3). Tissue from six healthy minipigs was used for structural comparisons. Stimulation was started 1 week after cSCI. Awake urodynamics was performed on a weekly basis. After 16 weeks follow‐up, samples from the urinary bladder were taken for analyses.

          Results

          SNM improved bladder function with better capacities and lower detrusor pressures at voiding and avoided the emergence of detrusor sphincter dyssynergia (DSD). PNM and untreated SCI minipigs had less favorable outcomes with either DSD or constant urinary retention. Structural results revealed SCI‐typical fibrotic alterations in all cSCI minipigs. However, SNM showed a better‐balanced distribution of smooth muscle to connective tissue with a trend towards the reduced progression of bladder wall scarring.

          Conclusion

          Early SNM led to an avoidance of the emergence of DSD showing a more physiological bladder function during a 4 month follow‐up period after cSCI. This study might pave the way for the clinical continuation of early SNM for the treatment of neurogenic LUT dysfunction after SCI.

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          Most cited references21

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          A novel porcine model of traumatic thoracic spinal cord injury.

          Spinal cord injury (SCI) researchers have predominately utilized rodents and mice for in vivo SCI modeling and experimentation. From these small animal models have come many insights into the biology of SCI, and a growing number of novel treatments that promote behavioral recovery. It has, however, been difficult to demonstrate the efficacy of such treatments in human clinical trials. A large animal SCI model that is an intermediary between rodent and human SCI may be a valuable translational research resource for pre-clinically evaluating novel therapies, prior to embarking upon lengthy and expensive clinical trials. Here, we describe the development of such a large animal model. A thoracic spinal cord injury at T10/11 was induced in Yucatan miniature pigs (20-25 kg) using a weight drop device. Varying degrees of injury severity were induced by altering the height of the weight drop (5, 10, 20, 30, 40, and 50 cm). Behavioral recovery over 12 weeks was measured using a newly developed Porcine Thoracic Injury Behavior Scale (PTIBS). This scale distinguished locomotor recovery among animals of different injury severities, with strong intra-observer and inter-observer reliability. Histological analysis of the spinal cords 12 weeks post-injury revealed that animals with the more biomechanically severe injuries had less spared white matter and gray matter and less neurofilament immunoreactivity. Additionally, the PTIBS scores correlated strongly with the extent of tissue sparing through the epicenter of injury. This large animal model of SCI may represent a useful intermediary in the testing of novel pharmacological treatments and cell transplantation strategies.
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            Early sacral neuromodulation prevents urinary incontinence after complete spinal cord injury.

            The study aim was to investigate potential influences on human nerves and pelvic organs through early implantation of bilateral sacral nerve modulators (SNMs) in complete spinal cord injury (SCI) patients during the acute bladder-areflexia phase.
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              Chronic spinal compression model in minipigs: a systematic behavioral, qualitative, and quantitative neuropathological study.

              The goal of the present study was to develop a porcine spinal cord injury (SCI) model, and to describe the neurological outcome and characterize the corresponding quantitative and qualitative histological changes at 4-9 months after injury. Adult Gottingen-Minnesota minipigs were anesthetized and placed in a spine immobilization frame. The exposed T12 spinal segment was compressed in a dorso-ventral direction using a 5-mm-diameter circular bar with a progressively increasing peak force (1.5, 2.0, or 2.5 kg) at a velocity of 3 cm/sec. During recovery, motor and sensory function were periodically monitored. After survival, the animals were perfusion fixed and the extent of local SCI was analyzed by (1) post-mortem MRI analysis of dissected spinal cords, (2) qualitative and quantitative analysis of axonal survival at the epicenter of injury, and (3) defining the presence of local inflammatory changes, astrocytosis, and schwannosis. Following 2.5-kg spinal cord compression the animals demonstrated a near complete loss of motor and sensory function with no recovery over the next 4-9 months. Those that underwent spinal cord compression with 2 kg force developed an incomplete injury with progressive partial neurological recovery characterized by a restricted ability to stand and walk. Animals injured with a spinal compression force of 1.5 kg showed near normal ambulation 10 days after injury. In fully paralyzed animals (2.5 kg), MRI analysis demonstrated a loss of spinal white matter integrity and extensive septal cavitations. A significant correlation between the magnitude of loss of small and medium-sized myelinated axons in the ventral funiculus and neurological deficits was identified. These data, demonstrating stable neurological deficits in severely injured animals, similarities of spinal pathology to humans, and relatively good post-injury tolerance of this strain of minipigs to spinal trauma, suggest that this model can successfully be used to study therapeutic interventions targeting both acute and chronic stages of SCI.
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                Author and article information

                Contributors
                esra.keller@pmu.ac.at
                Journal
                Neurourol Urodyn
                Neurourol. Urodyn
                10.1002/(ISSN)1520-6777
                NAU
                Neurourology and Urodynamics
                John Wiley and Sons Inc. (Hoboken )
                0733-2467
                1520-6777
                23 December 2019
                February 2020
                : 39
                : 2 ( doiID: 10.1002/nau.v39.2 )
                : 586-593
                Affiliations
                [ 1 ] Department of Urology and Andrology University Clinics Salzburg Salzburg Austria
                [ 2 ] Spinal Cord Injury and Tissue Regeneration Center Salzburg Paracelsus Medical University Salzburg Austria
                [ 3 ] Institute of Molecular Regenerative Medicine Paracelsus Medical University Salzburg Austria
                [ 4 ] Banat University of Agricultural Science and Veterinary Medicine Timișoara Romania
                [ 5 ] Klinik für Urologie Klinikum Lippe Detmold Germany
                [ 6 ] Department of Urology, Comprehensive Cancer Center Medical University Vienna Vienna Austria
                [ 7 ] Austrian Cluster of Tissue Regeneration Vienna Austria
                [ 8 ] Department of Urology American Hospital Dubai Dubai United Arab Emirates
                Author notes
                [*] [* ] Correspondence Dr. Elena E. Keller, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.

                Email: esra.keller@ 123456pmu.ac.at .

                Author information
                http://orcid.org/0000-0003-4560-1515
                Article
                NAU24257
                10.1002/nau.24257
                7027870
                31868966
                c7d5e9c7-ed2a-4f5d-950f-b600afee5d9c
                © 2019 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 11 June 2019
                : 03 December 2019
                Page count
                Figures: 4, Tables: 1, Pages: 8, Words: 4884
                Funding
                Funded by: Medtronic , open-funder-registry 10.13039/100004374;
                Award ID: ERP Grant
                Categories
                Original Basic Science Article
                Original Basic Science Articles
                Custom metadata
                2.0
                February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:18.02.2020

                Urology
                minipigs,pudendal neuromodulation,regeneration,sacral neuromodulation,spinal cord injury,urinary bladder

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