Clinical translation of a regeneration strategy for spinal cord injury
Author: Frostell, Arvid
Date: 2019-02-08
Location: Lecture hall J3:07 Sune Bergström, BioClinicum, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
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Thesis (20.11Mb)
Abstract
The complex and vulnerable tissue of the spinal cord does not heal after injury, leaving patients with lifelong disability after spinal cord injury (SCI). Many milestones have been reached during the last century through specialized centers for SCI, greatly increasing life expectancy and quality of life by battling common medical problems such as urinary tract infections, pressure ulcers, spasticity, neurogenic pain, and sexual function as well as providing means of rehabilitation to a meaningful and productive life after SCI. Despite the advances in preclinical knowledge of mechanisms in SCI and several clinical trials completed, to date no pivotal treatment exists for acute spinal cord injury or for the regeneration of lost function in the chronic state. The first reports of experimental regeneration of central axons through peripheral nerve grafts are more than a century old. In the last decades, regeneration of function after SCI has been reported by several research groups in different species using peripheral nerve grafts and FGF1. The regeneration strategy was furthered refined in our group by the use of a biodegradable scaffold for exact positioning of the nerve grafts. This thesis describes the translational process to reach a clinical trial of glial scar resection and implantation of peripheral nerve grafts and FGF1 using a biodegradable guiding scaffold.
In paper I, we show that both the cranial and caudal demarcation of a thoracic spinal cord injury can be defined with electromyography of intercostal muscles in chronic SCI patients. We also present an MRI protocol with acceptable image contrast despite the presence of spinal instrumentation and showed that the injury length found with electromyography correlates well with length of injury on MRI. In paper II, we use a novel conversion table between spinal cord neuronal segments and vertebral segments and combine data on human spinal cord cross-sectional diameters from different published sources to yield continuous estimates on human spinal cord size and variability. In paper III, we describe the design of a set of spinal cord injury guiding devices based on the data from paper II, covering the normal variability found in human thoracic spinal cord segments T2–T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels proposed. In paper IV, we detail the adverse events reported during the first 60 days postoperatively in the ongoing clinical trial “Safety and Efficacy of SC0806 (Fibroblast Growth Factor 1 and a Device) in Traumatic Spinal Cord Injury Subjects”. Early results from the first six complete (AIS-A) thoracic spinal cord injury subjects operated on in the ongoing trial show that with precise preoperative and intraoperative neurophysiology, surgery and implantation can be performed without negative effects on neurological level, and safety and tolerability are acceptable to merit the continuation of the trial. In paper V, we describe the construction of a cost-effective light-sheet microscope by modification of an outdated microarray-scanner. The microscope was applied to an experimental model of hypoglossal nerve avulsion injury, and proliferation of Iba1+ cells could be quantified automatically demonstrating a possible application of the microscope.
In conclusion, reaching clinical trial in a translational process is a significant and collaborative undertaking requiring co-operation of multiple institutions and professions as well as rigorous external control of data quality and adverse events to ensure safety of study subjects. The papers in this thesis detail some relevant steps necessary for the clinical translation of regeneration strategies in chronic SCI.
In paper I, we show that both the cranial and caudal demarcation of a thoracic spinal cord injury can be defined with electromyography of intercostal muscles in chronic SCI patients. We also present an MRI protocol with acceptable image contrast despite the presence of spinal instrumentation and showed that the injury length found with electromyography correlates well with length of injury on MRI. In paper II, we use a novel conversion table between spinal cord neuronal segments and vertebral segments and combine data on human spinal cord cross-sectional diameters from different published sources to yield continuous estimates on human spinal cord size and variability. In paper III, we describe the design of a set of spinal cord injury guiding devices based on the data from paper II, covering the normal variability found in human thoracic spinal cord segments T2–T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels proposed. In paper IV, we detail the adverse events reported during the first 60 days postoperatively in the ongoing clinical trial “Safety and Efficacy of SC0806 (Fibroblast Growth Factor 1 and a Device) in Traumatic Spinal Cord Injury Subjects”. Early results from the first six complete (AIS-A) thoracic spinal cord injury subjects operated on in the ongoing trial show that with precise preoperative and intraoperative neurophysiology, surgery and implantation can be performed without negative effects on neurological level, and safety and tolerability are acceptable to merit the continuation of the trial. In paper V, we describe the construction of a cost-effective light-sheet microscope by modification of an outdated microarray-scanner. The microscope was applied to an experimental model of hypoglossal nerve avulsion injury, and proliferation of Iba1+ cells could be quantified automatically demonstrating a possible application of the microscope.
In conclusion, reaching clinical trial in a translational process is a significant and collaborative undertaking requiring co-operation of multiple institutions and professions as well as rigorous external control of data quality and adverse events to ensure safety of study subjects. The papers in this thesis detail some relevant steps necessary for the clinical translation of regeneration strategies in chronic SCI.
List of papers:
I. Neurophysiological evaluation of segmental motor neuron function of the thoracic cord in chronic SCI. Arvid Frostell, Per Mattsson, Jonas K.E. Persson, Björn Hedman, Jonathan Nordblom, Anders Lindenryd, Katarzyna Trok, Lou Brundin, Mikael Svensson. Spinal Cord. 2012;50(4):315–9.
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II. A Review of the Segmental Diameter of the Healthy Human Spinal Cord. Arvid Frostell, Ramil Hakim, Eric P. Thelin, Per Mattsson, Mikael Svensson. Front Neurol. 2016;7:238.
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III. Guiding Device for Precision Grafting of Peripheral Nerves in Complete Thoracic Spinal Cord Injury: Design and Sizing for Clinical Trial. Arvid Frostell, Per Mattsson, Mikael Svensson. Front Neurol. 2018;9:356.
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IV. A Report of Adverse Events from an Ongoing Clinical Trial Evaluating Glial Scar Resection and Implantation of Nerve Grafts and FGF1 using a Biodegradable Scaffold in Chronic Traumatic Spinal Cord Injury. Per Mattsson, Arvid Frostell, Ann-Christin von Vogelsang, Jonas K.E. Persson, Hans Basun, Björn Hedman, Lou Brundin, Mikael Svensson. [Manuscript]
V. Light-Sheet Microscopy Using an Outdated Microarray Scanner and a Consumer Digital Camera. Arvid Frostell, Pendar Khalili, Ramil Hakim, Per Mattsson, Lou Brundin, Mikael Svensson. [Manuscript]
I. Neurophysiological evaluation of segmental motor neuron function of the thoracic cord in chronic SCI. Arvid Frostell, Per Mattsson, Jonas K.E. Persson, Björn Hedman, Jonathan Nordblom, Anders Lindenryd, Katarzyna Trok, Lou Brundin, Mikael Svensson. Spinal Cord. 2012;50(4):315–9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. A Review of the Segmental Diameter of the Healthy Human Spinal Cord. Arvid Frostell, Ramil Hakim, Eric P. Thelin, Per Mattsson, Mikael Svensson. Front Neurol. 2016;7:238.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Guiding Device for Precision Grafting of Peripheral Nerves in Complete Thoracic Spinal Cord Injury: Design and Sizing for Clinical Trial. Arvid Frostell, Per Mattsson, Mikael Svensson. Front Neurol. 2018;9:356.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. A Report of Adverse Events from an Ongoing Clinical Trial Evaluating Glial Scar Resection and Implantation of Nerve Grafts and FGF1 using a Biodegradable Scaffold in Chronic Traumatic Spinal Cord Injury. Per Mattsson, Arvid Frostell, Ann-Christin von Vogelsang, Jonas K.E. Persson, Hans Basun, Björn Hedman, Lou Brundin, Mikael Svensson. [Manuscript]
V. Light-Sheet Microscopy Using an Outdated Microarray Scanner and a Consumer Digital Camera. Arvid Frostell, Pendar Khalili, Ramil Hakim, Per Mattsson, Lou Brundin, Mikael Svensson. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Svensson, Mikael
Co-supervisor: Mattsson, Per; Brundin, Lou
Issue date: 2019-01-18
Rights:
Publication year: 2019
ISBN: 978-91-7831-328-0
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