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Vineet Mathur 10/30/15 Section A Literature Review The number of living Spinal Cord Injury (SCI) patients in the United States, as of 2012, is approximately 270,000 people. In addition there are about 12,000 new cases of spinal cord injury each year. SCI primarily affects young adults, the average age of injury was 28.7 years, and most occur between the ages of 16 to 30. These ages show a large impact on SCI patients, for a majority of their life they will lack movement, and or be in critical condition (for cases of higher severity). The main cause of SCI is vehicular related accidents, however other causes include of falls, violence, sports, and other/ unknown causes (shown in Figure 1) (National Spinal Cord Injury Statistics Center [NSCISC], 2012). Causes of SCI since 2005 SCI ocurrences 9.70% 8.20% Vehicular, 14.60% 39.20% 15.80% Falls Violence Imcomplete Tetraplegia 21.40% 40.80% Sports 28.30% Other/Unkn. 21.60% Complete Paraplegia Incomplete Paraplegia Complete Tetraplegia Figure 1 (above) shows a pie chart on the statistics Figure 2 (above) shows the occurrence of different of the causes of SCI since 2005 (NSCISC, 2012). spinal cord injuries since 2012 (NSCISC, 2012). Around 51.8% of SCI patient reported having a job when injured, and within after a year 11.7% reported employed, showing how the injury affects their pay and occupation status. About 89.3% of patients are sent back home to where they originally lived in order to gain help. The average cost of a SCI varies depending on the severity of the injury (Figure 2 below), and is roughly between 1.5 million to 4.5 million dollars each year (NSCISC, 2012). Figure 2 (above) shows average total expense for each type of SCI at two ages, 25 and 50 years old (NSCISC, 2012). Severity of Injury Average Yearly Expenses Estimated Lifetime Costs by Age At (In February 2012 dollars) Injury (discounted at 2%) First Year ($) Each Subsequent Year ($) 25 Years Old 50 Years Old High Tetraplegia (C1-C4) 1,023,924 177,808 4,543,182 2,496,856 Low Tetraplegia (C5-C8) 739,874 109,077 3,319,533 2,041,809 Paraplegia 499,023 66,106 2,221,596 1,457,967 Incomplete Motor function at any Level 334,170 40,589 1,517,806 1,071,309 Along with the increase expenses, life expectancy drastically decreases (Figure 3 below). Figure 3 (above) shows the years expected to live after injury for SCI patients at the ages 20, 40, and 60 years old (NSCISC, 2012). Life Expectancy (years) for post-injury by severity of injury and age at injury For persons who survive the first 24 hours AIS D Ventilator Motor Low High Dependent Functional Para Tetra Tetra At Any At Any Level Level 52.1 44.8 39.6 35.3 16.8 For persons surviving at least one year past the injury AIS D Ventilator Motor Low High Functional Para DependentTetra Tetra At Any Any Level Level 52.5 45.4 40.5 36.9 24.8 Age at Injury No SCI 20 58.8 40 39.9 33.8 27.4 23.2 19.7 7.5 34.1 27.9 23.9 21 12.3 60 22.5 17.5 12.8 10 7.8 1.6 17.7 13.2 10.4 8.6 3.8 In the past, the leading cause of death in SCI is renal failure, however, seems to recently be pneumonia and septicemia (NSCISC, 2012). Spinal Cord Structure The spinal cord is the most important connection between the brain and body. It is 40 to 50 cm long and is 1-1.5 cm in diameter. The spinal cord is divided into four sections, the cervical, thoracic, lumbar, and sacral. It consists of nerves that send the signals from the brain to the body through the CNS (central nervous system). The spinal cord contains neurons that axons mediate autonomic control for most of the visceral functions (Dafny, n.d.). In the spinal cord there are 31 segments that are divided among the four sections. The cervical section has 8 (C1-C8), thoracic (T1-T12), lumbar 5 (L1-L5), and sacral 5 (S1-S5), and each section has a specific function. The cervical section is responsible for the support of the head on the neck, and assists with involuntary functions. The thoracic section is responsible for holding the ribcage in place and protecting the heart. The lumbar section is responsible for the support of the weight of the body, which can be seen through the larger vertebrae in the section. The last section, the sacral section, is responsible for connecting the spine to the hips, giving motion to the lower body. Each vertebra specializes in a specific function (seen in figure 4 to the right), and a SCI patient that receives trauma in a specific vertebra will loose function in that vertebra as well as all vertebrae below that one (Dafny, n.d.). Figure 4 (above) shows the sections of the spinal cord along with the individual vertebra and their functions. The spinal cord is sheathed by three membranes: the Pia, arachnoid and Dura. The Dura is a tough outer layer of the spinal cord and serves to protect it. There are not many significant nerves that conduct impulses in the Dura, however previous research of shocking the layer has been preformed. The arachnoid is the middle layer of the three, and gets its name because of its spider web-like structure. The last, innermost layer is the Pia, which consists of thin vascular membranes of collagen fibers that closely adhere to the spinal cord (Figure 5). Peripheral nerves are attached to the Spinal cord (part of the PNS), and carry information from the brain for muscle movement, then carry sensory information back to the brain/ spinal cord so that is can be processed (Dafny, n.d.). Figure 5 (above) displays the three layers (Dura, arachnoid, and Pia) in respect to the rest of the structure of the spinal cord (Dafny, n.d.). The spinal cord is split into types of cells: cells that belong to the gray or white matter. The gray matter consists of cell bodies of both neurons and glia (connective tissue of, dendrites, and axon terminals of the neurons). On the other hand, white matter consists of axons connecting different parts of the gray matter together (Dafny, n.d.). The four different sections contain different vertebrae, however, most have the same basic structure as well as the same sections (Figure 6). Figure 6 (above) displays the different vertebrae in each section of the spinal cord (Dafny, n.d.). In the spinal cord vertebrae, white matter is on the outside, gray matter in the inside, and the central canal (filled with CSF cerebrospinal fluid) in the middle. The shape and size of the gray matter according the spinal cord level, at lower levels the ratio between gray matter and white matter is higher because these levels contain less ascending and descending nerve fibers. The gray matter is divided into four main sections, the dorsal horn, intermediate column, lateral horn, and ventral horn. The dorsal horn is found at all spinal levels and is comprised of many sensory nuclei that receive and process incoming somatosensory information (a complex sensory system that contains many receptors such as heat, light, chemical, and mechanical receptors). From the dorsal horn, ascending axons emerge to transmit sensory information to the brain. The intermediate column and lateral horn comprise autonomic neurons and innervating visceral and pelvic organs. The ventral horn compromises motor neurons that innervate skeletal muscles (Dafny, n.d.). Spinal Cord Cells In the gray matter of the spinal cord, neurons are classified as root cells, column or tract cells, and propriospinal cells. Root cells vary greatly in size and are located in the ventral and lateral gray horns. Their most prominent features are large multi polar elements exceeding 25 µm of their cell body. Root cells contribute their axons to the spinal nerves and are classified by two major groups: somatic efferent neurons that innervate the skeletal muscles and visceral efferent neurons that send their axon to various autonomic ganglia (Dafny, n.d.). Column or Tract neurons are in the CNS and located in the gray dorsal horn. Their axons form vertical ascending tracts that ascend in the white column and terminate upon neurons near the nose in the brainstem. One type of column cells sends their axons up and down the cord to terminate in the gray matter close to their origin. These are Intersegmental association column cells. Another type called commissure association column cells send their axons across midline to terminate in gray matter close to their origin. The last are called intrasegemntal association column cells, and their axons terminate within the segment in which they originate from. Propriospinal spinal cells are spinal are spinal interneurons whose axons do not leave the spinal cord proper. They account for about 90% of spinal neurons (Dafny, n.d.). Surrounding the gray matter is white matter that conducts signals up the ascending and descending tracts. It is composed of unmyelinated and myelinated neurons, and is divided into the dorsal, lateral, and ventral column. The three types of nerve fibers found in the white matter are long ascending nerve fibers that make synaptic connections to different brainstems (originate from column cells), long descending nerve fibers (originate from cerebral cortex and different brainstems to synapse levels such as the fibers responsible for reflexes), and shorter never fibers that interconnect various spinal cord levels. Ascending tracts are found in all columns; where as descending tracts are found only in the lateral and anterior columns (Dafny, n.d.). There are four different terms for the bundles of axons found in the spinal cord: funiculus, fasciculus, tract, and pathway. Funiculus describes a large group of nerve fibers in a specific area. Within a funiculus there are often smaller bundles of axons called fasciculus. Fasciculus refers to a morphological term, whereas tract or pathway refers to a function. A tract is a group of nerve fibers that usually have the same origin, destination, course, and similar function. A pathway usually refers to an entire neural circuit responsible for a specific function, and includes all the nuclei and tracts that are in the function (ex. Spinothalmic pathway) (Dafny, n.d.). Spinal Cord Tracts The Spinal Cord is composed of an ascending tract (Figure 7) as well as a descending tract (Figure 8). The nerve fibers that compose of the ascending tract arise from the first order of the DRG. The ascending tract transmits sensory information from the sensory information related to touch; two point discrimination of simultaneously applied pressure, vibration, position, movement sense, and conscious proprioception. The neospinothalmic tract located in the lateral column carries signals of pain, temperature, and crude touch from visceral and somatic structures. The dorsal and ventral spinocerebellar tracts carry unconscious proprioception from the muscles and joint of the lower extremity to the cerebellum. In the ventral column there are four common tracts. 1) The paleospinothalmic tract carries pain, temperature, and touch information to the brain stem and diencephalon. 2) The spinoolivary tract carries from Golgi tendon organs to the cerebellum. 3) The spinoreticular tract and 4) the spino-tectal tract (Dafny, n.d.). Figure7(above)depictstheascendingtractinthespinalcord (Dafny, n.d.). Graphene and Allotropes of Carbon Graphene is an allotrope of Carbon similar to Carbon Nanotubes (which have very similar properties and may be applied in this scenario), diamonds, charcoal, etc. It is a 2D crystalline material with many significant properties. It is substantially stronger than steel, an excellent thermal and electric conductor, relatively transparent, and other properties that relate to its pore size. The crystalline structure of Graphene resembles a honeycomb pattern, and is formed by a carbon atom covalently bonded to three other carbon atoms (Figure 8) (NA, 2010) Figure 8 (above) represents the honeycomb structure of Graphene (NA, 2010) Carbon has many different forms because of the atoms ability for it to bond to itself. The most common form of carbon is Graphite, which consists of many layers of hexagonal structured Graphene connected by hydrogen bonds. Another form of Carbon is in the form of Carbon Nanotubes (CNT)(Figure 9) or a sheet of Carbon atoms rolled into a tube to form a long, super conductive, material. Along with CNT’s another prominent form of Carbon is in the form of Fullerenes (Figure 9) or Bucky Balls. Fullerene has the structure of a soccer ball consisting of only carbon atoms (NA,2010). Figure 9 (above) represents the different allotropes of Carbon (NA, 2010) Graphene is a single layer of carbon atoms packed in a hexagonal (honey-comb) lattice with a carbon-to-carbon distance of around 0.142 nm. Graphene is also practically transparent: the optical region it absorbs only 2.3% of the light. In contrast to low temperature 2D systems based on semiconductors, Graphene maintains its 2D properties at room temperature. Graphene also has several other interesting properties, which it shares with carbon nanotubes. It is substantially stronger than steel, very stretchable and can be used as a flexible conductor. Its thermal conductivity is much higher than that of silver (NA,2010). One process to create Graphene is Carbon Vapor Deposition (CVD), in which a sheet of copper foil is heated up to a point a little less than it’s melting point, and a stream of Methane is run through the copper. The copper then hydrogenizes the methane as it diffuses through the foil created a thin layer of Graphene within the pocket of copper (De La Fuente, ND). Previous Paralysis Research In the Roman era it was believed by physicians that “ spirits” , such as humors, were conducted through nerves in the human body. This idea was widely believed until 1791 when Luigi Galvani published his theory of animal electricity. His work in this theory was stimulation of frog legs with electric sparks. His theory states that the brain sent animal electricity, which was then transported through nerves and stored in muscles. Over the next 75 years, experimentation on nervous system tissue occurred. During this time, Giovanni Aldini conducted experiments on the brains of oxen and spinal cord of decapitated criminals. These experiments causing slight contractions in muscles, proving electricity could be applied centrally with peripheral effects. In the recent past, experiment on stimulating certain parts of the brain or spinal cord to contract certain muscles has been performed (Tarsey, 2008). Modern experiments looking into the same issue involve research on avatar bodies or conductors for the body. New research on possible cortical-spinal prosthesis is under way. This research includes the creation of a neural prosthesis that uses neural activity from premotor neurons to control limb movement in paralyzed primates. Then by matching this data with real time spinal cord and muscle stimulation, producing limb movement to targeted locations. This is one possible future step to reconstituting limb movement (Shanechi, 2014). Another idea researched is the use of flexible conductors attached to the Dura matter in the spinal cord. In this research, a micro cracked gold with a silicone fill conductor was placed on the Dura matter of a spinal cord and was externally shocked. Movement was restored however only for a short period of time (Minev, 2015). Biocompatibility The Central Nervous System (CNS) is not only governed by a peripheral immune system, but also by resident cells. This means that materials that are biocompatible outside of the CNS may not be compatible in the CNS. Another feature of the CNS is that tissues within it have a relatively low growth and repair rates. Materials must be soft so that they do not disrupt cells causing damage and loss of multiple cells. If the polymer/ material used is rigid and causes scared tissue, inflammatory responses will occur causing harm to surround tissue and the organism as a whole. To decrease the chance of causing an inflammatory response, the use of a flexible material is necessary. Along with this, neurons tend to grow best on materials of less stiffness (around 1kPa) (Aurand, 2012). Graphene has many of the properties previously listed for biocompatibility making it a strong candidate for biocompatibility. Work Cited 1. Anatomy of the Spinal Cord (Section 2, Chapter 3) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston. (n.d.). Retrieved October 2, 2015. \ 2. Spinal Cord Injury Facts and Figures at a Glance. (2012, Feburary). Retrieved September 25, 2015 from https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/Facts%202012%20Feb %20Final.pdf 3. Shanechi, M., Hu, R., Williams, Z., (2014). A cortical-spinal prosthesis for targeted limb movement in paralyzed primate avatars. Nature Communications, 1-9. doi: 10.1038/ncomms4237 4. Minev, I, R. Musiekno, P. Hirsch, A. Barraud, Q. Wenger, N. Moraud, E, M. Gandar, J. Capogrosso, M. Milekovic, T. Asboth, L. Torres, R, F. Vachicouras, N. Liu, Q. Pavolva, N. Duis, S. Larmagnac, A. Voros J. Micera, S. Suo, Z. Gregoire, Courtine. Lacour, S. P. (2015). Electronic dura matter for long-term multimodal neural interfaces. 347, 159-163. 5. Scientific Background on the Nobel Prize in Physics 2010 GRAPHENE. (2010). Royal Swedish Academy of Sciences, 10-10. 6. De La Fuente, J. (n.d.). CVD Graphene - Creating Graphene Via Chemical Vapour Deposition. Retrieved November 15, 2015, from http://www.graphenea.com/pages/cvdgraphene#.VnOYWpMrKRs 7. Tarsy, D. (2008). History of Therapeutic use of Electricity on the Brain and the Development of Deep Brain Stimulation. In Deep brain stimulation in neurological and psychiatric disorders. Totowa, NJ, Massachusetts: Humana Press. 8. Aurand, E., Wagner, J., Lanning, C., & Bjugstad, K. (2012). Building Biocompatible Hydrogels for Tissue Engineering of the Brain and Spinal Cord. Journal of Functional Biomaterials JFB, 839-863. 9. Feng, L., & Liu, Z. (n.d.). Graphene in biomedicine: Opportunities and challenges. Nanomedicine, 317-324.