Reanimation of a Denervated Muscle Using Upper
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REANIMATION OF A DENERVATED MUSCLE USING UPPER MOTONEURON INJURED LOWER MOTONEURONS IN SPINAL CORD INJURY PATIENTS: A RAT MODEL by SREENATH NARAYAN Submitted in partial fulfillment of the requirements For the degree of Master of Engineering Thesis Advisor: Dr. Robert F. Kirsch Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY January, 2006 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Master of Engineering degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Contents 1 Introduction 6 2 Background 9 2.1 Injury to Peripheral Nerves ........................... 9 2.2 Current Techniques ................................ 9 2.2.1 Orthoses .................................. 9 2.2.2 Tendon Transfers ............................. 10 2.2.3 Peripheral Nerve Rerouting ....................... 11 2.2.4 Direct Muscle Neurotization ....................... 12 2.3 Related Experiments ............................... 13 2.3.1 Regrowth of Nerves Under Active Control Through an Empty Epineu- ral Sheath ................................. 13 2.3.2 Effect of Conduction Block ........................ 14 2.3.3 Diaphragmatic Reanimation ....................... 14 3 Methods and Materials 15 3.1 SCI and Denervation ............................... 16 3.2 Nerve Transfer .................................. 17 3.3 Post Chronic Surgery Care ............................ 19 3.4 Force Analysis ................................... 20 3.4.1 Muscle Characterization (Pulse Width Modulation) .......... 20 3.4.2 Spinal Cord Injury Completeness Testing ................ 22 1 3.4.3 Assurance of Graft Area Conduction .................. 23 4 Results 24 4.1 Animal Care .................................... 24 4.2 Pulse Width Modulation ............................. 26 4.3 Spinal Cord Injury Verification ......................... 30 4.4 Assurance of Graft Area Conduction ...................... 32 5 Discussion 34 5.1 Pulse Width Modulation ............................. 35 5.2 Spinal Cord Injury ................................ 36 5.3 Assurance of Nerve Graft ............................. 37 Acknowledgments 38 References 38 2 List of Tables 1 Summary of Force Data ............................. 31 3 List of Figures 1 Three Types of Nerves in SCI .......................... 6 2 Picture of Exposed Spinal Cord ......................... 17 3 Picture of Sciatic Nerve and its Branches .................... 18 4 Diagram of Procedure 1 ............................. 19 5 Diagram of Procedure 2 ............................. 20 6 Force Measurement Jig .............................. 21 7 Raw Muscle Force Data ............................. 26 8 Length-Tension Curve .............................. 27 9 Pulse Width-Force Curves ............................ 28 10 Spinal Cord Lesion Verification ......................... 30 11 Graft Area Conduction Efficiency ........................ 33 4 Abstract Reanimation of a Denervated Muscle Using Upper Motoneuron Injured Lower Motoneurons in Spinal Cord Injury Patients: A Rat Model Abstract by SREENATH NARAYAN This project aims to show that a denervated muscle can be reanimated following spinal cord injury using upper motoneuron injured lower motoneurons regrowing through non-electrically excitable nerves. The newly reanimated muscle can then be stimulated with command signals from an electrical stimulation system. A rat model was created with a spinal cord injury and a transection of the tibial nerve to create the denervation. One week post injury, the upper motoneuron injured peroneal nerve was transferred to the sheath of the tibial nerve. About five weeks after that, force analysis showed significant regrowth. The same force analysis was performed on both the experimental side, which had undergone the surgical procedures outlined above, and the contralateral side, which previously had not undergone any peripheral surgical procedures. The maximum experimental side gastrocnemius force was approximately 50% that of contralateral side. 5 1 Introduction There are approximately 11,000 new cases of spinal cord injury (SCI) each year [38]. Tetraplegia, in both the complete and incomplete form, accounts for 56.4% of all SCI [37, 38], and results in total or partial paralysis of the body from the neck down [48]. Often, tetraplegia means that the muscles of the shoulder are not under voluntary control, which lends itself to techniques such as Functional Electrical Stimulation (FES) to restore limited mobility [34]. In SCI, three types of motoneuron conditions exist, as illustrated in figure 1: those that have intact upper motoneurons (UMN) and intact lower motoneurons (LMN) (part a), those Figure 1: Illustration of the three types of nerves that can be found in a spinal cord injury patient: (a) Type 1 Nerve - Intact UMN and LMN. (b) Type 2 Nerve - Damaged UMN and intact LMN. Target muscle is paralyzed but innervated; nerve is electrically excitable. (c) Type 3 Nerve - Damaged LMN cell body. Target muscle is paralyzed and denervated; nerve is not electrically excitable. 6 that have intact LMN but do not receive signals from the brain due to damage to the UMN (part b) [46], and those that are dead, which have sustained damage to the cell body of the LMN (part c) [24, 34, 43]. Neurons with intact LMNs that lead to paralyzed muscles are referred to here as ”type 2 nerves”, whereas those with damage to the LMN cell body that lead to denervated muscles are called ”type 3 nerves”. FES can restore limited mobility to a SCI patient by artificially eliciting limited muscle contractions, which is done by stimulating the LMN of a paralyzed muscle, which serves as a conduit for the stimulation signal [1, 3, 31, 34]. However, if the cell body of the LMN is damaged due to the SCI, it will no longer conduct an action potential toward the neuromuscular junction [1, 34]. Furthermore, the neuromuscular junction degenerates [31], and muscle contractions cannot be elicited through any type of nerve stimulation [1, 31, 34]. It is possible, through direct stimulation of the muscle, to immediately generate an attenuated amount of force [22], and to eventually restore the electrical conditions of the muscle membrane to normal conditions [30, 31]. However, the muscle force generation is usually not sufficient to for functional applications [34], unless a large amount of current [22] is used to individually excite each single muscle fiber [31], which is not desirable. The project at hand aims to address the problem of denervation by attempting to regrow intact and electrically excitable LMNs through the non-electrically excitable sheath left behind after denervation. C4 through C6 level injuries account for a combined 39.4% of spinal cord injuries, while the rest of the injuries are almost evenly spread over the rest of the levels [37]. It is at these levels of the spinal cord that the majority of the LMNs that lead to the muscles of the shoulder and many of those that lead to the muscles of the elbow (especially the 7 biceps) emerge from the spinal cord [34], meaning that these muscles are often at least partially denervated [34, 42]. Peckham, et al., suggested that LMN injury could reduce the effectiveness of FES recipients with C4 level SCI [34, 42]. This claim was supported by Doerr and Long, who found that three out of four patients with C4 injury had damage to the LMNs of the biceps [11, 34]. Though the proposed technique can be used with denervation concomitant with all levels of SCI, the frequency of injury to the muscles of the shoulder and elbow makes a technique that can address denervation of these muscles especially attractive, which is why they were chosen to be the primary target of this research. Denervation is a generally pervasive problem in SCI, so other solutions, such as direct motor neurotization [41], tendon transfers [27] and voluntary nerve rerouting [55] have been proposed. However, the muscles of the elbow and the shoulder are are not conducive to many of these techniques due to reasons that will discussed here in more detail. For example, when the suprascapular nerve has suffered damage, many of these previous proposed methods may not be of benefit to the patient, but one of the intercostal nerves, which have been used in the past as donors [28, 55], could be used to reanimate the infraspinatus and supraspinatus muscles. Therefore, if the proposed technique proves suitable for restoring mobility, it will help further the goal of FES in restoring muscle function. 8 2 Background 2.1 Injury to Peripheral Nerves When a peripheral nerve is injured, it undergoes Wallerian Degeneration [32], a phenom- ena that is seen regardless of the mechanism of the injury [33]. Several events are indicative of Wallerian degeneration: the axoplasm undergoing disruption, fragmentation of neural tubules and neurofilaments leading to a loss of longitudinal orientation, the mitochondria becoming swollen, discontinuities developing in the axolemma, and proliferating Schwann cells and macrophages further degrading the axon [6, 33, 36]. Since these symptoms