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NERVE REGENERATION

Alessio Tovaglieri

Prachee Chaturvedi

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INTRODUCTION

Spinal cord injury- common cause industrial injuryand road traffic accidents.

National Spinal Cord Injury Statistical Center(NSCISC)USA reported an annual incidence of11,000 cases of new traumatic SCIs or 40 permillion population (upper end of the 15 to 40 casesper million seen worldwide), with a prevalence of250,000 cases.

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HINDRANCEINRECOVERY- COST

Continued functional dependency, healthcareneeds and costs, as well as caregiver burden andstress.

US MSCIS have estimated lifetime costs for a 25year-old high-tetraplegia patient as much asUS$2.9 million.

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PREDICTORSOFRECOVERY

Patient characteristics-

94.4% of subjects with neurological complete SCI at 1 yearremained so at the 5-year post-injury evaluation.

Only 3.5% improved from American Spinal Injury

Association (ASIA) grade A (complete motor and sensory)tograde B (sensory incomplete including S4-5).

Older individuals >50 years were found to do well withindependence as per activities of daily living (ADL) scales,and had shorter lengths of stay. However, they had lessfavorable outcomes with walking, bladder and bowelindependence, and a higher rate of complications.

women had significantly greater ASIA total motor scoresimprovement at 1-year then men. [1]

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CLINICAL ASSESSMENT, ELECTRO-

DIAGNOSTIC, ANDIMAGINGTOOLS

Initial 1-week sensory-motor examination

Ambulatory capacity

Somatosensory evoked potentials of the tibial and

pudendal nerves Motor evoked potentials (MEPs) of the upper and

lower limb muscles

MRI

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SURGICAL INTERVENTION

With greater incompleteness and neurologicpreservation, motoric improvements were more likely innon-surgical groups.

50% of cervical SCI patients undergoing immediate

spinal cord decompression treatment protocol improvedfrom their admitting Frankel grade, versus only 24% ofreference patients.

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STEROIDSFOR ACUTE INJURY

Steroids to limit the amount of cellular damage fromsecondary injury processes such as lipid peroxidation.

Intravenous MP at 30 mg/kg bolus/day followed by 23 hours ofinfusion at 5.4 mg/kg per hour, against naloxone bolus of 5.4

mg/kg with 4.0 mg/kg per hour for 23 hours showed significantimprovement in motor and sensory function.

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REHABILITATION INTERVENTION

Functional Electrical Stimulation

Body Weight Support Treadmill Training

Neural-activity Controlled Prostheses

Bioactive Agents and Neurotrophic Factors

Transplanted Cells and Tissues

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FUNCTIONAL ELECTRICAL STIMULATION

Activity-based recovery programmed with an integratedcomputer-assisted functional electrical stimulation (FES)

Induced cycling bicycle with the hypothesis that patternedneural activity might stimulate the central nervous system to

become more functional. Electrical stimulation is used in various neuro prostheses to

substitute for non-recovered motor sensory functioning.

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NEURAL-ACTIVITYCONTROLLEDPROSTHESES

Brain machine interface

Use of brain neural activity to directly control a machinesuch as a word processor, environmental control unit,wheelchair, or hand prosthesis.

Problems- Undesirability of electrodes implanted directly into the

brain

Difficulty in converting weak fluctuating neuronalrecordings into definite, discrete and specific commands

for the machine. Non-invasive electrodes placed over the scalp or head has

limitation because of resultant weakness and loss ofspecificity of neural signals.

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THE MIAMI PROJECT

Generation of new neuronal cells as well as promoting axonregrowth and remyelination of damaged neurons.

High content screening of drugs and genes that promoteaxonal growth and regeneration

Cell Transplantation- replacing lost neurons, promoting

regeneration of existing neurons, and filling in the spinalcord cavity to minimize further damage and inflammation.

Schwann cell transplantations

Stem cells

Chromaffin cells

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SCHWANNCELL

Schwann cell is a type of nervous system cell that is locatedin the peripheral nervous system

Dedifferentiate, migrate, proliferate, express growthpromoting factors, and myelinate regenerating axons

Trophic support for neurons

Production of the nerve extracellular matrix

Modulation of neuromuscular synaptic activity

Presentation of antigens to T-lymphocytes

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SCHWANNCELLCONTINUED

During development, neural crest cells give rise to Schwann cellprecursors.

The survival and maturation of Schwann cell precursors arecontrolled by -neuregulin, which derives from neurons.

After birth, the immature cells differentiate into myelin-formingor non-myelin-forming Schwann cells, a reversible processtimed by factors such as endothelins.

Schwann cell regulates axonal caliber and neuro-filamentphosphorylation.

The main function of Schwann cells is to surround peripheral-axons with a spirally wrapped myelin sheath, which iscomposed of mainly lipids (about 80% of myelin dry weight) and

proteins (about 20%). Schwann cells have a one-on-one relationship with axons (i.e.,

each myelin-generating Schwann cell provides one segment ofmyelin to one axon).

Schwann cell also has an important role in the endogenousrepair of peripheral nerves after injury.

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ESSENTIAL FOR PERIPHERAL NERVEREPAIR

Schwann cells also contribute in clearance process bydigesting myelin debris (macrophage).

Soon after injury, the Schwann cells in the distal nervededifferentiate into non-myelinating Schwann cells and then

proliferate extensively. The Schwann cells also start to increase their expression of

various growth factors, thereby creating a permissiveenvironment for axonal regeneration.

Schwann cell is key in the self-repair of the peripheral nerve

and central nervous system.

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ROLEOFSCHWANNCELLSAFTERINJURY

Endogenous Schwann cells invade and migrate into theinjured spinal cord.

Schwann cells were shown to migrate and myelinatesurviving sensory axons.

Schwannomas- The presence of abnormally organizedSchwann cells in the spinal cord of humans.

Process of Migration still unknown

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ISOLATION AND PROLIFERATIONOF SCHWANN CELLS IN VITRO

Brockes Method

From sciatic nerves of newborn rats.

Low yield

Mitogens can be used to increase yield.

Morrissey Method

From the adult peripheral nerve.

In 10 weeks, Combination can provide several millionsat purity of 98%.

Therapeutic cloning

From embryonic stem cells

Infection by Viral vector[2]

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HARVEST OF HUMAN SCHWANN

Host-derived, autologous peripheral nerves togenerate Schwann cells

Human phrenic nerve

Progressive nature of spinal injuries and thepresence of a limited time window

Schwann cell transplants promote axonalregeneration across the site of injury/grafting butnot beyond, which severely limits the changes forfunctional restoration.

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COMBINATORIAL STRATEGIES

Elevating intrinsic capacity ofinjured central nervoussystem (CNS) axons toregenerate

Reducing glial scar formation

and deposition of chondroitinsulfate proteoglycans

Overcoming CNS myelin-associated inhibitors

Enhancing directional growthwith neurotrophic factors

Enabling reinnervation ofdenervated targets

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NEURAL STEM CELLS

a/e/fNSC can differentiate into

Oligodendrocytes

Astrocytes

Neurons

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HESC DIFFERENTIATEDIN OLIGODENDROCYTES

REMYELINATION

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3 WEEKSAFTERTRANSPLANTATIONOF ESC-DERIVED OPCS(OGODENDROCYTEPRECURSORCELLS)

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N R

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SYNERGISTICEFFECTOF NEURAL STEM CELLSAND OLFACTORY ENSHEATHING CELLSON REPAIROF ADULT RAT SPINAL CORD INJURY

NEURONAL REPLACEMENT

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10 WEEKSAFTERTRANSPLANTATIONOFOECS + NCSS

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CLINICAL TRIALS

2009

FDA approved the first clinical trial with humanEmbryonic Stem cells (hES) for transplantation afteracute SCI (Geron)

2011 The clinical trial has been discontinued Geron declares

that the therapy has been well tolerated by the patientswith no serious adverse event

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REFERENCES

1. Lim PAC, Tow AM (2007) Recovery and regeneration after spinal cordinjury: A review and summary of recent literature. Annals Academy ofMedicine Singapore 36: 49-57

2. Oudega M, Xu XM (2006) Schwann cell transplantation for repair of theadult spinal cord. Journal of Neurotrauma 23: 453-467

3. Sandner B, Prang P, Rivera FJ, Aigner L, Blesch A, Weidner N (2012)Neural stem cells for spinal cord repair

4. http://www.themiamiproject.org

5. http://www.themiamiproject.org/page.aspx?pid=708

6. K T Ragnarsson(2008) Functional electrical stimulation after spinalcord injury: current use, therapeutic effects and future directions.Spinal Cord46, 255274

7. Xu XM, Chen A, Guenard V, Kleitman N, Bunge MB (1997) Bridging

Schwann cell transplants promote axonal regeneration from both therostral and caudal stumps of transected adult rat spinal cord. Journal ofNeurocytology 26: 1-16

8. Wang G, Ao Q, Gong K, Zuo H, Gong Y, Zhang X (2010) Synergisticeffect of neural stem cells and olfactory ensheathing cells on repair ofadult rat spinal cord injury. Cell Transplant 19:1325 1337

http://www.themiamiproject.org/http://www.themiamiproject.org/page.aspx?pid=708http://www.themiamiproject.org/page.aspx?pid=708http://www.themiamiproject.org/http://www.themiamiproject.org/http://www.themiamiproject.org/

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THANKYOU

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