Tissue Engineering and the Brain(and the rest of the nervous system(and the rest of the nervous system, 

too!)

Susan PerryBioengineering ProgramBioengineering Program

Lehigh University

OutlineOutline

• Introduction and Review of the components• Target areas for Neuroengineering Strategies

PNS InjurySpinal Cord Injuryp j yNeurodegenerative DiseasesTraumatic Brain Injury

• Regenerative Medicine and Tissue EngineeringRegenerative Medicine and Tissue Engineering Strategies: new thinking, creative design  and innovative technologies 

Axon RegenerationAxon RegenerationCell Replacement Drug DeliveryElectrical Stimulation

• Seeing is Believing – examples of new and emerging technologies

The brain is the last and grandest biological frontier, the most complex thing we have yet di d i i I i h d ddiscovered in our universe. It contains hundreds of billions of cells interlinked through trillions of connections The brain boggles the mindconnections. The brain boggles the mind.

James Watson

The Nervous System:

Peripheral Central

Nervous System (PNS)      Nervous  System (CNS)

Autonomic NS Somatic NS(sensory & motor)

Spinal Cord BrainEnteric

Sympathetic NSParasympathetic NS

Forebrain Midbrain Hindbrain

Telencephelon DiencephalonMesencephalon Metencephalon Myelencephalon

Specific Neuroanatomical Areas of the Brain

• Basic Research has provided us with anBasic Research has provided us with an incredible breadth of knowledge– Development p– Anatomy– Cell types– Organization– Connections– Stimulation– Synaptic transmission– Gene Regulation– Control systems– Malfunctions and insults

Insults to the Nervous SystemInsults to the Nervous System• PNS nerve problems

– Neuropathies, injury • Spinal Cord Injury

– Incomplete or complete• Traumatic Brain Injury• Traumatic Brain Injury

– Loss of cognitive function, loss of motor control, alteration in behavior

d i i• Neurodegenerative Diseases– Alzheimer's disease, Parkinson’s disease, etc.

• Sensory disordersSensory disorders– Deafness, hearing impairment– Vision LossL f T til ti d t i j– Loss of Tactile sensation due to nerve injury

Spinal Cord Injuries

•Approximately 12,000 new cases/year, with an estimated 260,000 living with SCI in US.

•Almost 81% of those injured are male

•Estimated costs:

Traumatic Brain Injury• Nondegenerative insult to brain from external mechanical force

• Estimated that 1.4 million people sustain TBI’s each year

• Approximately 5 3 million in US live with disability from TBI• Approximately 5.3 million in US live with disability from TBI 

• Compressive, tensile and shear deformations of brain tissue at moment of traumatissue at moment of trauma

• 2o injury: neurochemical mediators• Endogenous opioid peptidesg p p p

• Excitatory amino acids (glutamate, aspartate)

• Increased K+ flux

• Cytokines• Cytokines Rehman et al, (2008). 

Neurodegenerative Diseases and d ( f )Disorders (just to name a few)

Parkinson’s Disease – 1.5 million people, degeneration of p p , gdopaminergic neurons

Alzheimer’s Disease ‐5 million people, brain‐wide neuronal loss

Huntington’s Disease‐1 in 10,000,

multiple neuronal sets affected

Epilepsy 3 million people loss ofEpilepsy‐3 million people, loss of 

neurons in cerebral cortex, or 

neuronal damageneuronal damage

Multiple Sclerosis‐300,000 cases in US, 

degeneration of oligodendrocytes

Treatment strategiesgCurrently: Treatment focused, primarily, on limiting damage and 

slowing degeneration. Restoration of function not always iblpossible

On the doorstep or just around the corner: TechnologicalOn the doorstep or just around the corner: Technological interventions that provide solutions to neurological disease and other insults to the nervous system

On the horizon: Therapies, such as transplantation of stem cells or genetically engineered cells which will correct theor genetically engineered cells, which will correct the mechanisms of disease

Regenerative Medicine and Tissue Engineering Strategies

• Combinatorial Approach using neuroscience,Combinatorial Approach using neuroscience, bioengineering, materials science, developmental biology, computer science, nanotechnology

• 4 Main Areas of Attack– Axon guidance devices– Cell replacement– Drug delivery– Electrical stimulation

Axon Guidance DevicesAxon Guidance Devices• Strategy is to create physical or chemical pathways for regenerating axonsregenerating axons– Often used in combination with other tissue engineering strategiesg

• Have been used, with varying success for PNS nerve regrowth, spinal cord and brain nerve tract repair

• PNS repair has been more successful– Upregulation of regeneration‐associated genes (c‐Jun, GAP‐43, etc)

– Presence of Schwann cells (produce myelin, but also provide nutrients and aid in guidance)nutrients and aid in guidance)

• PNS: Nerve Guidance Channels• Entubulation techniques

– Synthetic or biological materials

– Well‐controlled bridge environment between 2 stumps

• Barrier to scar tissue

• Can be loaded with cells coated with ECM proteins or• Can be loaded with cells, coated with ECM proteins or growth factors to facilitate regeneration

• Can be designed to include electrical stimulation

• Where distal stump is present, over 5mm growth 

Axon Regeneration in the CNSg• Despite inability to functionally recover, CNS axons have intrinsic ability to regenerate and regrow

• Environment is largely inhibitory and non‐permissive (scar tissue)

• Oligodendrocytes, reactive astrocytes, myelin‐associated glycoproteins, CSPG 

Bi l i l d S h i B id i• Biological and Synthetic Bridges – incorporate physical guidance cues or controlled environment

B id l d h i l d bi l i l• Bridges also need chemical cues and biological cues• Optimal biomolecular surface coatings, mechanism for sustained release of therapeutic agents, co‐sustained release of therapeutic agents, cotransplanted cells

Cell Population RecoveryCell Population Recovery

• Advances in stem cell technologies mean most neuronal and gneural populations needed for repair can be derived from stem cells

• Functional consequences of using stem cells in vivo are currently unpredictable y p

• Goal:  to produce specific, functionally differentiated populations– sufficient quantities

– To maintain the differentiated states, in vitro, for transplanting, or inTo maintain the differentiated states, in vitro, for transplanting, or in the in vivo environment, as replacement cells

Hope for Parkinson’s DiseaseHope for Parkinson s Disease

• “Naked” cell/tissue transplantation‐p– good in theory, immunogenicity issues

• Most promising: 

– Cell/tissue encapsulation (into microparticles) 

• transplantation to substantia nigra• transplantation to substantia nigra

– Recruiting native progenitor cells (stem cells in SVZ) into substantianigra and inducing desired phenotypenigra and inducing desired phenotype

Drug Delivery: Implantable pumpsg y p p p• To facilitate axon regeneration

– To be most effective, should be administered in aTo be most effective, should be administered in a spatiotemporal manner

– Induce sprouting, axon elongation, synapse formation• Drugs that decrease scar tissue formation

• Neurotrophic factors for guidance and trophic support

• Sustained or timed release of medications to correct neurosecretion malfunctions, epilepsy, etc– No need to go through GI, liver etc; direct to area most in need

D li f i li f• Delivery of pain relief 

Electrical Stimulation• Bioengineering, rather than tissue engineering approachapproach

• Deep Brain Stimulation i l l i l d i l d– single or multi‐electrode arrays implanted to stimulate degenerating 

)neurons)

– Treatment of Parkinson’s, 

lepilepsy, OCD

• Cochlear Implants

• Vision Restoration

The Process of VisionLight waves enter and are focused on the retina

Specialized photoreceptor cells in the retinal layer absorb thelight, beginning a biochemical g t, beg g a b oc e cacascade

In the dark, positive ion channels in the h b k bphotoreceptor membrane are kept open by 

the presence of cyclic GMP, keeping voltages bacross membrane even

Stimulation of the photoreceptors by light causes a conformational change in the retinal portion of rhodopsin ….

causing a structural change that activates a signaling cascade, which catalyzes the hydrolysis of cGMP

Without cGMP, ion channels close and the inside of the cell becomes negative relative to the outside.  This voltage change triggers a change in neurotransmittervoltage change triggers a change in neurotransmitter release at the synaptic cleft

Result:

Chemical signals are converted into electricalChemical signals are converted into electrical signals, carried by the optic nerves, to the brain for processingbrain for processing.

Problems:

Abnormalities, injury, diseases of retina resulting , j y, gin partial or complete loss of vision

What hope is there for restoring vision?

Artificial Silicon Retina Argus II 5000 microscopic solar cells video camera/micro‐5000 microscopic solar cells video camera/micro

Powered by incident light chip converts patterns

Requires some intact retina into electrical pulses

sent to retinal implantsent to retinal implant

BrainPort Vision Technologyl f• Utilizes Cross‐Sensory input: using one type of sensory 

stimulation to convey info about a different type of sensory input

B i l t i t t i f ti if it b i t th h– Brain learns to interpret information as if it were being sent through traditional channels

• Patterns of light from a video camera converted into electricalPatterns of light from a video camera converted into electrical pulses in subcutaneous tissue (e.g. tongue) that represent the pattern– Electrical field generated on the tongueg gdirectly excites afferent nerve fibers normally responsible for mechanical touch sensation

Key Points to Remember– Neural Tissue Engineering requires a multidisciplinary approach

developmental biology engineering materials science– developmental biology, engineering, materials science, neuroscience, molecular biology, computer science

– 4 main areas of research– Axon guidance devices for regeneration and regrowth of 

axons– Cell population recovery– Drug delivery methods for enhancement of cell survival and proliferation, regulation of important cell functions, and for pain managementElectrical Stimulation– Electrical Stimulation

– Most regenerative technologies of the future will likely be combinatorial including biocompatible scaffolds, stem cells and the various factors necessary for their survival and function