Tissue Engineering and the Brain

Susan Perry

Bioengineering Program Lehigh University

“...all the most acute, most powerful, and most deadly diseases, and those which are most difficult to be understood by the inexperienced, fall upon the brain..”

Hippocrates

Outline

• Introduction and Review of the components

• Target areas for Neuroengineering Strategies

• Neuroengineering Strategies: new thinking, creative design and innovative technologies

Axon Regeneration and Innervation Cell Replacement Drug Delivery Electrical Stimulation

The Nervous System:

Peripheral Central

Nervous System (PNS) Nervous System (CNS)

Autonomic NS Somatic NS Spinal Cord Brain

Sympathetic NS Parasympathetic NS

Forebrain Midbrain Hindbrain

Telencephelon Diencephalon Mesencephalon Metencephalon Myelencephalon

Specific Neuroanatomical Areas of the Brain

Enteric

Spinal and Cranial Nerves

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

Insults to the Nervous System • PNS nerve problems

– Neuropathies, injury • Spinal Cord Injury

– Incomplete or complete • Traumatic Brain Injury

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

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

• Sensory disorders – Deafness, hearing impairment – Vision Loss – 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 (Compressive, tensile and shear deformations)

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

• Approximately 5.3 million in US live with disability from TBI

• 2o injury by neurochemical mediators

increases cell death

Rehman et al, (2008).

Neurodegenerative Diseases and Disorders (just to name a few)

Parkinson’s Disease – 1.5 million people, degeneration of dopaminergic 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 of

neurons in cerebral cortex, or

neuronal damage

Multiple Sclerosis-300,000 cases in US,

degeneration of oligodendrocytes

Sensory System Disorders

• Affecting vision, hearing, balance, position and other senses perceiving environmental stimuli

Current Treatment Strategies

Treatment focused, primarily, on limiting damage and slowing degeneration.

Restoration of function not always possible

Neuroscience + Engineering = The Next Wave

Neuroengineering Treatment Strategies

Technological interventions that provide solutions to neurological disease and other insults to the nervous system

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

Neuroengineering Strategies

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

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

Axon Guidance Devices • Strategy is to create physical or chemical pathways for

regenerating axons or for innervation of new tissue

biomed.brown.eduu

• Entubulation techniques – Synthetic or biological materials

– Well-controlled bridge environment between 2 stumps

• Bioactive scaffolds

• Carbon nanotubes, in combination with biological materials

• PNS repair has been more successful than CNS repair

• Upregulation of regeneration-associated genes and presence of Schwann cells

• Nerve Growth Channels – Barrier to scar tissue

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

– Can be designed to include electrical stimulation

– Can be designed to incorporate biodegradable drug delivery

– Where distal stump is present, over 5mm growth

Axon Regeneration in the CNS • Environment is largely inhibitory and non-permissive

(scar tissue) • Oligodendrocytes, reactive astrocytes, myelin-

associated glycoproteins, CSPG

• Experimental Strategies: – Biological and Synthetic Bridges – incorporate physical

guidance cues or controlled environment

– Optimal biomolecular surface coatings, co-transplanted cells, mechanisms for sustained release of therapeutic agents • Drugs that decrease scar tissue formation

• Neurotrophic factors for guidance and trophic support

Drug Delivery Systems for Targeted Delivery and Controlled Release

• Scaffold-Based Delivery – Degradation/Diffusion Based Systems

– Affinity-Based Systems (non-covalent)

– Immobilized Drug Delivery (covalent)

• Chemical Delivery Systems – Lipisomes, nanoparticles, microspheres

• Electrically controlled delivery – coating of neural electrodes

– microchips

Drug Delivery: Implantable pumps

• Delivery of pain relief

• Sustained or timed release of medications to correct

neurosecretion malfunctions, Parkinson’s, epilepsy, etc

Cell Population Recovery • Advances in stem cell technologies mean most neuronal and

neural populations needed for repair can be derived from stem cells

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

• Goal: to produce specific, functionally

differentiated populations – sufficient quantities

– To maintain the differentiated states,

in vitro, for transplanting, or in the in vivo

environment, as replacement cells

Hope for Parkinson’s Disease: Cell Population Recovery

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

• More promising:

– Cell/tissue encapsulation (into microparticles)

and transplantation to substantia nigra

– Recruiting native progenitor cells (stem cells in SVZ) into substantia nigra and inducing desired phenotype

Hope for Parkinson’s Disease: Electrical

Stimulation

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation.aspx

Electrical impulses produced by the neurostimulator interfere with and block the electrical signals that cause PD symptoms.

Electrical Stimulation, con’t

• Neuromodulation approach-coupling electrical sensing and stimulation capabilities – “closed loop” systems

• MEAs – Microelectrode Arrays – Cochlear Implants

– Brain/computer interfaces

– Vision Restoration

http://www.kevinwarwick.com/the_neural_interface.htm

The Process of Vision Light waves enter and are focused on the retina Specialized photoreceptor cells in the retinal layer absorb the light, beginning a biochemical cascade

Result:

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

Problems:

Abnormalities, injury, diseases of retina resulting in 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-

Powered by incident light chip converts patterns

Requires some intact retina into electrical pulses

sent to retinal implant

BrainPort Vision Technology • Utilizes Cross-Sensory input: using one type of sensory

stimulation to convey info about a different type of sensory input – Brain learns to interpret information as if it were being sent through

traditional channels

• Patterns of light from a video camera converted into electrical pulses on the tongue that represent the pattern Nerve fibers normally responsible for touch sensation are stimulated

Key Points to Remember – Neuroengineering requires a multidisciplinary

approach – 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 through stem cell technology – Drug delivery methods for enhancement of axonal growth,

cell survival and proliferation, regulation of important cell functions, and for pain management

– Electrical Stimulation to tune excitable cells

– Most therapies of the future for treatment and cure of neurological diseases and nervous system injury will likely be combinatorial