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 Axon Regeneration and Innervation Cell Replacement Drug Delivery Electrical Stimulation Neuroengineering Strategies: new thinking, creative design and innovative technologies Parkinson s Disease Vision Restoration
The Nervous System: Peripheral Nervous System (PNS) Spinal and Cranial Nerves Central Nervous System (CNS) Autonomic NS Somatic NS Enteric Spinal Cord Brain Sympathetic NS Parasympathetic NS Forebrain Midbrain Hindbrain Telencephelon Diencephalon Mesencephalon Metencephalon Myelencephalon Specific Neuroanatomical Areas of the Brain
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 270,000 living with SCI in US. Almost 81% of those injured are male Estimated costs: Average Yearly Expenses (in February 2012 dollars) Estimated Lifetime Costs by Age At Injury (discounted at 2%) Severity of Injury First Year Each Sub.Year 25 yrs old 50 yrs old High Tetraplegia (C1-C4) AIS ABC $1,023,924 $177,808 $4,543,182 $2,496,856 Low Tetraplegia (C5-C8) AIS ABC $739,874 $109,077 $3,319,533 $2,041,809 Paraplegia AIS ABC $499,023 $66,106 $2,221,596 $1,457,967 Incomplete Motor Functional at Any Level AIS D $334,170 $40,589 $1,517,806 $1,071,309 Data Source: Economic Impact of SCI published in the journal Topics in Spinal Cord Injury Rehabilitation Volume 16 Number 4 in 2011.
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 Compressive, tensile and shear deformations of brain tissue at moment of trauma 2 o injury: neurochemical mediators Endogenous opioid peptides Excitatory amino acids (glutamate, aspartate) Increased K+ flux Cytokines 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 May arise from injury, congenital abnormalities, aging, or as a associated complication of another medical issue (e.g. diabetic retinopathy).
Current Treatment Strategies Treatment focused, primarily, on limiting damage and slowing degeneration.
Neuroscience + Engineering = The Next Wave
Neuroengineering Solutions 4 Main Areas of Attack Cell Replacement Drug Delivery Axon guidance devices Electrical Stimulation Combinatorial Approach
Axon Guidance Devices Strategy: to create physical or chemical pathways for regenerating axons or for innervation of new tissue biomed.brown.edu Entubulation techniques u 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 designed to include multiple types of signals (biological, chemical and electrical)
Axon Regeneration in the CNS Environment is largely inhibitory and non-permissive (scar tissue) Oligodendrocytes, reactive astrocytes, myelinassociated 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 Brain tumors Sustained or timed release of medications to aid in axon guidance, cell replacement and 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 Remain in desired location Establish connections and FUNCTION!
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 Electrical impulses produced by the neurostimulator interfere with and block the electrical signals that cause PD symptoms. http://www.parkinson.org/parkinson-s-disease/treatment/surgical-treatment- Options/Deep-Brain-Stimulation.aspx
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 4 main areas of solutions-driven 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