Tissue Engineering and the Brain. Susan Perry Bioengineering Program Lehigh University

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1 Tissue Engineering and the Brain Susan Perry Bioengineering Program Lehigh University

2 ...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

3 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

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5 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

6 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

7 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

8 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:

9 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 2 o injury by neurochemical mediators increases cell death Rehman et al, (2008).

10 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

11 Sensory System Disorders Affecting vision, hearing, balance, position and other senses perceiving environmental stimuli

12 Current Treatment Strategies Treatment focused, primarily, on limiting damage and slowing degeneration. Restoration of function not always possible

13 Neuroscience + Engineering = The Next Wave

14 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

15 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

16 Axon Guidance Devices Strategy is to create physical or chemical pathways for regenerating axons or for innervation of new tissue Entubulation techniques biomed.brown.eduu Synthetic or biological materials Well-controlled bridge environment between 2 stumps Bioactive scaffolds Carbon nanotubes, in combination with biological materials

17 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

18 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

19 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

20 Drug Delivery: Implantable pumps Delivery of pain relief Sustained or timed release of medications to correct neurosecretion malfunctions, Parkinson s, epilepsy, etc

21 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

22 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

23 Hope for Parkinson s Disease: Electrical Stimulation Electrical impulses produced by the neurostimulator interfere with and block the electrical signals that cause PD symptoms. Options/Deep-Brain-Stimulation.aspx

24 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

25 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

26 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

27 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

28 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

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31 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