Today- Nov. 30 th
• Review
– Neurophotonics
• Optical Neural Recording – Dyes, SPR,
– Spectrum of Fast Optical Signal: Optical Scattering due to Transient Cell Volume Change
• Optical Stimulation – INS
• Questions? Projects?
• Remaining Schedules
– Dec. 5th and Dec. 7th Project Presentations – Dec. 12thFinal Exam
– Office hours Dec. 7th afternoon Dec. 9th(Friday) afternoon Room 301-1006 – Phone 010 9066 1812 email kimsj@snu.ac.kr
• Neurophotonics
– Optical Neural Stimulation
• GNR mediated Enhanced INS (GNR=Gold Nano Rod)
– Optogenetics
• Regulation
• Quest Lecture: “Startup” by Dr. Kyusik Min, CEO of TODOC
Neural Prosthetic Engineering
Neurophotonics
2
Local Heating of Gold Nanorods (GNRs)
• Localized surface plasmon resonance of GNRs
– Local heat generation
Absorption spectrum of GNRs 977 nm
GNRs distribution near neuronal membrane
Neural Prosthetic Engineering
Effect of GNRs enhanced INS
• GNRs assisted INS could induce neuronal depolarization
– Stimulation threshold
• Using the GNRs stimulation threshold were found to be 0.159 J/cm2 while 0.480 J/cm2 for the one without GNRs which is three times smaller
– Responsivity
• Using the GNRs neural responsivity increases by 5.7 times
w/ GNRs w/o GNRs
[14] K. Eom et al., Small, 2014.
4
Contents
1. Optical Neural Recording
1. Dye based Imaging (Voltage dye, Calcium dye) 2. SPR based neural recording
3. Spectrum measurements of Fast Optical Neural Signals
2. Optical Neural Stimulation
1. Infrared Neural Stimulation (INS),
2. GNR mediated Enhanced INS (GNR=Gold Nano Rod)
3. Optogenetics
Neural Prosthetic Engineering
Optogenetics
6
[1] M. Scanziani, Nature Review, 2009.
• Method of the Year 2010 (Nature
Methods)
• https://www.youtube.
com/watch?v=B4-
LpZ-MiL4
Optogenetics for neuromodulation
Optogenetics?
• Optical methods for controlling genetically targeted neurons
• The principle was discovered by Dr. Miesenboeck in 2002
• “Optogenetics” was first used (coined) in 2006 by Dr. Karl Deisseroth of Stanford.
Why do we need it?
• Specificity: control only target cells
• Speed: milliseconds
Neural Prosthetic Engineering
Optogenetics for neuromodulation
Channel proteins
• Channelrhodopsin (ChR2)
light-activated cation channel
• Halorhodopsin (NpHR)
light-driven ion pump, specific for Cl- ions
Channelrhodopsin-2 (ChR2) and Halorhodoptin (NpHR)
• Channelr-:
– Discovered in green algae – Nonspecific cation(+) channel.
– Depolarize neuron
– Peak absorbance: ~488 nm Blue light
• Halor-
– Discovered from archaebacteria – Light activated Chloride pump – Hyperpolarize neuron
– 580 nm Yellow light
Neural Prosthetic Engineering
Optogenetics Methods
10 http://www.etudogentemorta.com/wp-content/uploads/2010/05/optogenetics.jpg
http://www.nature.com/news/2010/100505/full/465026a/box/2.html
Optogenetics for neuromodulation
1. Specificity can be achieved by illuminating only the target cells
2. Millisecond control speed can be used to time- modulate the target cells
3. Potential applications:
A. Can excite cells related with Parkinson’s disease B. How about artificial retina?-by exciting neurons in
degenerated retina
Neural Prosthetic Engineering
Optogenetics –problems to solve
• Power density:
– Needs at least mW/mm**2- this is like having a laser pointer pointed at your retina, actually more-
– Some promotor proteins are being worked on that operates with longer wavelength where damage is less-but still-
• Danger associated with viral transfection
– Virus transection is the process needed for the genetic targeting of neurons – Virus infection into Brain??
– may not have a good cell specificity (For example, you need to only transfect bipolar cells rather than other cells in retina structure)
– Some viral transfection methods are being worked on that affect only certain cells not others
• SAFETY problems
– With these problems, Optogenetics are still too risky to use – Limited clinical testing approved by FDA in 2015?
• Also Fiber optic instrumentation—microLED, Optrode etc.
Future Optical Neural Interface
Light Source for
Non-invasive Stimulation/Recording
Cell type specific Stimulation/Recording via Nanoparticles
Stimulation Target for Parkinson’s Disease (STN)
Stimulation Target for Hearing Restoration (Auditory Cortex)
Stimulation Target for Vision Restoration (Vision Cortex) Reporter Nanoparticles
Neural Prosthetic Engineering
References
[1] M. Scanziani et al, Nature review, 2009, 461, 930.
[2] S. Chemla et al, Journal of Physiology, 2010, 104, 40.
[3] C. Grienberger et al, Neuron, 2012, 73, 862.
[4] S. A. Kim et al, Optics Letters, 2009, 1, 914.
[5] J. Lee et al, NeuroImage, 2010, 51, 713.
[6] G. Buzsáki, Nature Neuroscience, 2004, 7, 446.
[7] E. Pastrana, Nature Method, 2011, 8, 24.
[8] A. Izzo et al, Journal of Biomedical Optics, 2005, 12, 021008-1.
[9] J. Well et al, Journal of Biomedical Optics, 2005, 10, 064003-1.
[10] M.G. Shapiro et al., Nature Communications, 2012, 3, 736.
[11] J. Wells et al, Lasers in Surgery and Medicine, 2007, 39, 513.
[12] W. Ni et al, ACS NANO, 2008, 2, 677.
[13] E. Sassaroli et al, Physics in Medicine and Biology, 2009, 54, 5541.
[14] K. Eom et al, Small, 2014, 10, 3853.
[15] G. Viviana, et al, The Journal of neuroscience 27.52 (2007): 14231-14238.
14
Regulatory Approval of
Implantable Medical Devices
Neural Prosthetic Engineering
Contents
• Regulatory approval process in US
– Classification – 510(k)
– PMA – HDE
– Example: Argus II
• Regulatory approval process in EU
– Notified Bodies
– Classification
Food and Drug Administration (FDA)
• Overview
– Formed in 1906
– Annual budget: $3.8B – Employees: ~15,000
• Scope
– Human and veterinary drugs
– Vaccines and other biological products – Medical devices
– Food supply – Cosmetics
– Dietary supplements
– Products that give off radiation – Tobacco
Neural Prosthetic Engineering
How to Market Your Device
• Center for Devices and Radiological Health (CDRH) of FDA
• Three steps to obtain Market Clearance from CDRH
– 1. Define Your Device:
• “The definition of a MEDICAL DEVICE” (201(h) of FD&C Act)
– 2. Classify your Device
• Three classifications determined by FDA
• Classification identifies:
– level of regulatory control
– Marketing process (PMA or 510(k))
– 3. Demonstration
• Get data/information to obtain FDA clearance to market
• For most PMA applications, clinical performance data is required
– Clinical trials can be conducted in accord with IDE (Investigational Device Exemption)
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm
Class I
• Description
– Not intended to help or sustain or be substantially important in preventing impairment to human health
• Process
– General controls
• Prohibition against adulteration and misbranding
• Requirements for establishing registration and device listing, adverse event reporting, and good manufacturing practices (GMP)
– Formal FDA review is not required for most cases
• Examples
– Bandages, gloves, hand-held surgical instruments, dental floss
Neural Prosthetic Engineering
Class II
• Description
– Devices designed to perform as indicated without causing injury or harm to patient or user
• Process
– General controls with Special controls
• special labeling, mandatory performance standard, post-market surveillance
– Clearance for Premarket notification application(510(K)) is required before being marketed
• Examples
– X-ray machines, powered wheelchairs, infusion pumps, surgical needles, hearing aid, cardiac catheter, amalgam alloy
510(K): Premarket Notification
• The manufacturer must demonstrate that the new device is
“substantially equivalent” to a previously marketed device
• Substantially equivalence:
– The same intended use
– the same technological characteristics
• 99% of new medical devices enter marketplace via this process (ex. 242 cases in Jan. 2013)
• Rarely requires clinical trials (~10%)
• Not considered as “approved” by FDA, but referred as “cleared”
devices
Neural Prosthetic Engineering
Class III
• Description
– Life-sustaining/supporting that are substantially important in preventing impairment of human health
– Or present a potential risk of illness or injury
– Insufficient information exists to assure its safety and effectiveness
• Process
– General controls with Special controls AND Premarket Approval (PMA) – PMA approval requires the safety and effectiveness of the device
• Examples
– implantable pacemaker, heart valves, coronary stents, silicone gel-filled breast implants, endosseous (intra-bone) implants,
PMA: Premarket Approval
• New or high-risk medical devices that require a more rigorous scientific and regulatory premarket review than the 510(k) pathway.
– Similar to new drug approval – Typically clinical trials are required
– 17 cases in Jan. to Jun. in 2013 (cf. 242 cases of 510(k) in Jan. 2013)
• Applicant should demonstrate the safety and effectiveness of the device
• Data Requirements
– Non-clinical study
• microbiology, immunology, biocompatibility, stress, life, animal tests… in compliance with 21CFR Part 58
– Clinical Investigations
• Protocol, safety & effectiveness data, adverse reactions, device failure, patient information, patients complaint, statistical analyses
• Investigational Device Exemption (IDE)
• Premarket Application Fee: $248,000 (standard), $62,000 (small business)
Neural Prosthetic Engineering
Clinical trials
• Clinical trials to collect safety and effectiveness data to support PMA (or 510(k))
• Investigational Device Exemption (IDE)
– Approved by IRB (Institutional Review Board) – Allows the device to be used in clinical studies
• Procedure
– In vitro biocompatibility test in vivo animal test pilot trial
pivotal trial
• Pilot trial: establish basic safety and initial indications of effectiveness
• Pivotal trial: generate data for safety and effectiveness
HDE (Humanitarian Device Exemption)
• For “humanitarian use device” (HUD)
– “A medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in US per year”
• Essentially same as a PMA process, but exempt from the effectiveness requirement
– Requirements: Safety and Probable benefits
• Incentive for devices whose research and development costs could exceed its market returns for diseases or conditions affecting small patient populations.
• For example:
– Argus II retinal prosthesis for RP patients
Neural Prosthetic Engineering
PMA- and HDE-approved devices
2013.1-2013.7
Notified Bodies
• EU system relies heavily on “Notified Bodies,”
• Notified Bodies
– Independent commercial organizations for regulatory control over medical devices
– Designated, monitored, and audited by pertinent member states via national “competent authorities”
– Perform many functions of FDA/CDRH in US
• Device certification (CE mark)
• Assessment and verification of quality systems
• Device type designation
• Review of the design history files and high-risk devices
Neural Prosthetic Engineering
Notified Bodies
• A manufacturers can choose any Notified Body selected to cover particular class of device under review
– Currently more than 75 active Notified bodies in EU
• After approval
– Post-market surveillance is responsibility of the member state via competent authorities
• Higher flexibility, but more fragmented and highly variable criteria than FDA
• Competent authorities:
– National regulatory oversight agency of each EU states
European device classification
• Class I
– Low-risk
– Often self-certified by manufacturer
• Class IIa
– Low-medium risk devices
• Ex: hearing aids, electrocardiogrphs, ultrasonic diagnostic equipment
• Class IIb
– Medium-high risk devices
• Ex: surgical lasers, infusion pump, ventilators intensive care monitoring equipment
• Class III
– The highest risk
• Ex: balloon catheters, prosthetic hear valves
– Devices with new materials or components that have
• no history of performance
• Target a new indication
Neural Prosthetic Engineering
• Class 1:
• No bodily contact or
• nearly no risk on contact
• Class 2:
• some potential risk but no treat to life or functional disability
• Class 3:
• Implantable for some period or
• high potential risk
• Class 4:
• Permanently implantable or
• direct contact to heart, central nervous system, or central circulatory system or
• using animal tissue or extracts or
• using materials with insufficient safety records
Korean device classification by KFDA
Reference
• Chhatbar, Pratik. "The future of implantable neuroprosthetic devices: ethical considerations." Journal of long-term effects of medical implants 19.2 (2009).
• Zhou, David D., and Elias Greenbaum. Implantable Neural Prostheses. Dordrecht: Springer Verlag, 2009.
• Colvin, Mike. "Regulatory Approval of Implantable Medical Devices in the United States and Europe." Implantable Neural Prostheses 1. Springer US, 2009. 353-370.
Neural Prosthetic Engineering
Startup
Kyou Sik Min, Ph.D
CEO of TODOC Co., Ltd.
Introduction
• Kyou Sik Min
– 2014 Ph.D in Electrical Engineering (Seoul National University) – 2014~2015 Senior Engineer, Samsung Electronics
– 2015~ CEO, TODOC
• TODOC
– Product: Next-Generation Cochlear Implant System – 2015.10 Foundation
– 2016.2~2016.4 Invited by KIC Silicon Valley
– 2016.5 Grand Prize in HUGEL Open Innovation (Won $30,000) – 2016.5~2016.10 Funded > $1,000,000
– 2016.11 Grand Prize in K-ICT Demoday (Won $3,000)
Neural Prosthetic Engineering
Pre-Flight Check
•
•
•
•
•
What Successful Entrepreneurs
Achieved
• Valuation > $ 1,000,000,000
– Google – Amazon – Paypal
– Tesla Motors
Neural Prosthetic Engineering
Plan
•
•
funding
• Initial Funding:
FFF – Family – Friends
– The Foolish
•
•
•
•
•
•
•
Neural Prosthetic Engineering
Valuation
• Pre-Money Valuation
– valuation of a company or asset prior to an investment or financing.
http://www.investopedia.com/ask/answers/114.asp#ixzz1WQq46zn0
• Post-Money Valuation
– the value of a company after an investment has been made. This value is equal to the sum of the pre-money valuation and the amount of new equity
Get Venture by Mark Peter Davis: Venture Valuation Overview
When should I start a
Business?
Neural Prosthetic Engineering
Just Start before everything is planned
If you want to plan everything before your business, You can never start.
Pitching
• Meeting someone for the first time
• The elevator pitch (30~45 seconds)
• 2-3 minutes
• 4-5 minutes
• 10-20 minutes
Neural Prosthetic Engineering
Elevator pitch
• Hi my name is Abe, ceo and founder of TODOC. I’d like to introduce our liquid crystal polymer based cochlear implant
system. We apply semiconductor fabrication process on liquid crystal polymer film and can make the manufacturing cost become 1/10 of conventional method. It is
biocompatible, long-term reliable, and has much lower water-absorption rate than
other biocompatible polymers like polyimide or parylene-C.
What VCs Want is…
Low Risk High Return
Neural Prosthetic Engineering
Must-have Items
• Problem(-Solution)
• Value
• Market Opportunity
Elevator pitch rev.
•
Neural Prosthetic Engineering
LEAN startup
•
•
5 Principles of Lean Startup
1. Entrepreneurs are everywhere.
2. Entrepreneurship is management.
3. Validated Learning
4. Build-Measure-Learn
5. Innovation Accounting
Neural Prosthetic Engineering
