Bio-Electronics, Bio-Sensors, Smart Phones, and Health Care

1. A/Prof Jeffrey Funk Division of Engineering and Technology Management National University of Singapore For information on other technologies, see http://www.slideshare.net/Funk98/presentations

2. Laptops MP3 Players Calculators Video Set-top boxes E-Book Readers Digital Games Web Browsers Digital TV Watches Mobile Digital Cameras Smart Phones PCs Phones PDAs Tablet Computers Bio-Electronics, Wearable Computing and Health Care are the Next Frontiers for Moores Law Whats Next? Whats Next?

3. Source: AStar Adding MEMS and other Functions to Integrated Circuits is Often Called More Than Moore More than Moore is enabling better bio-sensors and other components for Wearable Computing and Health Care Many of these components are a type of MEMS with micro-fluidic channels Many of these things are called bio-electronics

4. What Kinds of New Products and Services will these Improvements Enable? Faster and cheaper testing services Many of these services will be done closer to patients, increasing convenience (point of care diagnostics) Theranos, member of billion dollar club, offers these services Faster and better bio-sensors, that can be integrated with skin patches and other wearable devices New forms of wearable computing that monitor and facilitate medial care Better point of care diagnostic devices Exoskeletons that help old and injured Integrated circuits for testing drugs (organ on chip)

5. Which ones will become cheaper and better, provide most value? We need to understand how improvements occur

6. Which Ones will Become Cheaper and Better? Hard to say But this is the critical question Some components/devices will get better as feature sizes get smaller Some components/devices will get better as new materials are used The following slides provide examples Session 8 addresses wearable computing and how these devices can be put together in different ways For your projects, you need to provide better information on which components/devices are more likely to get better and/or how this impacts on health care and/or wearable computing

7. Session Technology 1 Objectives and overview of course 2 How/when do new technologies become economically feasible? 3 Two types of improvements: 1) Creating materials that better exploit physical phenomena; 2) Geometrical scaling 4 Semiconductors, ICs, electronic systems 5 Sensors, MEMS and the Internet of Things 6 Bio-electronics, Health Care, DNA Sequencers 7 Lighting, Lasers, and Displays 8 Roll-to Roll Printing, Human-Computer Interfaces 9 Information Technology and Land Transportation 10 Nano-technology and Superconductivity This is Sixth Session of MT5009

8. Outline What is bio-electronics? Geometric scaling in bio-electronics Similarities between ICs and bio-electronics Applications for bio-electronics Point-of-care diagnostics skin patches other bio-sensors Drug delivery Bionic eyes Exoskeleton Organ-on-a-chip Challenges for Bio-electronics are similar to those for MEMS

9. Early Applications: cardiac pacemaker and cochlear implant

10. http://www.siliconsemiconductor.net/article/69596-Efficient-mixing-in-milliseconds-with-lab-on-a-Chip.php Another Type of Bio-Electronics: Simple form of MEMS with Micro-Fluidic Channels

11. Another view of a bio- electronic IC (some- times called lab- on a chip) Analyzing Polymer Additives and Synthesis of Co-Polymer Surfactants

12. Blood Analysis MEMS compared to a Newer Technology, Nanopores, which is another form of Bio-Electronics

13. http://www.youtube.com/watch?v=JvDZh8hmR84 DNA Sequencers also involve micro-fluidic channels and are one type of bio-electronics But the next session will focus more on the improvements in DNA sequencers that have occurred over the last 30 years

15. Source: AStar More than Moore is enabling better bio-sensors and other components for Wearable Computing and Health Care Many of these components are a type of MEMS with micro-fluidic channels Many of these things are called bio-electronics

16. Another Way to Look at More Than Moore http://www2.imec.be/content/user/File/MtM%20WG%20report.pdf

17. Figure 2. Declining Feature Size 0.001 0.01 0.1 1 10 100 1960 1965 1970 1975 1980 1985 1990 1995 2000 Year Micrometers(Microns) Gate Oxide Thickness Junction Depth Feature length Source: (O'Neil, 2003)

18. Benefits of Reductions in Feature Sizes Is larger for Bio-Electronic ICs than for MEMS Higher Resolution

19. Higher Resolution: Reductions in Feature Size Enable Bio-Electronic ICs to Analyze Smaller Biological Materials Viruses are infectious agents that replicate inside the living cells of organisms Bacteria are multi-cell micro-organisms Proteins carry out duties in cell according to DNA

20. The Goal is to Analyze Even Smaller things such as Proteins and Molecules

21. Smaller sizes (mM milli moles) are needed for smaller detection limits and to analyze more data intensive applications (millimole)

22. http://www2.imec.be/content/ user/File/MtM%20WG%20report.pdf

23. Smaller Sizes Requires Better Tools Scanning tunneling microscope

24. http://inhabitat.com/silicon-chips-embedded-in-human-cells-could-detect-diseases-earlier/ How Smaller ICs Might Impact on the Biological World

25. February 2013, http://www.i-micronews.com/reports/BIOMEMS/4/345/

26. Outline What is bio-electronics? Geometric scaling in bio-electronics Similarities between ICs and bio-electronics Applications for bio-electronics* Point-of-care diagnostics skin patches other bio-sensors Drug delivery Bionic eyes Exoskeleton Organ-on-a-chip Challenges for Bio-electronics are similar to those for MEMS Many startups: https://angel.co/medical-devices

27. Applications in Laboratories and in Homes are Emerging as Improvements are Made to Bio-Electronics Labs:

28. Not Just Physicians End-users might be technicians, nurses or consumers Very useful in rural areas where there are few doctors Share devices just like mobile phones are shared in some rural areas This might occur automatically; place bio-electronic ICs in toilet, bathroom mirror, and clothes mirror may detect a disease such as cancer through the presence of a mutated protein called P53 (exists in 50% of cancer treatments) Or place them in your body Or a skin patch on your body It depends on how cheap these systems become.. Source: Michio Kaku, Physics of the Future: How Science Will Shape Human Destiny and Our Daily Lives by the Year 2100 (2011)

29. U.S. Laboratory Testing Market $60 billion a year in US $25 billion for testing equipment ($56 billion globally) Most tests are done in hospitals or by third parties in response from hospitals Two big players in U.S.: LabCor and Quest Diagnostics Can new technology and new providers change this market? Much faster and cheaper than current ones A new law in U.S. allows anyone to offer lab services, without seeing a doctor Theranos serves Pfizer and GlaxoSmith Wants to sell directly to consumers

30. Theranos is Most Successful of New Entrants Member of billion dollar startup club Now valued at $9 Billion Offers hundreds of tests that use drop of blood (also urine) and lab-on chip technology, a few dollars per test For detection of cancer, heart disease, diabetes Started with services for drug firms such as Pfizer and GlaxoSmith Now aiming for consumers through partnership with Walgreen pharmacies (>8000 in U.S.) Even if Theranos succeeds, some types of mobile phone and wearable tests will eventually succeed CEO Elizabeth Holmes

32. Flexible Electronics/Skin Patches Many kinds of skin patches But emergence of flexible displays (Next Session) is changing the field of skin patches Organic materials are revolutionizing displays (See Session 7) and ICs (organic ICs) for the displays (Session 4) Thinner materials are more flexible than thicker materials Adding a stretchy electronic mesh of islands that is connected by springy bridges (i.e., conformal electronics) Conformal electronics can monitor bodily functions of athletes and others deliver drugs facilitate control of prosthetic devices Enable electronic skin

33. http://pubs.rsc.org/en/content/articlelanding/2010/cs/b909902f#!divAbstract

34. Improvements in Mobility may Lead to Greater Use of Flexible Materials Mobilitycm2/Vs Single Crystal Si Ribbon Oxide Semiconductors Amorphous Silicon Organic Semiconductor 1995 2000 2005 2010 0.001 0.01 0.1 1 100 10 1000 Si Mono- Crystal Si Poly- Crystal 2013 Year

35. Improvements in Flexibility Improvements in flexibility, which includes both bendabiilty and stretchability, have come from thinner materials and a so-called island-bridge design. Extreme Thinness Leads to Flexibility of Semiconductor Materials Island-bridge design enables much higher levels of flexibility

36. build a stretchy mesh with electronics on thin islands connected by springy bridges print mesh onto thin plastic which holds the entire mesh together Source: MT5016 group presentation in 2012

37. build body-worn stickers which seamlessly measure our body activity breathablewaterproof yet Source: MT5016 group presentation in 2012

38. core technology deployed to allow conformal coupling to the human body all on an ultrathin patch that mounts onto the skin like a temporary tattoo digital health - moderate development cycle - high growth potential - white space opportunity modular system with onboard sensing, processing, power and communication Source: MT5016 group presentation in 2012

39. wireless connectivity informed user continuous data analysis seamless sensing digital health - moderate development cycle - high growth potential - white space opportunity Source: MT5016 group presentation in 2012

40. How far in the Future? From Skin Patches and Sensors to Artificial Skin Science Vol 340, 7 June 2013, pp. 1162-1165

42. Will these Sensors Become Cheaper and Better? Glucose monitoring for diabetes (smart contact lens, test strips attached to phones, or tattoo)? Urine testing with test strips attached to phone for detecting many diseases? Vibration sensor for detecting epileptic fits? Breath analyzer for detecting lung cancer? bad breath through volatile sulphur compound sensors? alcohol consumption? Accelerometer for head impact detection? Electric potential sensor for measuring ECG (electro- cardiogram) signals? Infrared sensor for monitoring blood oxygen? Source: Mobile Device for Health Care, Hi-Tech Sensors Personalized Health Care, Spring 2015 projects

43. Smart Contact Lens Google and Novartis are working to develop contact lens that monitor glucose levels for diabetics Can also monitor Lacryglobin levels that are biomarker for cancer Intraocular pressure that results from liquid buildup in eyes of glaucoma patients Drug delivery is also a possibility Other possible features Autofocusing lens Infrared sensitive for night vision http://www.technologyreview.com/news/529196/what-else-could-smart-contact-lenses-do/

44. Can Mobile Phones be Platform for Managing Data Phones have high-performance processors, memory, and displays Can send data wirelessly, without cables Easy to develop and download apps Can phones handle multiple diagnostics/diseases maybe with one bio-electronic IC, like microprocessor? What about creating accessories/attachments test strips to analyze blood, skin, saliva; check for flu, insulin and other sicknesses microscope to analyze cells, electrodes for electro-cardigram Others for ultrasound, MRI, etc. Useful for athletes, sick people http://www.economist.com/news/technology-quarterly/21567208-medical-technology- hand-held-diagnostic-devices-seen-star-trek-are-inspiring

45. Examples of Attachments for Mobile Phones Portable spectrometer http://blogs.wsj.com/digits/2015/03/05/israeli- startup-can-turn-your-smartphone-camera-into- a-star-trek-tricorder/ Portable dosimeter Water contaminant Analyzer Portable ultrasound Lens free microscopes Blood glucose meter Other diagnostic imaging Remotoscope Spirometry Hemoglobe StethoCloud How cheap will they become in the next five years? Will they offer better value in poor rural areas than do current equipment?

46. Falling Price of Ultrasound over the last 20 years

47. David Shoemaker, FDA-Regulated Mobile Medical Apps Mobile MiM

48. David Shoemaker, FDA-Regulated Mobile Medical Apps Remotoscope A diagnostic tool for ears

49. SpiroSmart Home spirometry can detect pulmonary exacerbations and improve outcomes of chronic lung ailments Spiro Smart is a low-cost mobile phone application that performs spirometry sensing using built-in microphone An analysis of 52 subjects showed that the mean error when compared to a clinical spirometer is 5.1% for common measures of lung function David Shoemaker, FDA-Regulated Mobile Medical Apps

50. Hemoglobe Hemoglobe estimates the haemoglobin level of the user. One application is detection of pregnant mothers with anaemia Hemoglobe functions by principle of absorption spectrophotometry: sensor is placed over patients fingertip and different wavelengths of light are emitted, which are then absorbed by the red blood cells in the capillaries Estimated costs are US 10 to 20 dollars. David Shoemaker, FDA-Regulated Mobile Medical Apps

51. StethoCloud David Shoemaker, FDA-Regulated Mobile Medical Apps StethoCloud is designed to listen and digitalize a patients breathing sounds and patterns Those patterns are compared against medical database via cloud infrastructure. Automated report is generated though Algorithmic Artificial Intelligence Decision Support Such software could potentially allow earlier diagnosis of pneumonia and reduce mortality of children in developing countries.

52. iBGSTAR iBGStar is first blood glucose meter it can be used on its own or connected directly to an Apple iPhone or iPod touch For display, manage and communicate diabetes information David Shoemaker, FDA-Regulated Mobile Medical Apps

53. Near Eye Tool for Refractive Assessment (NETRA) NETRA combines inexpensive optical elements, programmable display and interactive software Can measure refractive errors, focal range, and focusing speed David Shoemaker, FDA-Regulated Mobile Medical Apps

54. How Far in the Future? Qualcomm will give $10 million USD for first Star Trek Tricorder. Improvements in bio-electronic ICs and other technologies (e.g., fMRI see later session) will probably make this possible (http://gbmnews.com/wp/?p=254)

55. A Faster Way for Detecting Cancer in the Future? Cancer is usually detected too late, is there faster way? Blood tests can be used to test for cancer Could test for hundreds or thousands of biomarkers in one blood test with a single chip Then look for the location of the cancer With a radioactive or fluorescent probe (see next session) and a scanner (Computer tomography or positron emission tomography) Then kill the tumor with heat, radiation, or other things (see next session) Source: The End of Medicine, Andy Kessler

56. Outline What is bio-electronics? Geometric scaling in bio-electronics Similarities between ICs and bio-electronics Applications for bio-electronics Control of implants Point-of-care diagnostics, including skin patches Drug delivery, Bionic eyes, Exoskeleton Organ-on-a-chip Challenges for Bio-electronics are similar to those for MEMS

57. Smart Pills: A New Form of Drug Delivery Conventional methods Injections Pills skin patches The problem with conventional methods is they often affect both good and bad cells Smart pill Pills that can administer drugs directly to specific places in a persons body

58. Smart Pills for Killing Cancer Cells (1) Most cancer treatments kill healthy cells even as they try to kill cancer cells Another approach is to use smart pills/nano- particles to kill cancer cells Example: illumination from a white light within smart pill/nanoparticle kills the cancer cell Example: cause tiny magnetic disks to vibrate violently when they are near the cancer cells. This is done by passing a small external magnetic field over them Cameras embedded in the smart pill enable doctor to see inside

59. Source: http://www.slideshare.net/AsadAliSiyal/nanorobotics-nanotechnology-by-engr-asad-ali-siyal

60. Smart Pills for Killing Cancer Cells (2) One problem with nano-particles (molecular cars) is that they have no engine Mother Nature uses the molecular adenosine triphosphate has her energy source Possible engines A nano-rod can be moved with a mixture of water and hydrogen peroxide Embed nickel disks or antenna inside these nanorods. one can use an ordinary magnet or a radio transmitter from the outside of the body to steer a nanorod through the inside of a body

62. MEMs and Bionic Eyes MEMS playing an important role in improving eyesight of people who suffer from macular degeneration, a disease that affects the retina Disease renders photoreceptors useless although the remaining parts of the eye such as the pupil, cornea, lens, iris, ganglion cells and optic nerve remain operative About two million people suffer from this disease in the U.S. or about 0.5% of Americans

63. All of the components in a Bionic Eye are Experiencing Rapid Improvements in Cost and Performance

64. How does it Work? A chip combines visual and transmitted (infra-red) images Chips are 1mm across, covered with elements 75 microns wide that are made of three photosensitive diodes and two electrodes When hit by infra-red light, the diodes generate an electric current and via the electrodes, stimulate nerve cells in retinal tissue Easy to implant chips, using special syringe that pushed them through eyeball Hopes to improve resolution to 40 microns Bionic eyes, economist, February 21, 2015, p. 73

65. Source: Biomaterials 29(2425): 33933399 MEMS-Based Electrode Electrode Implanted Into Retina MEMS-Based Electrodes for Bionic Eyes

66. Increases in the Number of Electrodes Leads to Higher Performing Bionic Eyes

68. Source: Cyberdyne Corporation, www.cyberdyne.jp Examples of Exoskeletons

69. 50 23 20 15 60 160 240 300 0 30 60 70 1000 800 500 200 0 200 400 600 800 1000 1200 0 50 100 150 200 250 300 350 HAL-3 (1999) HAL-5 (2005) HAL-5 (2008) HAL-5 (2011) Suit Weight (Kg) Operating Time (mins) Weight Lifting (kg) Response Time (ms) From better materials From better batteries From better materials Right Axis: from better bio-electronic and conventional ICs Improvements in HALs Exoskeleton Suits

70. What About Robots that look like Humans http://www.huffingtonpost.com/2014/08/13/robot-sex_n_5675212.html?cps=gravity

71. Organ-on-a-Chip Chips that mimic processes of an organ Contains smallest number of cells needed to mimic organ Examples Build them from IC fabrication techniques and from 3D printers. Goal is multiple organs on a chip: body-on-a chip Suppliers include CN Bio, Wyss Institute. Early customers are surprise, the military Towards a body-on-a-chip, Economist, June 13, 2015, p. 71. http://www.thelatestnews.com/organ-chip-breakthrough-replace-lab-animals/

72. Organ-on-a-Chip (2) Why? Enables faster drug testing avoidance of animals Made with IC-based techniques but with synthetic material like polymer Cells grown inside the chips Blood and air travel down micro-fluidic channels Need material that doesnt absorb blood Testing procedure introduce disease into chip then introduce drug into chip Basic test starts at $22,000, still less than tests on animals Towards a body-on-a-chip, Economist, June 13, 2015, p. 71. http://www.thelatestnews.com/organ-chip-breakthrough-replace-lab-animals/

73. Outline What is bio-electronics? Geometric scaling in bio-electronics Similarities between ICs and bio-electronics Applications for bio-electronics Control of implants Point-of-care diagnostics, including skin patches Drug delivery, Bionic eyes, Exoskeleton Organ on a chip Challenges for Bio-electronics are similar to those for MEMS

74. Like MEMS, development costs are very high for Bio- Electronic ICs so applications must have very high volumes Integrated Circuits Bio-Electronic ICs Materials Roughly the same for each application Different for each application Processes Roughly the same for each application (CMOS) Different for each application Equipment Roughly the same for each application Different for each application Masks Different for each application. But common solutions exist! Microprocessors, ASICs Different for each application

75. Solutions? Can we identify common materials, processes, equipment that can be used to make most bio-electronic ICs? Using common materials, processes and equipment involve tradeoffs Use sub-optimal ones for each application But benefit overall from economies of scale; similar things occurred with silicon-based CMOS devices One obvious option Can we make Bio-Electronic ICs with materials, processes, and equipment used to fabricate CMOS ICs? Or look for different materials, processes, equipment?

76. Conclusions and Relevant Questions for Your Group Projects (1) Cost and performance of bio-electronics have experienced large improvements and still have a large potential for improvements can potentially follow path similar to (or steeper than) Moores Law thus can lead to changes in health care that are similar to changes in electronic systems from Moores Law They have already enabled dramatic reductions in the cost of many types of medical products point-of-care diagnostics Sequencing, synthesizing equipment (covered next week)

77. Conclusions and Relevant Questions for Your Group Projects (2) These improvements will probably continue create new applications within diagnostic equipment, drug delivery, and chips embedded in clothing, body, etc. Lead to greater use of bionic eyes, artificial organs, exoskeletons How much cheaper and better will bio-electronics become in the next 10 years? What specific types of products and services will these improvements enable? Will these products and services be appropriate for advances countries or rural areas of less rich countries?

78. One-Page Write-ups 4 one-page write-ups on topics related to technologies covered in sessions 4 through 10 (20% of your grade) If you had two months to investigate one of these topics, what would you do? What types of data would you gather and how would you gather the data? Who might you interview? Topics are listed at end of these slides, of each session, and in assessment section of IVLE 2 one-page write-ups on topics related to technologies covered in group presentations (10% of your grade) Topic should be main points of presentation propose a different method of analysis than the group did It should not take you longer than 2 hours to do each assignment

79. Be Careful! The one-page write-ups on topics (related to technologies covered in sessions 4 through 10) are different than the 2 one- page write-ups on (group presentations) They require very different answers Even for one-page write-ups on topics related to technologies covered in sessions 4 through 10 Each question is different because cost and performance depends on different things for each technology Each question is also different because amount of information is different If technology has been commercialized, there is more info about technology costs, performance, benefits, needs If it has not been commercialized, there is less information Some technologies depend more on improvements in components than do others Thus, the answers will be different

80. Session 6 Topics for Write-ups Skin patches: How would you assess the costs and benefits from skin patches and when they will become widely used in Singapore (>10% of Singaporeans)? Smart contact lens: How would you assess the costs and benefits from smart contact lenses and when they will become widely used in Singapore (>10% of diabetics in Singaporeans? Attachments to mobile phones such as ultrasound and glucose meters (choose one of them): How would you assess the costs and benefits from using ultrasound or glucose meter attachments to mobile phones and when they will become widely used in Singapore (>10% of measurements in Singapore? Bio-fuels from DNA sequencing and synthesizing (GMOs): How would you assess the costs and benefits from using DNA sequencer and synthesizers to develop better bio-fuels (choose one such as cellulosic ethanol or algae) and when they will become widely used in Singapore (>10% of energy production in Singapore?

Business

Bio-Electronics, Bio-Sensors, Smart Phones, and Health Care