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Medical Diagnosis and Monitoring via Smartphone Part 2 – by Dr David David Maddison Last month we looked at some of the newest Smartphone Apps requiring little or no “extra” hardware to measure, record and even diagnose ailments. But there’s a host more apps which work with some add-ons to the smartphone. S ome medical diagnostic applications require capabilities beyond that provided by a phone’s builtin hardware, so an external electronic device is required. This can interface with the phone via wireless (such as Bluetooth or WiFi), or it can plug into a wired port; eg USB or Apple’s Lightning. Detecting cancer with an “artificial nose” There are a number of claims, dating back to a report in “The Lancet” in 1989, that a dog can be trained to detect certain forms of cancer which are revealed by a distinctive smell of the breath, perspiration or urine. These are apparently caused by chemical compounds generated by the tumour. While some people are sceptical of Fig.12: a patient’s breath being sampled by the handheld Na-Nose. Image source: Technion. 16 Silicon Chip such claims, based on this idea, Israeli scientist Professor Hossam Haick set about in 2007 to develop the Na-Nose (short for Nano-artificial Nose). This device is modelled on the olfactory system and brain of a dog so that it can detect, via a breath sample, diseases such as certain cancers, Parkinson’s disease, multiple sclerosis, Alzheimer’s, gastric ailments, kidney disease and others (Fig.12). Each disease produces a unique “breathprint”. The idea is to be able to detect disease conditions early, before a patient is even aware of them, when much more effective treatment can be given. The Na-Nose uses nanotechnology, with gold nanoparticles and carbon nanotubes making up part of the sensor. These nanoparticles and nanotubes are coated with organic ligands. A ligand can form a complex in the presence of specific organic molecules, Fig.13: a panel showing the SniffPhone features. Australia’s electronics magazine siliconchip.com.au consortium that includes several European companies (Figs.13, 14 & 15). See the video called “Sniffphone, a Phone So Smart It Sniffs out Disease - Hossam Haick -Technion” at: http:// siliconchip.com.au/link/aamr Portable DNA analysis Fig.14: the prototype version of the SniffPhone, which now wirelessly connects to a smartphone. Fig.15: the prototype Na-Nose and SniffPhone sensor array. changing its properties and this change can be detected. When a molecule of interest is detected, the electrical resistance between the nanoparticles or nanotubes changes and the resulting signal is analysed. Pattern recognition software in the computer, which has learned various disease signal patterns from machine learning, is then used to diagnose the disease. The Na-Nose was initially trained to detect 23 diseases and was used in 19 hospitals worldwide, with 8000 patients to teach its machine learning software. In follow-up trials, it was found to detect gastric cancers with 92-94% accuracy and it could also detect 17 different diseases in a trial of 1404 people with an accuracy of 86%. You can see a video with more details, titled “Detecting Disease Through Breath Prof. Hossam Haick Technion” at: siliconchip.com.au/ link/aamq The plan is now to miniaturise the Na-Nose to create a device called the SniffPhone, which will be used as a peripheral for a smartphone. The SniffPhone (www.sniffphone. eu/) is under development lead by Technion-Israel Institute of Technology’s professor Hossam Haick, with a siliconchip.com.au Q-POC is a system under development by UK-based QuantumMDx (siliconchip.com.au/link/aams). This device will give DNA analysis within 10-20 minutes of taking a sample from a patient. The device looks for specific DNA markers associated with certain diseases, or susceptibility to certain drugs. It amplifies DNA using PCR (the polymerase chain reaction) – all in a handheld device! (Fig.16) It can be used to determine if a patient is sensitive to a particular drug or not and whether it may have adverse effects if it is administered. It can also determine drug susceptibility for treatment of tuberculosis, sensitivity to warfarin anticoagulant and provides rapid detection of certain infections that otherwise would take 48 hours of laboratory tests. It can also detect asymptomatic cases of malaria, so that drugs can be given early during the onset of the disease. This device will have many applications for a variety of health professionals, including in a doctor’s office in Western countries, and for field workers in developing countries without healthcare infrastructure. The tests will be cheap and reliable. The initial target price for the device is £1,000 (~AUD$1750) with a cost per test of £3 (slightly more than AUD$5). The release date was initially expected to be 2018 but as of January Fig.16: the QuantumMDx Q-POC device, currently under development. Australia’s electronics magazine Wound Analyser App Further to our look at diabetes-related smartphone apps in part one of this feature, as we went to press an article appeared in “New Atlas” on a smartphone app which would give much more consistency in the treatment of diabetic ulcers and wounds. It’s called “Swift Skin and Wound” and was developed by Dr Sheila Wang at McGill University in Montreal, Canada. One of the (many!) side effects of diabetes is the significant slowing of the body’s ability to repair damage due to lower blood flow to the wound site. Normally, increased pain would alert patients/clinicians to problems but a lack of nerve endings in many diabetics means wounds might go untreated. Traditionally, wounds have been analysed simply with a ruler to check whether they are increasing, remaining the same or diminishing. It’s an imprecise system, relying on judgement which has been unreliable. Swift Skin and Wound uses an iPhone camera to compare the current area of a wound to a marker of a known size, which is placed on the skin. It can additionally incorporate a phone-mounted FLIR infrared camera, which can detect infection via increased skin temperature. In use by Montreal’s McGill University Health Centre (MUHC) since 2016, the app has been shown to produce more consistently accurate readings than a ruler and to be as accurate as a measuring tool known as a digital planimeter. Unlike a planimeter, however, the app allows clinicians to store and track measurements over time, and to share them with physicians in other locations via the internet. This could be a particularly valuable feature in remote regions, where high staff turnover means that multiple successive clinicians end up tracking the same wound. Swift Skin and Wound uses a smartphone camera to take images of a wound against a marker placed on the skin. As well as being much more precise, images can be stored and/or transmitted to a specialist. See siliconchip.com.au/link/aamt March 2019  17 The device uses blood from a finger prick and no processing of the sample is required. SAW devices generate acoustic waves by piezoelectric means and the presence of a mass on the device (such as captured virus particles) causes a change in the properties of the acoustic signal which can be measured. The mass can then be determined, leading to the identification of the substance under test (Fig.17). Zika virus Fig.17: HIV detection using surface acoustic wave (SAW) sensors in around 10 seconds. (a) prototype configuration (b) image of prototype (c) a phase shift is generated on the SAW device due to the presence of the virus particle, which is measured (d) the disposable SAW chip (e) How the SAW biochip captures HIV particles on special capture proteins, leading to a phase shift (f) HIV structure. Image source: www.nature.com/articles/s41598-017-11887-6 2019 there has been no news of its release. For more information, see the video titled “Inside Q-POC: Translating genetic code to binary” at: siliconchip. com.au/link/aamu Virus detection Scientists at the University of Surrey (England) have developed a 10-second HIV test using disposable surface acoustic wave (SAW) biosensor devices that plug into a smartphone. Fig.18: the nanotechnology scheme and smartphone device used to detect the Zika virus. 18 Silicon Chip Australia’s electronics magazine Another virus which is being heavily researched is the Zika virus. It is a significant public health concern as it can cause severe complications in infants if their mothers catch the virus during pregnancy. The virus mainly affects third world tropical countries but there have been cases of travellers bringing the disease back to Australia. Researchers at Brigham and Women’s Hospital in Boston, USA (siliconchip.com.au/link/aamv) have developed a smartphone-connected device that uses nanotechnology to cheaply and easily detect the virus. This will be especially welcome in countries that cannot afford more expensive diagnostic technology. The device is intended for use both by both medical professionals and for couples who are trying to conceive. Virus diagnostics are frequently based upon detecting antibodies in the blood, however, in the case of Zika, similar viruses such as dengue can elicit the same response, leading to false positives. To solve this, the Brigham and Women’s Hospital team have developed a completely non-conventional approach. They developed polystyrene (PS) microbeads (3 microns diameter) that have an affinity for the virus, as well as platinum (Pt) based nanomotor structures that also have an affinity for the virus. (A nanomotor is a molecular-size motor made from atomic components.) Both the beads and the nanomotors have Zika-specific antibodies attached to them. When the virus attaches to the microbeads and the nanomotors in a hydrogen peroxide (H2O2) solution, the motion of the Zika, bead and nanomotor complex can be detected using a microchip and the camera on a siliconchip.com.au Fig.20: the sickle cell testing device in use. It is a similar size to a smartphone. Fig.19: (a) diagram of sickle cell tester (b) sample illumination and magnets (c) 10 micron diameter microspheres undergoing magnetic levitation (d,e,f) various view of the 3D-printed prototype (g) image of magnetically levitated spheres on a smartphone (h) a conventional microscope laid on it side, doing a similar job. Image source: https://doi.org/10.1038/srep15022 smartphone (see Fig.18). Other viruses in the solution move much slower than the Zika virus, so the faster-moving Zika complex can be distinguished. The sensitivity of the technique is such that one virus particle per microlitre can be picked up. The technology is called the “nanomotor-based bead-motion cellphone” (NBC) system and could potentially be used to detect other viruses in future magnetic properties to normal blood cells and when placed in a magnetic field in a special solution, will levitate to a different degree (Figs.19 & 20). The device will have particular ap- Fig.21: prototype blood-pressure monitoring smartphone peripheral, mounted on the back of the phone. plicability in Africa, where there are few medical testing facilities and the disease is common. See: siliconchip.com.au/link/aamw Detecting sickle cell anaemia Scientists at the University of Connecticut (US) and colleagues from Yale, MIT and Harvard have developed an experimental smartphone-based device to perform quick, inexpensive tests for sickle cell disease. The test relies on the fact that the deformed blood cells have different 20 Silicon Chip Fig.22: how blood pressure is measured with a smartphone and associated peripheral. Australia’s electronics magazine siliconchip.com.au Fig.23: a prototype of the flexible microfluidic cytometry wristband. Image source: https://doi.org/10.1038/ s41378-018-0019-0 Blood pressure monitoring Researchers at Michigan State University (USA) siliconchip.com.au/ link/aamx have recently developed a smartphone peripheral and app that measures blood pressure at the finger. It uses a force and optical sensor, which works on the same principle as a cuffed blood pressure measuring device. It allows for blood pressure to be quickly and easily tested with reason- Fig.24: the Apple Watch Series 4 smartwatch with cardiac monitoring feature. able accuracy. The peripheral communicates with the phone via Bluetooth (Figs.21 & 22). For more details, see the video titled “This modified smartphone measures blood pressure directly from your finger” at: siliconchip.com.au/link/aamy There are also many other commercial smartphone-connected blood pressure monitors on the market which interface to a smartphone, however, all of these use a traditional cuff. They includes the QardioArm, Omron Evolv, Kinetik Bluetooth blood pressure monitor, Pyle PHBPB20, Omron 10 Series and iHealth Feel. Tracking blood counts (cytometry) Cytometry involves the determination of the physical and chemical characteristics of cells such as blood cells. Cytometry can be used to provide significant insights into a patient’s health a Fig.25: the AliveCor KardiaMobile ECG App and its associated hardware. Now available in Australia, it consists of a device and app that enables you to record and review electrocardiograms (ECGs) anywhere, anytime. The device attaches to the back of most iOS and Android devices, and communicates wirelessly with the free Kardia app, providing powerful display, analysis and communication capabilities. siliconchip.com.au c Fig.26: MELISA (Mobile Enzyme-Linked Immunosorbent Assay), a mobile version of the gold standard for laboratory biochemical analysis (ELISA). This prototype enclosure is 3D printed and the incubation function is controlled by an Arduino. The light to illuminate the sample trays is provided by an LCD screen. Image capture is done with a smartphone. Usually, the door of the MELISA is closed for image capture but is open here for demonstration purposes. Australia’s electronics magazine March 2019  21 Fig.27: the prototype mReader. It contains 96 sample wells which change colour if a particular biomarker is present. The smartphone detects and analyses that colour change. such as measuring white or red cell counts or platelet levels. Researchers at Rutgers University (see siliconchip.com.au/link/aamz) have developed a wearable wristband that performs flow cytometry via a microfluidic device that analyses a sample of tiny amounts of blood. Many other biomarkers in the blood such as proteins and nucleic acids can also be sensed (Fig.23). Data is sent to a smartphone and then possibly to a central database. The device can be used to monitor the health of patients on a continual basis, such as those undergoing chemotherapy, to ensure their blood counts remain at an acceptable level. Cardiac monitoring The Apple Watch Series 4 can monitor cardiac activity such as heart rate and it also has basic ECG (electrocar- Fig.28: the TRI Analyzer, showing a cartridge with multiple samples being inserted into the device. diogram) functionality. The ECG measures the electrical activity of the heart and the apple Watch does this by making a connection between the watch on the wrist on one side of the body and a finger of the opposite side of the body, held to the crown of the watch (Fig.24). This is equivalent to a single-lead ECG, as opposed to the traditional 12-lead ECG used in hospitals and by medical staff. An app associated with the watch can detect normal sinus rhythm and a condition known as atrial fibrillation which requires urgent medical attention. (We published a DIY ECG project in the October 2015 issue; see siliconchip. com.au/Article/9135). The AliveCor (www.alivetec.com/) KardiaMobile ECG app and hardware is a single-lead ECG monitoring device that works with smartphones (Fig.25). Like the Apple Watch, it can warn of atrial fibrillation. A recent study by the Intermountain Medical Center Heart Institute in Salt Fig.30: Dynamic Biomarkers’ Tricorder device showing smartphone interface and drawers of the unit showing various diagnostic accessories. 22 Silicon Chip Fig.29: the DxtER kit with peripherals and tablet. It has been developed to diagnose 34 conditions including diabetes, atrial fibrillation, obstructive pulmonary disease, urinary tract infection, sleep apnea, stroke, tuberculosis, pneumonia and more. Lake City (USA) found that the app could also be used to diagnose a type of heart attack known as an ST-Elevation Myocardial Infarction (STEMI), in which a major artery to the heart is blocked, almost as accurately as a 12 lead ECG. In the study, the device was moved around the body to record the same signals as a traditional 12-lead ECG. Mobile lab-quality tests The Mobile Enzyme-Linked Immunosorbent Assay (MELISA) is a prototype mobile version of the gold standard of laboratory biochemical analyses, ELISA, which has been developed by researchers at the University of South Florida (see Fig.26). The device incubates samples in a medium which changes colour according to the amount of sample under test. The colour change is analysed by the camera on a smartphone, to measure the amount of the substance of interest. The device has been demonstrated measuring the female hormone progesterone and is being developed to Fig.31: the My UV Patch. It is about the size of a 50c piece and half the thickness of a human hair. Different parts change colour according to the UV exposure received. The patch contains flexible electronics that store a unique ID. Australia’s electronics magazine siliconchip.com.au Fig.32 (left): the smartphone App which reads the My UV Patch. Fig.33 (right): “exploded” view of UV Sense device which is attached to the thumbnail. It is 2mm thick, 9mm in diameter and can be worn for up to two weeks at a time. which are detected by a smartphone. The patient samples are deposited in specially treated wells with reactants that undergo a colour change in response to the presence of certain viruses or bacteria. Portable spectrometer measure other substances. It is expected to be used in applications such as clinics in remote areas and third world countries. The device and tests are very much cheaper than the equivalent ELISA equipment and tests. Similarly, mReader (mobile reader) is a prototype device from the Washington State University and University of Pennsylvania, designed primarily for use in third world countries, which can simultaneously check 96 different patient samples for 12 different bacterial or viral infections (see Fig.27). Diagnosis is made by colour changes Fig,34: enlargement of the internal electronics of UV Sense. siliconchip.com.au The TRI Analyzer was inspired by the fictional Tricorder from Star Trek. TRI stands for transmission, reflectance and intensity. It was developed by scientists at the University of Illinois at UrbanaChampaign. It is a spectrometer and can perform common laboratory tests on blood, urine and saliva samples (see Fig.28). The device can be used to perform any standard biochemical test that produces a colour change or generates light in the form of fluorescence, such as the standard ELISA test (enzymelinked immunosorbent assay). The 3D-printed device uses the smartphone’s flash as a light source or uses a laser diode to illuminate a test sample and the light from the sample is guided via optical fibres throughda diffraction grating to the smartphone camera. Multiple samples can be tested in one session, by pushing a cartridge containing the samples through the device. General health diagnostics DxtER (www.basilleaftech.com/dxter/) was originally developed to win the Qualcomm Tricorder X-Prize (see panel last month) but has now been developed to diagnose 34 conditions including diabetes, atrial fibrillation, chronic obstructive pulmonary disease, urinary tract infection, sleep apnea, leukocytosis, pertussis, stroke, tuberculosis and pneumonia. The device and associated technologies are still under development (see Fig.29). Dynamic Biomarkers also developed a device for the Qualcomm Tricorder Fig.35: the Nima peanut testing device. Results can be uploaded to a database so other users can see what products contain peanuts or what establishments have peanuts in their menu items. There is also a similar device to determine if products are gluten-free or not. Australia’s electronics magazine March 2019  23 Fig.36: a sweat analysis patch before being fitted, with the various sensors and antenna clearly visible. Fig.37: the sweat analysis patch sensors use the principles of microfluidics, ie, fluids moving through extremely small channels. X-Prize, winning second place. It comprises a smartphone, vitals signs monitoring set, a scope set and gives the ability to perform blood, urine and breath tests (see Fig.30). Vital signs that can be monitored include temperature, heart rate, blood pressure, respiration, and oxygen saturation. Signal processing techniques are also used to assess the risk for conditions such as atrial fibrillation and sleep apnoea. It also includes a Bluetooth-enabled magnifying camera, to obtain high-resolution images of the skin and ear membrane. Machine learning is used to analyse acquired images and calculate the risk for either melanoma or otitis media (middle ear infection). Extra computing power beyond what can be provided by the smartphone comes from cloud computing. Blood, urine and breath tests are employed to analyse fluids or breath dynamics to diagnose conditions such as urinary tract infection, diabetes and chronic obstructive pulmonary disease. Work is underway to develop a next-generation version of this device for use in developing countries. For more information, see the video titled “Final Frontier - Qualcomm Tricorder XPRIZE” at: siliconchip.com. au/link/aan0 microns) adhesive patch that is applied to the skin (see Figs.31 & 32). It contains a number of coloured squares with UV sensitive dyes that change colour with UV exposure. It also has some fixed reference colours. It also contains some flexible electronics that are 15 microns thick. The electronics communicate with the smartphone via NFC (Near Field Communication) and convey an ID which is unique to the patch. A smartphone app images the patch with its camera and the colour changes in the UV-sensitive dyes are used to determine personal UV exposure. The app takes into account the user’s geographic location too, determined via GPS. The disposable patch can be worn for up to five days. L’Oréal has also developed smartphone-connected UV monitoring products to enable improved skin care. They allow the user to measuring their exposure to harmful UV, enabling them to reduce it if exposure is excessive. They have produced two devices. My Skin Track (siliconchip.com.au/link/aan1) is available now, in the form of a wearable sensor that can be hung around the neck or attached to clothing. It is waterproof and requires no batteries. A LED is used to sense UV light and it too communicates with a smartphone app via NFC (Near Field Communications). The app also displays environmental data downloaded from the internet such as pollen count, pollution and weather. It indicates the proportion of maximum allowable UV exposure that has been reached according to a user’s skin type. UV Sense is a solar-powered device which attaches to Monitoring UV light exposure Overexposure to UV light causes sunburn and can increase the risk of skin cancer, which is a serious public health problem in Australia. “My UV Patch” is a product from La Roche-Posay which is intended to help users avoid this. It is a wearable, flexible, stretchable, extremely thin (50 Fig.38: various “Tech Tats” by Chaotic Moon Studios. Fig.39: the miCARE App, (still under development) monitors risk factors during pregnancy. 24 Silicon Chip Australia’s electronics magazine siliconchip.com.au a thumbnail. It can store up to three months of UV exposure data. It can be worn for up to two weeks at a time, then reattached with additional adhesive (see Figs.33 & 34). The device was developed in conjunction with MC10 Inc, a leading wearable technology company, and professor John Rogers at Northwestern University (Illinois, USA – www.northwestern.edu/) It will be released globally later this year. Picking up food-based allergens Nima (https://nimasensor.com/) have developed smartphone-connected devices that detect if food is gluten-free or whether it contains peanuts. The devices work by using antibodies that react to the proteins in gluten or peanuts and this results in a change in the antibody properties, which is detected by the device and the results can be sent to a smartphone for display and logging (see Fig.35). Sweat analysis Fig.40: a 3D printed smartphone microscope. Either the smartphone flash or sunlight is used for illumination. Free 3D printer files are available to make this device yourself. All that is required apart from the 3D print is a cheap lens. Image source: https://doi.org/10.1038/s41598-018-21543-2 siliconchip.com.au Scientists at Northwestern University have also developed a stretchable, disposable electronic patch that adheres to the skin and which changes colour when exposed to sweat, revealing various body parameters such as pH, glucose, chloride and lactate. Electronics in the patch trigger a smartphone bought to close proximity, which takes a picture and uses the colour changes to determine the values of these biomarkers (see Figs.36 & 37). Skin sensors “Tech Tats” is a concept from Chaotic Moon Studios, Australia’s electronics magazine March 2019  25 Suffer from Gout? You should read this! A number of Australian universities are currently calling for volunteers who suffer from gout AND own a smartphone with internet access to take part in the Australia-wide study of a new smartphone app to help manage and/or control their gout. Gout is a form of inflammatory arthritis that develops in some people who have high levels of uric acid in the blood. The acid can form needle-like crystals in a joint and cause sudden, severe episodes of pain, tenderness, redness, warmth and swelling. To take part in the study, you will: • Use a mobile app for one year and record gout attacks; • See your GP and have blood tests at least 3 times a year; • Fill out 3 surveys, including questions about your gout and treatment. You will be reimbursed for your time with a $30 gift voucher, after completing both a blood test and a survey at each time point of the study: the start, at 6 months, and 12 months ($90 in total). If you know of anyone (including yourself!) who might be interested in participating, please feel free to share the study with them using the following link: https://mygoutapp.com/ Texas, USA – (www.chaoticmoon.com) of electronics attached directly to the skin that can monitor various physiological parameters or carry data such as banking information or identity confirmation. As you can see, they aren’t really tattoos but look a bit like they are (see Fig.38). For more information, see the video titled “Chaotic Moon Studios - Tech Tats” at: https://vimeo.com/144913588 Monitoring complicated pregnancies There is a host of pregnancy-related apps available, in development or proposed – if you’re interested, google “pregnancy apps” and you’ll find them. One which caught our eye is the UK-based miCARE, an app still under development but is designed to monitor various risk factors during pregnancy, such as detecting gestational diabetes. The app monitors parameters such as blood glucose, blood pressure, weight and kidney function, however, it will not use specially designed peripherals to do this. Rather, the app gets its data from existing equipment that is already in the at-risk pregnant mother’s home (eg, via Bluetooth – see Fig.39). Fig.41: the mobile phone microscope by ARC Centre for Nanoscale BioPhotonics in use. Note the microscope slide in the first image. Image source: https://doi.org/10.1038/s41598-018-21543-2 oPhotonics (Macquarie University, Sydney) has overcome these disadvantages, creating an inexpensive 3D-printed design suitable for medical applications. Specimens as small as 1/200th of a millimetre in diameter can be imaged, making it possible to view blood cells and cell nuclei among other things (see Figs.40 & 41). The same Centre has also developed a bioassay device (see Fig.42). If you have a 3D printer, you can actually make one of the ARC Centre-designed microscopes devices yourself. You can download the required files from http://cnbp.org. au/online-tools All you need to add is a cheap lens from a mobile phone camera, which can be purchased online (or obtained from one of the estimated 23 million unused mobile phones hidden in drawers and cupboards at home . . .). The future The future for mobile-phone based medical devices is promising. Ongoing miniaturisation will likely see these types of devices incorporated directly into smartphones of the future, which will enable them to become general-purpose medical monitoring devices. That should lead to improved health outcomes and reduced health care costs SC Smartphone microscope for medical uses Numerous smartphone microscopes have been developed over the years and they are all potentially suitable for medical applications such as the diagnosis of malaria, detection of E. coli or salmonella in food or assessment of water for parasites. This would be especially useful in third-world countries which lack proper laboratory facilities. However, many smartphone microscopes have drawbacks such as bulkiness, the requirement of an external light source, difficulty in cleaning and the inability to view images in real time due to image processing overhead. An Australian team at the ARC Centre for Nanoscale Bi26 Silicon Chip Fig.42: the smartphone bioassay device by ARC Centre of Excellence in Nanoscale Biophotonics. Certain colour channels of the smartphone camera are monitored to determine the amount of fluorescence from substances under test. Image source: https://doi.org/10.3390/s150511653 Australia’s electronics magazine siliconchip.com.au