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Medical Implanted Sensors

From Hip Joints to Glucose Testing Contact Lenses

Carl Mazzurco Professor Benton Scientific & Technical Report Writing March 30, 2014

2 MEMORANDUM Date: To: From: Subject: March 30, 2014 Sheri Benton Carl Mazzurco Sensor Implants

The concept of a sensor is not a radical new technology. Sensors play a role in thermostats, lights, cameras, and even sliding doors in stores. In todays world sensors exist at ones fingertips. A smartphone can monitor movements, tally calories, calculate sleeping rhythms, and even detect when ones face is not directed at the screen! Various forms of sensors are also commonly used by physicians to gather valuable health information about their patients. This is seen in the form of EMG machines for example. As the technology associated with sensors becomes better, so too will the application of sensors. Sensor implants are simply small sensors that can be implanted into the human body to collect essential health information such as brain waves, glucose levels, and even offer long term analysis of medical conditions. Sensor implants are an important topic in todays society for a variety of reasons. Primarily, sensor implants can offer the ability to better treat individuals suffering from certain conditions. For example, someone that may occasionally experience abnormal sleep patterns that drastically alter their ability to function may not always be able to replicate these patterns in a sleep lab. An implanted sensor can monitor this persons brain waves and offer more insight to physicians. The use of implanted sensors may also offer deeper insight into how the human body actually works on a daily basis instead of only simulated situations in a lab or research trial. The data that is collected from sensors can then be utilized to adjust certain treatments to better suit someones needs. If an implanted sensor can detect problems early on, the person can seek treatment before the situation becomes worse. This early detection can also save more lives. Much research currently revolves around perfect the design of previously developed sensors and beginning to hold clinical human trials. Human trials are an essential step for a medication or device to be approved for use in treating people. Tremendous advancements in the sensor technology through the use of carbon nanotubes shows the combination of engineering, biology, and chemistry all devoted to helping mankind. Implantable gels are being developed and tested to assess the impacts of cancer on the cellular level reveal the need for long term data collection. Sensors for diabetics that are implanted in the human eye or on a contact lens are currently undergoing live trials as well. Though lots of work needs to be done, sensor implants are no longer a thing of science fiction, yet there is a long way to go before true integration can occur.

3 Contents Page Executive Summary.4 Introduction..5 Background..5 Problem....6 Investigational Research7 Major Issue..9 Future of Research...10 Conclusion..11 Resources....12

4 Executive Summary The modern world we live in is no stranger to the concept of sensors. We have been utilizing sensors for decades and rely on them to detect and report any changes that we may not directly see. Things such as a car alarm that goes off when a car is bumped, thermometers that reveal the temperature, and motion-activated cameras are all examples of basic, everyday use of sensors. As society advances in knowledge and discoveries, so too technology changes Sensors that were once bulky, expensive, and easily susceptible to calibration errors are now obsolete. Everything from the smartphone in our pocket to cars that automatically brake utilizes sensors to detect some sort of information. Oftentimes sensors are able to detect much smaller differences and react much faster than any human on planet Earth. The primary focus now is complete integration between the human body and sensors. The ability to constantly monitor ones heart output or even glucose levels can help alert the person to a discrepancy and ultimately avoid the catastrophic outcomes of certain medical conditions. Sensor implants are of particular importance as they allow for massive amount of continuous, real-time data to be collected and analyzed. No longer will doctors be limited to a scheduled appointment to determine what is wrong with a patient. By introducing sensors that are selfsustaining, safe, and accurate into the human body, doctors and scientists can know exactly how certain cells are reacting to a condition or new medication. A sensor can even one day detect a heart attack days before it occurs because of how precisely it is calibrated. The purpose of medicine is not only to treat, but to prevent illness and injury. As we continue to push the boundaries of what is possible, scientists work diligently to accomplish this integration. Accomplishing this is no easy feat and they face many challenges. Sensors are no longer a box that releases an infrared beam that stops a circuit when the beam is broken. Sensors being developed today and tested for future clinical application come in a variety of shapes and sizes. Certain hydrogels are created by mixing nanotubes with fluorescent molecules that can travel freely through the blood stream. Other sensors may soon free diabetics from the constant finger prick of blood-glucose testing. Sensors that are implanted or placed on the eye are now able to reveal in real-time the glucose levels in someones blood which can save them from glycemic shock. Measuring bladder pressure without an invasive catheter, collecting data on friction and heat generation in hip-joint replacements, and even sensors that guide themselves into correct position for optimal results are a small fraction of the advancements to come.

5 Introduction As science and technology makes tremendous strides, so too do medical advancements. From a Civil War surgeons containing a saw and scissors to modern surgeons utilizing microscopic cameras, medical advancements have seen drastic developments in a short period of time. The goal of medicine is to treat, cure, and prevent illness and injury and return people to their everyday lives. Though there are many advances, an issue facing medicine is one of accessibility to patient information. Doctors currently rely on the information they can collect during a doctors visit and/or results of tests done at the hospital. How can someone guarantee their acid-reflux will be active enough to show up on a test for an appointment two months in the future? Scientists and doctors alike have been asking the same question and new medical technology is trending towards devices that constantly gather patient data. And just in case someone doesnt want to lug around an EKG machine, implantable sensors that constantly transmit data are on the horizon. Background An implant is a medical device that is utilized to replace or augment a missing or damaged biological structure. Medical implants range from the screws used to stabilize a bone after surgery to a pacemaker keeping someones heart beating. Some implants are made with metals like titanium such as bone screws and hip implants. Some implants serve a more functional role and contain electronics. These can include pacemakers or cochlear implants for people that are deaf. Even other implants can be considered bioactive such as subcutaneous drug delivery devices that come in the form of long-term pills, i.e. long-term birth control. Three classifications of medical devices exist as determined by the US Food and Drug Administration. Class I devices are considered to pose the lowest level of risk and require the least amount of control. These can include arm slings. Class II devices need more regulation and require specific regulation by the FDA. This can include X-ray systems and electrocardiogram (EKG) machines. Class III devices require strict regulation as many support and sustain human life. These can include heart valves or cerebral stimulators for Parkinsons. Many implants typically fall under Class II and III to make sure they are controlled. (FDA Medical Devices) Implanting foreign objects into the body can have a tremendously positive effect and restore someones quality of life. On the other side of this, implants tend to suffer complications that can lead to severe injury, pain, and even death in some cases. The human body is designed to function with living tissue. Each tissue serves a purpose and interacts with the surrounding tissue. Introducing a foreign object, such as a titanium screw, is not always well accepted by our bodies because the screw is not recognized (Ratner, 2004). Implanting a medical device often times involves an invasive medical procedure, just like many surgeries. Not even covering the complications associated with implants, surgeries alone have increased risk of infection, inflammation, and pain. Other complications that are associated with medical implants include rejection of the implant, clotting problems surrounding the implant, and the body may have an

6 allergic reaction to the implant. These complications can lead to further hospital stays, more treatments, surgery to remove to implant, etc. It is possible for implants to even fail. Failure of implants can have varying consequences depending on nature of the implant and what function it serves. If a screw or hip replacement becomes infected it can possibly be treated by removing it and replacing it. If an artificial heart valve fails, the life of the individual may be threatened (2004). Scientists and doctors alike have shifted their focus from implants that simply serve to maintain or improve a condition, to implants that can collect and transmit real-life data to the doctor. When the doctor is able to analyze a persons condition using data that is collected over a period of time and not solely in an appointment, the doctor can better assess and determine a treatment or procedure for the patient. Sensor implants are an important topic in todays society for a variety of reasons. Primarily, sensor implants can offer the ability to better treat individuals suffering from certain conditions. For example, someone that may occasionally experience abnormal sleep patterns that drastically alter their ability to function may not always be able to replicate these patterns in a sleep lab. An implanted sensor can monitor this persons brain waves and offer more insight to physicians. The use of implanted sensors may also offer deeper insight into how the human body actually works on a daily basis instead of only simulated situations in a lab or research trial. The data that is collected from sensors can then be utilized to adjust certain treatments to better suit someones needs. If an implanted sensor can detect problems early on, the person can seek treatment before the situation becomes worse. This early detection can also save more lives.

Problem One thing that will never change about the human race is that it will continue to suffer from medical conditions. As man continues to suffer from a cold or a fractured bone he will need to be treated in a medical facility. From 2003 to 2009, the mean wait time U.S. emergency departments increased 25% from 46.5 minutes to 58.1 minutes (Hing 2012). From 1999 through 2009, the number of visits to emergency departments increased 32%. With more people going to hospitals to be treated and wait times increasing, doctors seem to have less and less time per patient. Before a doctor can make a diagnosis or recommend a treatment he needs to collect pivotal data about the patient. Data collection can include anything from blood-draws to MRI body scans. These take time, resources, and dont allow doctors immediate access to information. When attempting to determine if someone suffered a minor heart attack or a minor stroke, time is of the essence. It is for this reason that medical researchers and professionals have been determined to discover a way to collect medical data in real life and over time. In hospitals it is easy to be hooked up to a heart monitor, but it is not plausible to walk around with a full EKG machine. In order to collect medical data on a patient that doesnt interfere with everyday activities, research has turned to sensors that can be implanted in the patient and work wirelessly.

7 The major problem now is implementing this technology in such a way that doesnt harm or impair the patient yet accurately collects and transmit the appropriate data. Furthermore, determining how long the implant will last in the body and accounting for any possible rejection of the implant are integral for the success of sensor implants Investigational Research What seems like something out of a science-fiction novel, implantable sensors are now a very real technology. One utilizes sensors every single day, from a cell phone to a hospital and everything in between. The current focus in the scientific and technological world is how to integrate electronic devices that report real-time data into the human body. Modern medicine can already implant a pacemaker, but sensors are a much more advanced and delicate technology. The focus in research now is on how to incorporate electronics directly into the body that can sense and operate without a cord or machine guiding it. As mentioned previously, implants can be bioactive such as implantable medications. No longer is medicine limited to implanting medicine as shown by research. Soon bioactive implants will be able to monitor specific bodily functions. Nitric oxide is one of the most important signaling molecules in living cells as it carries messages within the brain and serves a role in immune systems. Research has shown that in cancerous cells, the nitric oxide levels are altered but the relationship has not been analyzed thoroughly. The major reason the relationship hasnt been further analyzed is because of the inability to collect the necessary amount of data. In order to draw any conclusions, scientists need to be able to analyze how nitric oxide levels fluctuate for weeks or even months. Science has stepped up to the challenge and there soon may be a way to quantify and understand this relationship. In 2013, researchers out of MIT have developed a new sensor that can monitor nitric oxide levels in living animals for more than a year. These sensors are implanted under the skin and used to monitor inflammation. Inflammation is a process that produces nitric oxide and researchers believe that cancer cells can trigger inflammation. MIT researchers have utilized carbon nanotubes, hollow, one-nanometer-thick cylinders made of pure carbon, that have a natural fluorescence. Researchers then combined the nanotubes with a molecule that binds to nitric oxide. This molecule is designed to either brighten or dim when it binds to the molecule which can be seen when an infrared laser is shined on them. This is the first time that nanosensors have been demonstrated to be used for long periods of time. These same researchers have also developed long and short term nanosensors. Long term sensors can be embedded under the skin, whereas short term sensors can be injected into the bloodstream. When injecting the short term sensors into mice it was found that the particles can flow through the heart and lungs without causing damage. The long term sensors are embedded in a polymer gel that is then implanted under the skin, akin to tattoo ink, for example (New Implantable Sensor, 2013). Diabetes is an epidemically growing disease that affects millions of people worldwide(citation). In those with diabetes, there is a malfunction in the production of insulin

8 levels that help regulate blood glucose. Too much glucose in the blood can lead to damage in the cardiovascular system, and not enough glucose can lead to loss of body function. In order for diabetic patients to make sure they have a proper glucose level it is necessary to test their blood multiple times a day. This is commonly done via a finger pinprick to draw blood which is then read using a glucometer. Constant finger pricks can lead to severe pain and some loss of function. Electrochemical sensors currently exist that can be attached to the skin, but these sensors last only a week, at most, and there is an increased risk of infection as the electrode has to pierce the skin. This testing is not continuous and requires the patient to maintain a strict testing regimen. Furthermore, patients do not regularly record their glucose levels and then have the doctor analyze them as it would require significant work from both parties. In order for treatments for diabetes to improve it is necessary to collect more data. To do this, continuous monitoring of constantly changing glucose levels is necessary to see how exactly diabetes affects the body. This can be accomplished through implanted glucose sensors which may arrive sooner than we believe. The same researchers from MIT that produced the nitric oxide sensor have also been developing glucose sensors. They take the same nanotubes and are testing different molecules that they can combine. These sensors would be connected to an insulin pump that would deliver insulin when needed and also track fluctuations that can then later be processed for statistical analysis (New Implantable Sensor, 2013). Though implantable glucose sensors that collect and transmit data may be in the works, glucose sensors implanted in the eye have undergone the first human clinical trials. Through the use of a subconjunctival glucose monitoring system (SGMS) that consists of an ocular mini implant, researchers can test blood glucose levels by looking at the eyes. The implantable sensor utilizes the same fluorescence technology as mentioned previously. Researchers take a polymer hydrogel disk and cover it with these fluorescent molecules and then proceed to implant it directly below the conjunctiva which is the clear, thin membrane that covers the human eye. When an orange light-emitting diode is shined on the sensor from a handheld fluorescence photometer the implanted sensor emits light back to the photometer. This photometer reads the intensity of the light which is then translated to a glucose level. In order to test this on humans, researchers implanted the sensors in five diabetes patients for two weeks. Researchers then manipulated each patients glucose levels with glucose and insulin injections. Upon testing the sensor implants results, 98% of the readings fell within the acceptable clinical range (Muller, 2012). Though this sensor doesnt act on its own it does eliminate the need for finger pricks and allows for continuous glucose monitoring. Continuous glucose monitors serve four main purposes in the management of diabetes, which are as follows: 1. Detecting and predicting hyperglycemia in real time 2. Detecting and predicting hypoglycemia in real time 3. Assessing overall glycemia 4. Determining how much glucose levels fluctuate over time

Hyperglycemia and hypoglycemia may require diabetics to go through days of intensive therapy in order to return blood glucose levels to a healthy state. In severe cases of hypo/hyperglycemia a diabetic may go into glycemic shock which can lead to death if not cared for immediately. By utilizing a continuous glucose sensor the rates of hyperglycemia and hypoglycemia can be drastically reduced and allow for diabetics to have an overall increased quality of life (Klonoff 2007). Glucose level is not the only thing that can be monitored through the use of sensors on the eyes. Glaucoma is a condition that causes damage to the eyes optic nerve to the buildup of excess pressure in the eye. Tests for glaucoma are usually done at the ophthalmologists office with a special pressure test. Eye appointments are not usually something people schedule regularly so therefore the possibility of detecting glaucoma early is decreased. Researchers have developed a sensor placed on a contact lens. This sensor consists of two titanium-platinum sensing resistive strain gauges that record changes in the circumference of a specific portion of the eye. A microprocessor is also embedded in the contact lese that sends an output signal to a portable battery-powered recorder. As a result of human clinical studies, researchers were able to conclude that the lens is safe and well-tolerated by the patients. They were also able to conclude that lens sensor can detect changes in intraocular pressure but not as effectively as a test conducted by a doctor (Mansouri, 2012). Though the sensor still needs to be modified to obtain more accurate results this lens has the potential to help detect and prevent glaucoma before it causes blindness. Implantable sensors also have utilized to help measure pressure changes in the bladder of those suffering from conditions that can cause issues with urinating and incontinence. Neurological conditions or spinal injuries can damage the nerve supply to the bladder. This can prevent people from being able to know when their bladder is full and requires emptying. This can cause a buildup of high pressure in the bladder which affects the kidneys and can lead to lifethreatening damage. Currently, bladder pressure can be tested using a catheter which is uncomfortable for the patient. To overcome this inconvenience and pain researchers have developed a tiny sensor that can be implanted in patients to monitor pressure changes. A thin needle is inserted through the skin and into the bladder where the sensor is positioned without causing discomfort to the patient. This allows the patient to live and act normally without a disruptive catheter or increased risk of infection. The data from this sensor is currently transmitted through a very thin wire with wireless possibilities being tested currently. The long term plan is to create a sensor that can function independently, takes regular measurements, and that can be implanted for several months or years (Dragland, 2013). Major Issue Facing Implants With any new technology there will exist issues and complications that must be addressed for the ultimate success of the technology. Since the first bone screw was utilized,

10 implants have faced a series of issues including infection, allergic reaction to the implant, and even implant rejection. These complications can lead to increased medical costs, more medical procedures, and worsened quality of life which is something doctors want to avoid. When dealing with implantable sensors, doctors and scientists face the same possible complications. The most commonly seen issue facing implants today is that of infection. Implants often require invasive surgery and an increased recovery time as the body must adjust to the new implant. This increased time also increases the time that a wound is present and capable of being infected. The rise in development of biomaterials used for implants has been beneficial in helping in certain cases but researchers believe more in-depth studies are necessary. As technology constantly changes and everyone is looking for the next best thing, sometimes the long term impacts of a product are overlooked. With a rise in biomaterials researchers have also revealed a rise in biomaterial-associated infections. There also exists a lack in development of antimicrobial properties to address these infections. There appears to be a disconnect between research and initial development stage and actual clinical implementation( Grainger, 2013). In order for sensor implants to be safe and provide accurate and effective information the risk of infection and complications needs to be drastically reduced. Instead of constantly creating new materials researchers should consider perfecting the ones we have currently. Future of Research Current developments in sensor implants have taken drastic strides in the past few years as technology keeps changing. Many projects exist today that are evaluating potential future roles of sensor implants in the medical field. Hip implants serve an integral in relieving hip pain and restoring joint function allowing for mobility. In a full hip replacement the entire ball-socket joint of the hip is replaced. Hip implants are made of metal such as titanium and are implanted so that they lock into place with the pelvic bone. When participating in continuous activity such as walking or running, hip prosthetics have been shown to heat up due to friction between the metal surfaces. This can lead to damage to the implant, joint pain, and necessary for future corrective procedures. The effect of certain articulating materials and bioengineered joint lubricants are unknown as studies for this are essentially nonexistent. Researchers have proposed an instrumented hip implant that has heat sensors in the structure of the implant. These sensors transmit data wirelessly via magnetic pulses which are then collected by an external recorder. Researchers hope that through the implementation of this technology they will be able to better understand temperature changes within the hip joint and how to create materials to counteract this friction. The biggest hurdles to overcome will be the effectiveness of the actual sensor as well as ensuring accurate data transmission (Bergmann, 2012). The future of sensor implants may also reveal implants that assist the doctors in guiding itself to the proper position. In order for implants to work correctly they must be properly positioned. If a hearing aid or cochlear implant is not placed deep enough into the cochlea the

11 patient will not obtain all of the benefits the implant has to provide. Currently, doctors guide implants with the knowledge obtained from previous implantations as well as their own general acuity. In the case of cochlear implants, soon the sensor may be guiding itself. A cochlear implant restores hearing to those suffering from deafness by translating sounds into electric signals that travel down a narrow probe which directly stimulates auditory nerve fibers. To place a cochlear implant, surgeons must thread the probe into the interior of the cochlea at a very specific depth. Many times doctors are too cautious and the implant does not reach the optimal depth. A prototype implant includes very specific sensors along the length of the entire probe. These sensors produce signals that doctors can then use to determine how deep the implant is and when to stop threading. This can help doctors give patients the optimal results from an implant and increase the overall effectiveness and quality of life for those that are deaf (Weiss, 2006). Conclusion Medicine and technology are intimately connected and serve to improve the quality of life for all of mankind. As technology and our understanding continues to evolve, so too will medical procedures, equipment, and effectiveness. In a world where everything is going wireless it only makes sense that our medical care will as well. Previously it was thought that to complete any medical test it was necessary to devote tremendous amounts of time from scheduling the appointment early, to waiting the hospital, to undergoing the test, and then waiting for the results. In certain medical conditions waiting can mean the difference between life and death and time is of the essence. This waiting and being connected with various cords and wires that beep randomly may soon be a thing of the past with the advancements seen in wireless sensor implants. Implants used to only involve screws, joints, heart valves that served to replace or augment damages. Now, to better understand the human body and how certain medical conditions affect the body, science has turned to sensory gels, contact lenses with microchips, nanotubes that glow, and even self-guiding implants. Sensor implants will allow researchers and doctors to collect real-time health data on their patients allowing for improved detection, treatment, and understanding of how ailments afflict the human body. Though the improvements have been great the total implementation of live-acting sensors faces many difficulties. The human body does not adapt well to inorganic materials inside of it leaving science to figure out how to minimize implant rejection. More long-term studies are necessary to evaluate how the sensors will affect the human body over time. The materials used in the sensors need to be strong enough to withstand damage and degradation and minimize possibility of infection all while being minimally invasive with little to no pain. If a doctor from the early 1900s was told that in 100 years people born deaf will have the ability to hear because of a computer chip or that a sensor in the eye can read blood-glucose levels, he would believe it to be complete sciencefiction. Modern-day science pushes the boundaries of science fiction on a daily basis and it can be expected that sensor implants will become common in the prevention and diagnosing of our society.

12 Resources Bergmann, G., Graichen, F., Dymke, J., Rohlmann, A., Duda, G. N., Damm, P., et al. (2012). High-Tech Hip Implant for Wireless Temperature Measurements In Vivo. PLoS ONE, 7(8), e43489. Dragland, A. (n.d.). Lifesaving sensor for full bladders. sintef.com - SINTEF. Retrieved March 29, 2014, from http://www.sintef.no/home/Information-and-CommunicationTechnology-ICT/News/Lifesaving-sensor-for-full-bladders/ General Controls for Medical Devices. (n.d.). Medical Devices. Retrieved March 29, 2014, from http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/Generalan dSpecialControls/ucm055910.htm Grainger, D. W., Mei, H. C., & Jutte, P. C. (2013). Critical factors in the translation of improved antimicrobial strategies for medical implants and devices. Biomaterials, 34(37), 92379243. Retrieved March 29, 2014, from the EbscoHost - Academic Search Complete database. Hing, E. (2012). Wait time for treatment in hospital emergency departments: 2009. NCHS Data Brief,102. Retrieved March 29, 2014, from http://www.cdc.gov/nchs/data/databriefs/db102.htm Klonoff, D. C. (2007). The Benefits of Implanted Glucose Sensors. Journal of Diabetes Science and Technology, 1(6), 797-800. Retrieved March 29, 2014, from the EbscoHost Academic Search Complete database. Mansouri, K., Medeiros, F. A., Tafreshi, A., & Weinreb, R. N. (2012). Continuous 24-Hour Monitoring of Intraocular Pressure Patterns With a Contact Lens Sensor. archives of ophthalmology, 130(12), 1534. Retrieved March 29, 2014, from the PubMed database. Muller, A. J., Knuth, M., Nikolaus, K. S., & Herbrechtsmeier, P. (2012). First Clinical Evaluation of a New Long-Term Subconjunctival Glucose Sensor.Journal of Diabetes Science and Technology, 6(4), 875-883. Retrieved March 29, 2014, from the EbscoHost Academic Search Complete database. New implantable sensor paves way to long-term monitoring. (n.d.). MIT News Office. Retrieved March 29, 2014, from http://newsoffice.mit.edu/2013/new-implantable-sensor-pavesway-long-term-monitoring Ratner, B. D. (2004). Biomaterials science an introduction to materials in medicine (2nd ed.). Amsterdam: Elsevier Academic Press. Weiss, P. (2006). Hearing Implant Knows Where It Goes. Science News,169(2), 29. Retrieved March 29, 2014, from the EbscoHost - Academic Search Complete database.