Nanobots For Glucose Level Monitoring
Abstract
Diabetes is one of the deadliest disease of the century. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. Tedious and painful methods for its monitoring on daily basis has to be carried out by people suffering from it which involves pricking their fingers many times a day, which may cause infections and side effects. As an alternate, nanobots serve as a potential diagnosis technique which is very much safer than other available methods. Nanobot sensors are said to set a new milestone in the development of medical studies. The primary object of the bot will be to stay in the blood stream and carry out continuous monitoring of the blood glucose levels of the person and report it to an external data management system to store and track the readings for drawing conclusions and getting a treatment, if required. The bots have a structure of a multiwall carbon nanotube, with walls having individual roles and performing the diagnosis in a procedural manner. This novel idea will be actively used within the public when it passes its first human trial. In this review, we focus on continuous monitoring of blood glucose levels. Since the bot can be programmed and is capable enough to carry a payload, it can also be used to diagnose any other parameter as a secondary target. Creation of nanobots has been under progress already and may come within the public after an estimated time of 5 years.
Introduction
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels.
With approximately 346 million people worldwide living with diabetes, it is no surprise that this disease is costly. An estimated 3. 4 million sufferers of diabetes die from poor management of blood glucose. According to the World Health Organization, the number of deaths as a result of diabetes is estimated to double between the periods of 2005 and 2030. Poor diabetes management can be due to a number of factors including the patient’s diet and poor compliance to monitoring blood glucose levels on a regular basis. Glucose monitors are paramount to helping patients to regularly keep track of blood glucose levels and adjust their diet, medication, and exercise routine. Traditional methods to measure blood glucose involve measuring blood glucose levels in the lab which provides the most accurate representation of a patient’s blood glucose concentration. However, careful measurement techniques and regular extraction of sample blood can be physically demanding for the patient and time-consuming.
Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. In 2014, 8. 5% of adults aged 18 years and older had diabetes. In 2016, diabetes was the direct cause of 1. 6 million deaths and in 2012 high blood glucose was the cause of another 2. 2 million deaths.
Some Statistics Related to Diabetes
The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes among adults over 18 years of age has risen from 4. 7% in 1980 to 8. 5% in 2014. Diabetes prevalence has been rising more rapidly in middle- and low-income countries. In 2016, an estimated 1. 6 million deaths were directly caused by diabetes. Another 2. 2 million deaths were attributable to high blood glucose in 2012. Graph 1 shows the prevalence of diabetes over the years in different continents. Almost half of all deaths attributable to high blood glucose occur before the age of 70 years. WHO estimates that diabetes was the seventh leading cause of death in 2016.
Diabetes (diabetes mellitus) is a metabolic disorder which results in high levels of blood glucose. It can be classified as either Type 1 or Type 2, depending on the reason for the high glucose levels. Type 1 diabetes means that the pancreas cannot produce insulin (a hormone which enables the uptake of glucose by the liver, muscle and fat tissue), whereas Type 2 means that the body's cells do not respond to the presence of insulin. Whilst Type 1 diabetes can be fatal if untreated, most patients today survive into old age - however, they must inject insulin several times a day to allow their body to use the glucose from their food.
Our understanding and ability to treat insulin has been improving steadily, ever since the first insulin injections were carried out in the early 1920s by Banting and Best. Despite all the advances which have been made, insulin cannot be cured altogether, and a good deal of research effort is aimed at improving quality of life for diabetic patients, making their glucose tests and insulin injections as easy and non-invasive as possible, and potentially devising a permanent cure for diabetes.
Consequences of Diabetes
Over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves. Combined with reduced blood flow, neuropathy (nerve damage) in the feet increases the chance of foot ulcers, infection and eventual need for limb amputation. Diabetic retinopathy is an important cause of blindness, and occurs as a result of long-term accumulated damage to the small blood vessels in the retina. 2. 6% of global blindness can be attributed to diabetes.
Preventive Measures
Diabetes can be treated and its consequences avoided or delayed with diet, physical activity, medication and regular screening and treatment for complications.
Nanotechnology in Monitoring Glucose Levels
Several improved methods for non-invasive, continuous monitoring of blood glucose have been proposed in the last few years. Many of these take advantage of the advances in medical technology made possible by nanotechnology. However, this needs more research because there are chances that nanoparticles could be mistaken as unwanted foreign bodies by our immune system. There are various methods to overcome the immune responses to the nanoparticles. There may be issues with ensuring the biocompatibility of the sensors, as they would need to remain implanted in the body for a long period of time. Nanorobotics is the technology of constructing robots in the nanometer scale (10−9 m). It is an emerging technology in the recent times. Nanorobots and their application in the medical field are currently under development. In collaboration with medicine, nanorobots are programmed to perform specific biological tasks. When they are injected into the blood, they can perform certain tasks like treatment of cells, drug delivery, imaging, diagnosis, etc. as per they are programmed. Nanorobots merged with biological research will set a new milestone in the development of medical studies. The shortcomings of the present methods are taken into account to hit upon a better way to measure the glucose levels to keep a check on the alarming disease. This novel idea will be actively used within the public when it passes its first human trial. Creation of nanobots has been under progress already and may come within the public after an estimated time of 5 years.
Motivation
Considering the properties of nanorobots to navigate as blood-borne devices, they can help important treatment processes of complex diseases in early diagnosis and smart drug delivery. Current methods of blood glucose monitoring are invasive and often painful. The finger-prick test has been associated with non-adherence to treatment regimes by diabetic patients. It also has very limited accuracy - it cannot be performed during other activities, such as driving, or sleeping, and its intermittent nature means that it can miss important and potentially dangerous spikes and fluctuations in blood glucose levels in between tests. One of the main disadvantages to the finger-prick test is the inconvenience and heightened chance of contaminating a blood sample. There is the obvious issue of not being able to monitor night-time variation in the patient’s blood glucose levels and so there has been a big demand in the medical industry to introduce techniques that with have better control over blood glucose monitoring without this being a burden on the patient’s lifestyle.
Nanorobots with chemical nanobiosensors can be programmed to detect different levels of blood sugar levels and wireless communication can be utilised to report the results for further monitoring.
Construction
The bots to be constructed will have the structure of a Carbon Nanotube(CNT).
Carbon Nanotubes
Carbon nanotubes (CNTs) are cylindrical molecules that consist of rolled-up sheets of single-layer carbon atoms. Like their building block graphene, CNTs are chemically bonded with sp2 bonds, an extremely strong form of molecular interaction. This feature combined with carbon nanotube’s natural inclination to rope together via van der Waals forces, provide the opportunity to develop ultra-high strength, low-weight materials that possess highly conductive electrical and thermal properties.
As the process of diagnosis involves a series of steps, a multi-walled Carbon nanotubes (MWCNT), consisting of several concentrically interlinked nanotubes, with diameters reaching more than 100 nm has to be constructed where each layer will have a specific task to perform. MWCNTs exhibits several traits that ensures the longevity and dependency for accurate diagnosis. MWCNTs are always conducting and achieve at least the same level of conductivity as metals. Their mechanical tensile strength can be 400 times that of steel; they are very light-weight – their density is one sixth of that of steel (hence will make sure that it doesn’t alters the blood density by much and hence not initiating any side effects or toxicity); their thermal conductivity is better than that of diamond (hence will adapt to the surrounding medium – blood); they have a very high aspect ratio greater than 1000, i. e. in relation to their length they are extremely thin.
Synthesis of CNT
There are three main methods that are currently available for the production of CNTs: arc discharge, laser ablation of graphite, and chemical vapour deposition (CVD).
In the first two processes, graphite is combusted electrically or by means of a laser, and the CNTs developing in the gaseous phase are separated. All three methods require the use of metals (e. g. iron, cobalt, nickel) as catalysts.
The CVD process has currently been the most efficient, since it allows the production of larger quantities of CNTs under more easily controllable conditions and at lower cost. In the CVD process, manufacturers can combine a metal catalyst (such as iron) with carbon-containing reaction gases (such as hydrogen or carbon monoxide) to form carbon nanotubes on the catalyst inside a high-temperature furnace.
Purification
The current synthesis techniques have been successful in obtaining high purity carbon nanotubes. But the formation of by-products give rise to some impurities like metal encapsulated nanoparticles, metal particles in the tip of a carbon nanotube, and amorphous carbon. Also some structural defects may occur during synthesis. The foreign nanoparticle impurities and the defects alter the physio-chemical properties of the carbon nanotubes hence there is a requirement for purification. It can be done by Acid treatment or by use of ultrasound after the production process.
Enzyme Carrier
The bot has to carry an enzyme in order to oxidise the blood and hence use the products to generate an electric pulse that has to be measured. The hollow inner cavities of a carbon nanotube can serve as potential containers for delivery purpose, if utilised properly. Keeping their biomedical compatibility in mind, they have to be superficially be modified.
This can be achieved by a simple technique of doping. It was observed that nitrogen doped CNTs showed better biomedical compatibility. Taking advantage of this, Alexander Star, and his team used nitrogen doping of CNTs which resulted in formation of cup-shaped compartments in CNTs uniquely suitable for encapsulation. The nanocups were obtained from fibrous nitrogen-doped CNTs by ultra-sonication. It was later managed to effectively cork the nanocups by gold nanoparticles to create a new type of cup-shaped nano-containers with corked opening.
The potential application of this work is to use the nanocups as nanoscale containers, especially as enzyme delivery vehicles. Star points out that the gold nanoparticle corked nanocups have all the desired properties for biomedical applications, including their hollow, self-confined cup structures, diverse reactivity, and biocompatibility. The gold nanoparticle corks can be designed to be open under certain stimuli, to achieve a controlled release of enzyme.
Sensors/Transducers
Most sensors based on CNTs are field effect transistors (FET) – although CNT are robust and inert structures, their electrical properties are extremely sensitive to the effects of charge transfer and chemical doping by various molecules. The CNTs will have to be made keeping the analyte in mind to make it specific.
Electrodes
Carbon Nanotubes have been used as electrodes for sensing in different domains. They have excellent electrical properties and have high materialistic strength, hence are durable. The Uni-molecular nature of its walls provides a large surface area for conduction and makes room for region specific electron transfer capabilities.
Power Sourcing
The bots have to be in the blood stream for quite a long time so power sourcing emerges as an important factor to keep in mind. There can be different ways to handle this task. One way is to incorporate the bot with thermal charging batteries which use the high body temperatures to charge the battery. Another way can be to replicate some of the natural organisms Like bacteria cells or use nuclear technology, Researchers consider it highly likely that when equipped with a thin film of radioactive material, nanobots will be able to fuel themselves on particles released by decaying atoms.
Summing up the Construction
The bot will be designed as a MWCNT structure, with each wall performing a specific task. Glucose will be able to easily diffuse through the bot. The outer most wall will have nanocups which contain the enzyme which will oxidise the blood. The next few walls will act as a series of sensors and electrodes that will measure and report the magnitude of the electric pulse generated, which being proportional to the glucose levels will serve the purpose. To design and stimulate the structure of the nanorobots, the researchers use an open-source software, called Cadnano.
Working Methodology
The multiwall structure of our tube gives us different components working together in a synchronous manner to serve the purpose. The carbon nanotube is insulated by a porous layer. The exterior wall will be loaded with an enzyme in its nanocups, which will be followed by two electrode layers: one working electrode and one counter electrode connected to a transducer which feeds data to an embedded chip. The carbon Nanotubes work in a step by step procedure, with each layer having a specific task to perform. An electrochemical method will be used to carry out the diagnosis. The electrochemical method for testing blood glucose concentrations is driven by a current that is directly proportional to the level of blood glucose present in a blood sample. The blood is drawn between two electrodes. The outermost layer is loaded with an enzyme that converts glucose into gluconic acid. Here glucose oxidation occurs transforming the glucose molecule from Beta-D-glucose to D-glucagon-1,5-lactone and then hydrolysed to D-gluconic acid. Glucose can diffuse freely through the tube, so when sugar levels are high, the enzyme produces large quantities of gluconic acid. This reaction generates an electrical current that forces electrons to flow between the working electrodes and counter electrodes. The working electrode has an impregnated enzyme present so that, when in contact with glucose, a current is generated. Based on this working principle, the more blood glucose present in a sample, the stronger the voltage generated. The electrical current generated is interpreted by a transducer which records the current in a specific timeframe and feeds a reading of blood glucose concentration in mM or mg/dL. This data could then be fed to an embedded microchip, which could send the data wirelessly to a wearable computer.
Preliminary Trials on Nanobots and Its Mechanism
In 2013, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology along with some of its partner organisations and institutes designed Injectable Nano-Network for Glucose-Mediated Insulin Delivery. Their system consists of a gel-like structure with a texture similar to toothpaste. The gel contains a mixture of oppositely charged nanoparticles that attract each other, keeping the gel intact and preventing the particles from drifting away once inside the body. Using a modified polysaccharide known as dextran, the researchers designed the gel to be sensitive to acidity. Each nanoparticle contains spheres of dextran loaded with an enzyme. Glucose can diffuse freely through the gel, so when sugar levels are high, the enzyme produces large quantities of gluconic acid, making the local environment slightly more acidic. That acidic environment causes the dextran spheres to disintegrate, releasing insulin.
In 2012, scientists at the Wyss Institute at Harvard University loaded fluorescent-labelled antibodies against human leukocyte antigens into the nanobots to make them bind to the cancer cells in particular. On detecting the target proteins, the bots would release the payload. Also, in a major advancement in nanomedicine, Arizona State University scientists, in collaboration with researchers from the National Centre for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences, have successfully programmed nanorobots to shrink tumours by cutting off their blood supply.
Recently, researchers at the California Institute of Technology have built nanobots which could sort and deliver the drug. The bot consists of three parts - a “leg,” a “hand” with an “arm” which carries the drug and delivers it. There is another component which directs the delivery of the drug. Due to its shape, the bot looks as if it is crawling when it moves. Although these bots were built without any particular purpose, they have a very good application in cancer treatment.
Scientists have lately built up nanobots that deliver thrombin, an enzyme which clots the blood that goes to the tumour and thereby destroys the tumour. This trial has given hope that nanobots are safe enough and can be used as an effective cancer treatment method.
Advantages
The speed and durability of the bots are its main advantages. Use of nanobots can omit human error and readings obtained will be highly precise and accurate. Presence of sensors in the blood stream itself for a long period of time will reduce degree of invasiveness, hence avoiding the chances of getting an infection. Nanobots will serve as a faster, smarter and a highly sensitive diagnostic tool. Once the nanobots enter the human body, they can be programmed to do other tasks and cure other diseases as well. Therefore, they serve as a complete package for tackling a disease, starting from its diagnosis and regular monitoring to its potential treatment, with the intelligence of a human via its programming and accuracy of a machine.
Disadvantages
Nanorobotics is still an upcoming technology and more research needs to be done to make precise predictions of models and to measure its drawbacks and limitations. Designing something at such a small scale is a very tedious task and will require loads of human effort apart from advance tools, resources and large capital. Injecting foreign particles into the bloodstream will trigger a counter response by the body. Hence, the design and functionality of the bot has to be in such a way that it doesn’t affect normal body functioning, hence escaping the body’s immune response. As all the operations will take place inside the body, there is no room for malfunctioning and its actions should be highly accurate. After all, Nanobots are machines which are programmed to perform a specific task and un-ethical use of them by terrorist and hackers make them a potential bioweapon. So, this raises concerned safety issues which poses a serious question to the researchers. Also, if nanobots self-replicate at an uncontrolled rate, a harmful version of the bots could be created. There have been several talks regarding the toxicity of the bots and their disposal methods.
Conclusion
In this paper, we devised a new and an effortless method for continuous blood sugar monitoring. Keeping a track of Glucose levels has always been a tedious task for people having diabetes. They need to prick their fingers regularly and suffer the pain of those needles and syringes, with the danger of getting an infection back of their mind. These nanobots will ease the process to check for blood sugar level and will provide highly accurate results. All the assumptions made and proposals are based on the previous developments done by researchers in different parts of the world and are subject to further research and trials.
If the trial succeeds, then nanotechnology will be a breakthrough in medical studies. If this technology is used as a replacement for the current treatments, side effects can be prevented. Scientists are also into trying acoustic communication among nanobots so that they coordinate and act on the specific site. Although they are still in the research and development phase, their potential is innumerable. Nanorobots should help, through medical target identification, to improve diagnosis and provide new therapeutic procedures. In the long run, nanotechnology will clearly open up many routes to treatments and cures for diabetes, as it will for many of the diseases and conditions that currently plague mankind. Whilst some of these technologies are quite far-fetched, there is evidence that we will see significant advances in the treatment and management of diabetes quite soon.
Future Perspectives
In the future, medical treatment will expand enormously, reducing the risk and cost because of development in the field of molecular nanotechnology. The idea described here can be expanded to tackle treatment as well. As the basic mechanism remains same for manufacturing of a nanobody, this bot can be further programmed to diagnose other parameters as well. With more trials and research, we will see these bots making a huge impact in the medical field. The bots are expected to reach the common man within 5 years.
