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Reverse iontophoresis is a process in which molecules are removed from within the body via a negative charge on the skin that causes solvent flow towards a cation9. This process has already been extensively used as a monitoring device and is recognizable in the commercial device known as the GlucoWatch9.? Reverse iontophoresis has also been proven to effectively monitor urea and potassium in in vitro experiments.
When low amplitude current is applied to the skin, the barrier properties are altered, which allows for transport of molecules through the skin.? Potassium is a positively charged molecule and moves towards the cathode via electro-migration.? Urea, on the other hand, is an uncharged molecule6 and moves towards either the cathode or anode through a process called electro-osmosis, which is where an EMF is created by an applied potential that drives the flow of the molecule2 (Figure 1). A major benefit of this process is that it is non-invasive and can be completed in its entirety on the surface of the skin.
Up to this point, reverse iontophoresis has been used primarily as a monitoring mechanism.? However, since small amounts of molecules are already removed in order to monitor the concentration of molecules in the blood, it is logical to extrapolate that reverse iontophoresis could be used to perform the same function as a dialysis machine.? This conclusion leads us to hypothesize that reverse iontophoresis can efficiently perform the task of a dialysis machine in a non-invasive manner.
While it might seem like reverse iontophoresis could be a saving grace from invasive procedures, there are several downsides to the current procedure.? One necessary improvement is the application time.? Current dialysis takes three to five hours for the procedure itself, not including travel time, and reverse iontophoresis has a lag time of approximately fifteen minutes12.? This lag time, although small in comparison, needs to be reduced to only a few minutes.? In addition, there is an issue of safety with the actual device.? While increasing the current will decrease the lag time, a current of 17 to 99 mA is sufficient to kill a human being17.? Finally, the accuracy of the device, while already quite good, needs to be improved before reverse iontophoresis can potentially replace dialysis.

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A1) Importance: Current methods of kidney dialysis are invasive and very time intensive for the patient. The use of reverse iontophoresis is non-invasive and has the potential to dramatically reduce the amount of time necessary for treatment. As of 2008, there were over 380,000 people in the US being treated for end stage renal disease (ESRD) at a cost of almost $40 billion11.? The vast majority of those diagnosed with ESRD were treated with dialysis, the most common method being hemodialysis.? With hemodialysis, an artificial kidney called a hemodialyzer is inserted into the body and connected to blood vessels with either a catheter or fistula (Figure 2). ??Then, three times a week for four to five hours, the patient must be hooked up to a dialysis machine so the blood can be cleaned and filtered.? The only alternative to traditional dialysis is peritoneal dialysis.? With this type of dialysis, you either insert a bag of dialysate into your peritoneal cavity, where it stays for four or five hours before being drained (Continuous Ambulatory Peritoneal Dialysis (CAPD)), or hook up to a machine called a cycler at night (Continuous Cycling Peritoneal Dialysis (CCPD)).? The CAPD method needs to be done four to five times a day and the CCPD method needs to continuously cycle overnight12.
Even once the hemodialyzer is inserted into the body, one cannot have a totally normal life like most others.? Already mentioned was the necessity to have dialysis treatments performed on a weekly basis.? For those diagnosed with ESRD, these treatments will continue for life because dialysis is not a cure to kidney disease; it merely keeps one in healthy condition until a donor kidney is available.? In addition, patients on dialysis could have side effects directly from the dialysis treatments, may need an altered diet, and may need to find a new job or career if their previous job required heavy lifting12.?
Some progress has been made in the portability of dialysis machines, however. The company NxStage Medical has designed a portable dialysis unit that looks almost like a briefcase14.? An immediate detriment to the unit is that the patient still needs to be tethered to the unit for dialysis to be performed, and the company is unsure of the long-term user costs.? Another breakthrough has been the Wearable Artificial Kidney (Figure 3), which allows dialysis to occur continuously for twenty-four hours a day, seven days a week13.? The downsides to this device include the fact that the patient has to continually wear the device, the device weighs ten pounds, which may be heavy for someone who has other medical issues, and the long-term side effects are unknown. ??However, both of these devices show promise for the future of portable dialysis units.
A final issue with the current method of kidney dialysis is the life expectancy. ?The five year survival rate for those on kidney dialysis is only 34.5% and the ten year survival rate drops to 10.5%11.? Clearly, there is a need for a quicker, more effective and cost efficient method of removing wastes from the body when the kidneys cannot.? A method that has the potential to do this is reverse iontophoresis.
A2) Critical Barriers: Currently the use of reverse iontophoresis has been predominantly relegated to matters involving glucose levels in the body. For the method of reverse iontophoresis to be applicable as an alternative for kidney dialysis, its use as a technique of urea removal must first be proven. In a previous study, reverse iontophoresis was used on the forearm of five healthy individuals and eighteen patients with chronic kidney disease1. The purpose of reverse iontophoresis in this application was to monitor blood urea levels without using invasive testing methods. It was determined through this study that it is possible to remove urea through reverse iontophoresis, and the concentration of urea present at the cathode of the iontophoresis controller (Figure 4) was linearly correlated with plasma urea. ??Due to the fact that urea removal from the body was successful in this study with a current of only 250 ?A for two hours, it seems plausible that by increasing the current of the controller, the concentration of urea removed from the body can be scaled up accordingly1.
Other barriers for the use of reverse iontophoresis as an alternative to kidney dialysis include the properties of the skin and safety issues regarding the application of an electric current to the skin. As mentioned previously, a current in the range of 17 to 99 mA can kill a human being so the reverse iontophoresis device must operate under this range17.? Not only must the current be held under this range, but there is also the psychological issue of having a current on one?s skin that must be overcome in order for a reverse iontophoresis device to be applicable. According to OSHA, a current of at least 5 mA can be uncomfortable to a human and the current used in the device should be under this value as well17. The final barrier is that the pH of the skin must be kept around a neutral value of 7.4 in order for reverse iontophoresis to be successful. This neutral pH is necessary as changes in pH can affect both the permeability of the skin and the ionization state of the solutes which the device is attempting to remove2.
A3) Improvement of Scientific Knowledge: Through investigation of the applicability of reverse iontophoresis as an alternative for kidney dialysis a greater understanding of the overall process will be achieved and its compatibility for other treatment types can be assessed. While dialysis has been an effective solution to renal failure, other methods should be encouraged as a better alternative to the present system.? One such method, reverse iontophoresis, is a non-invasive and convenient technique to draw certain substances in bodily fluids out through the skin.? Today, it is currently being utilized as a method to monitor glucose levels in diabetic patients? blood.? Potentially, it can reduce the presence of the urea, potassium, phosphorus, and other constituents of the patient?s blood to levels similar to that of existing dialysis processes.? In addition, reverse iontophoresis could be extended to an unlimited number of capabilities.? Beyond the ability of monitoring glucose levels in the blood, devices could also be invented to perfect regular iontophoresis as a way to send insulin through the skin to regulate the sugar levels in the patient?s body.
B1) Reverse iontophoresis has previously been used as a monitoring system for glucose levels, but its application as a method of removing molecules from the blood has not been investigated. Currently, reverse iontophoresis is successfully utilized in a glucose monitoring device called the GlucoWatch4 (Figure 5). ??The GlucoWatch uses the process of reverse iontophoresis and sends very low currents through the skin.? This slightly breaks up the skin barrier and allows small of amounts of body fluid to escape.? The GlucoWatch can then measure the amount of glucose in these samples and provide a blood sugar reading9.? The advantage of this method over the traditional method of measuring blood sugar is that the GlucoWatch is non-invasive and does not require the pricking of a finger and it can monitor blood sugar over the course of twelve hours7.? Tests have shown that the GlucoWatch is safe for children older than seven and that the GlucoWatch is just as accurate as traditional methods9.? While this is promising, the process of reverse iontophoresis in this case has only been used as a monitoring mechanism, not as an active filtration mechanism.
B2) Reverse iontophoresis has the potential to be an at-home treatment versus the traditional method of kidney dialysis, which is usually administered at the hospital. Due to the GlucoWatch successfully utilizing reverse iontophoresis in a passive manner, it stands to reason that reverse iontophoresis can be used in a more active role.? Studies have shown that reverse iontophoresis can successfully remove urea, which is a waste product of the body, from the blood1.? Once again, however, this study was not done as a long-term treatment model.? Our group believes that reverse iontophoresis can be extrapolated to the point where it is used in place of kidney dialysis.? Typically, 500 ?A of current are sent through the skin when reverse iontophoresis is used in a monitoring capacity2.? However, this value can be increased several times before a patient would feel pain (current in the range of 17 to 99 mA is considered enough to be lethal) 17.? By doing so, we hypothesize that urea can be drawn directly out of the blood in a non-invasive manner.? In addition, the time required to do so would be much shorter than a typical kidney dialysis treatment and the packaging of the device would be self-contained so a patient could continue with normal daily activities in a manner not possible with traditional dialysis treatments.? We intend to investigate the practicality of using reverse iontophoresis as an alternative to kidney dialysis as a quicker, more efficient, and cheaper treatment for individuals with ESRD.

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