dmicroprosthetic Implant for the Treatment of Erectile Dysfunction

Transcription

1 dmicroprosthetic Implant for the Treatment of Erectile Dysfunction Robert Douglas and Matthew Schwartz Biomedical Engineering, Vanderbilt University Senior Design Advisor: Franz Baudenbacher, Ph. D. April 27, 2010

2 Abstract Erectile dysfunction is a disease that plagues men across the country. Currently there are many different treatment options for the problem, but none offer a biomimetic solution. Remedies such as Viagra and Cialis must be taken far in advance. Implants like penile prosthetics require an invasive surgery that shows no remorse for the testicular region. In order to restore the quality of life some of these men have lost, we propose a novel drug delivery device. This device has been fabricated using Medtronic's IsoMed constant flow pump as the driving force of the drug delivery system. Unfortunately, after designing a circuit and equipping the pump with two Lee series 120 nozzles it was discovered that the pump's 1ml/day flow rate was not fast enough. In order to permit for a.2ml injection per erection the pump must deliver at 1728 ml/day. Capillary tubing within the device is used to restrict flow. It was calculated that by changing the diameter of the capillary tubing to 1ml I.D., the desired flow rate would be achieved. A microcontroller was programmed and assembled in order to best demonstrate the basic concept of the device's signal filtering process. The microcontroller successfully filters out accidental pushes by forcing the user to press the pushbutton three times within ten seconds in order to activate the valves. If a third push is not achieved within 10 seconds, the device falls to sleep and becomes dormant, an energy efficient process. Due to the inability to achieve the desired flow rate; the valves output was significantly different than expected. It took ~4.8 hours to administer a dose that should have taken seconds.

3 Pathophysiology of Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to sustain an erection suitable for satisfactory sexual intercourse. 1 The physiological mechanisms that cause ED are variable and occasionally complicated by the fact that causes may overlap. However, prior to discussing the causes of ED, it is important to have an understanding of the physiology of penile erection and Figure 1. The corpus cavernosum receives vascular supply from the dorsal artery and the cavernous branch of the internal pubic artery. 4 detumescence (the return of the penis to its natural flaccid state). The key anatomy in achieving erection is the penile erectile tissue. This includes the cavernous smooth muscles as well as the smooth muscles of vascular walls in the penis as seen in Figure 1. In the natural flaccid state, these smooth muscles remain constricted. This effectively limits blood flow in the penis to be satisfactory for nutritional purposes without sustaining an erection. 2 This low blood flow is evidenced by a blood partial pressure of oxygen (PO2) of approximately 35 mmhg in the flaccid state. 3 Upon sexual stimulation, the release of neurotransmitters from the cavernous nerve terminals yields relaxation of these smooth muscles, thus triggering a series of events that leads to erection. With the smooth muscle relaxation, the arterioles and arteries to the penis dilate, allowing for increased blood flow to the corpus cavernosum. Simultaneously, incoming blood is trapped by the spongy cavernosum tissue, and venous outflow is reduced to a minimum level through compression and occlusion

4 of the local venous structures. This leads to an increase in PO2 levels to approximately 90 mmhg. The physiology of detumescence involves a reduction in pressure through the return of venous outflow. 2 Knowledge of the neuroanatomy and neurophysiology involved in penile erection is also crucial to understanding the mechanisms of ED. Penile innervation involves both the autonomic and somatic nervous systems. The sympathetic and parasympathetic nervous systems are contained in the cavernous nerves. These nerves enter the corpora cavernosa and are primarily responsible for the neurovascular events of both erection and detumescence. Meanwhile somatic innervation of the penis, achieved with the dorsal nerve, is responsible for sensory function and conscious contraction of the local muscles. The exact paths that these nerves take to reach the penis are important because they dictate what sort of injuries or procedures can adversely affect erectile function. The autonomic innervation of the penis stems from the pelvic plexus as shown in Figure 2. Branches from the pelvic plexus also innervate the rectum, bladder, prostate and sphincters. As such, the cavernous nerves can be damaged easily in radical Figure 2. Different views of the autonomic innervation of the penis show the location and physical path of the cavernous nerves. excision of these organs. These autonomic pathways are responsible for carrying the cerebral impulses to signal erection. 2

5 However, there is also evidence that there is a reflex involving the somatic pathways that can stimulate erection without cerebral processing. 5,6,7 Animal studies have shown the medial preoptic area as well as areas within the hypothalamus and hippocampus to be major integration centers for male sexual function. 8,9 Erectile function is also dependent on the molecular mechanism of smooth muscle contraction and relaxation. The level of contraction or relaxation of the smooth muscle is primarily regulated by cytosolic Ca 2+ levels. The binding of free Ca 2+ to calmodulin causes on conformational change that exposes sites to myosin light chain kinase. This process catalyzes phosphorylation of myosin light chains, developing force along the actin filaments. There are also calcium sensitizing pathways that act when the cytosolic Ca 2+ returns to basal levels. Figure 3 shows the detailed signal pathways involved with penile smooth muscle relaxation along with several ED treatment drugs, such as papaverine and sildenafil, and their respective pathway effects on the overall signal pathways. These drugs, called phosphodiesterase type V inhibitors, work by circumventing certain parts of this signal pathway, thus forcing smooth muscle relaxation and increasing the likelihood of achieving erection. 2 The pathophysiology of ED is complicated by the fact that there are several causal mechanisms that can overlap to cause ED. As such, ED is typically broken down into categories for classification. These classifications primarily include psychogenic, neurogenic, arteriogenic, and venogenic causes, but there may be other more specific causes for individual cases of ED. 2 Figure 4 shows a classification system recommended by the International Society of Impotence Research.

6 Psychogenic impotence, being caused by the brain, was previously believed to be the most common type of ED.11 The mechanism of psychogenic impotence is likely rooted in the limbic system, the hypothalamus, and the cerebral cortex, which control sexual behavior and penile erection. Thus in psychogenic impotence, it is possible that either the brain is sending excess inhibitory signals, or there could be a chemical imbalance issue.12 In either case, it has been Figure 3. The chemical signal pathways involved in penile smooth muscle 10 relaxation can be bypassed by certain drugs. demonstrated that cerebral control plays an important role in achieving erection. Estimations of the percentage of ED cases related to neurogenic causes range from 10 to 19%.13,14 There may also be a significant portion of neurogenic ED in the population that is iatrogenic (caused by a physician). As previously mentioned, the cavernous nerves are in very close quarters with the rectum, bladder, and prostate. As such surgical techniques performed in this area on these other organs can cause peripheral damage to the cavernous nerves, causing varying degrees of ED. Diseases or trauma occurring in the brain or spinal cord can also cause significant ED depending on type and location. Damage to the peripheral sensory nerves can reduce the potential for reflexogenic stimulation, which is an important factor in achieving erection. Being that erection is a neurovascular event, essentially any neurological damage

7 along the stimulation pathway can cause ED if the stimulation signal is not transmitted properly. 2 Arteriogenic causes of ED reflect the inability to get sufficient blood flow into the penis in order to achieve erection. Factors such as atherosclerosis or occlusion of vasculature can limit blood flow into the penis. There are also several diseases and behavioral factors that have high correlation with ED, likely due to their effect on blood flow such as hypertension, cigarette smoking, diabetes mellitus, and pelvic trauma When the vasculature of the penis is compromised, the normal stimulation from the nerve signals may not be enough to cause satisfactory vasodilation. Similar to arteriogenic ED, if there is not adequate venous occlusion after blood has entered the penis, there will be venous leak and an erection will not be sustained. Venous leak can stem from large venous channels, degenerative changes such as Peyronie s disease, traumatic injury, and inadequate expansion during the filling stages. The reason that inadequate filling also leads to venous leak is because the filled tissue in turn occludes the venous outflow. 2 The treatment methodology of our proposed device specifically targets the neurologic and arteriogenic causes of ED. Hopefully, by treating the ED in this fashion, the venogenic causes will be overcome through adequate filling which causes Figure 4. The medication injected dilates the arteries of the penis and allows blood to flow in. Depending on the drug used, an erection occurs anywhere from 5 to 15 minutes after injection. 33 venous occlusion. Current Treatment Methods

8 This device implements existing technologies in an attempt to correct a physiological problem plaguing men all over the world. Utilizing MEMS technology as well as the proper drug and drug dosage, this device proposes a potentially non invasive biomimetic solution to ED. Today, there are many different treatments for erectile dysfunction, but amongst these treatments there are no devices and or drugs that can initiate an erection without the patient s triggering of an event. Such events include taking drugs, using Figure 5. The three piece internal penis pump is the most technologically advanced penile implant. Urologists consider the 3 piece inflatable implant to be the "gold standard" of penile implants. 21 injections, using pumps, and receiving penile implants. The most commonly used erectile dysfunction drugs are Viagra, Cialsis, and Levitra. These drugs are effective in triggering the onset of an erection, but do not provide an immediate response to sexual stimulation. Additionally, drugs that are ingested orally require a much larger dosage compared to the minimum amount needed to stimulate the target. By utilizing a local drug delivery system, higher concentrations in the form of smaller dosages can be administered at the site of the target site. 18 A common method of local drug delivery comes in the form of injections to the corpus cavernosum. As shown in Figure 4, the injection is placed in a general location, whereas an implantable device will be able to administer drugs to a much more specific site. The three most common injections are papaverine hydrochloride, phentolamine, and prostaglandin E1. These drugs are very effective, but men do not enjoy the thought of sticking a needle into their

9 penis. These drugs can also leave scarring at the injection site, as well as contribute to prolonged and uncomfortable erections. 20 A more invasive strategy for some men is the penile implant or prosthesis. Such devices are either malleable or inflatable. The simplest form consists of a pair of bendable rods that are surgically implanted within the corpora cavernosa. This type of implant causes the penis to have a permanent semi rigid state, and requires that the penis be lifted or adjusted into the erect position in order to proceed with intercourse. Alternatively, many men choose a hydraulic, inflatable prosthesis. The hydraulic prosthesis involves a serious surgery requiring general anesthesia, and weeks of recuperation. These prostheses are implanted in 20,000 30,000 men annually worldwide. 19,20,21 The hydraulic implant (Figure 5) has a 95% success rate, but involves the use of a mechanical pump to achieve an erection. A less invasive and more tabooed solution involves a vacuum constriction device or a penis pump. In contrast to implantable devices and pumps, some surgical techniques have been performed in order to increase direct blood flow to the penis. This surgery is referred to as vascular reconstructive surgery, and is technically difficult, costly and not always effective. 22

10 Our described device incorporates aspects from three existing erectile dysfunction treatments. The device takes the effectiveness and speed of injection based drugs, resides within the body like the prosthetic implant, and delivers a small and precise quantity of a favorable a drug to promote an erection just as Viagra does. Design: Proof of concept: In order to fully understand the concept of constant drug Figure 6. This block diagram shows that the dorsal nerve of the penis bears responsibility for transmitting sensory signals. However, these signals can still be used to trigger drug release with this device. 24 delivery, a constant drug delivery device was fabricated. In order to accomplish this, a siphon bladder was placed within a sealable container. One input of the bladder was connected to a one way valve (bike tire valve) and the other was connected to a latch valve. On the upper casing of the sealable container existed another one way valve that allowed for the device to be pressurized. In order to refill the siphon bladder a handheld bike pump was use. In order pressurize the vessel; the same hand pump was used. In order to properly seal all leaks and holes extra strength epoxy was used. Prototype:

11 In an effort to reduce costs and FDA testing time, Medtronic's IsoMed pump was utilized for constant drug flow delivery. Attached to the device is.04" silicone tubing. The tubing splits into two by means of a polycarbonate Y connector with 1/16 openings. The tips of the Y connector are each fastened with a single 5V series 120 Lee valve. The valves are controlled via a parallax bs2 Microcontroller, a 6V battery and a silicone coated push button. The microcontroller is inherently in a dormant state, optimizing power consumption. Once the use clicks the pushbutton the processor awakens and searches for more impulse. If the user presses the pushbutton three times within ten seconds, the microcontroller sends an impulse to both valves. When the valves receive an impulse, the pressurized fluids are released to the site of target. The microcontroller is embedded on a 2" OD PCB board, and has one input (the button) and two outputs (the valves). The embedded chip is housed within a 3" aluminum casing. Two separate microcontrollers were built, one that most accurately depicts the filtering process and another that can be used for demonstration purposes. The parallax controllers were programmed in basic and contained roughly 50 lines of code. The microcontroller has basic functions that make programming 7 segment displays fairly simple. In addition to the mechanical design of the system, the IsoMed pump was filled with a potent and effective drug called papavarine. Papavarine's shelf life and effectiveness make it a prime candidate for use in the device. Results:

12 Because the prototype devices that we obtained did not match our specified flow rate, it would not have been helpful to determine the accuracy of this prototype. Instead we focused on calculations that would help show that it would be feasible to modify the IsoMed pump to meet our requirements. To do so we used the Hagen Poiseuille equation. This equation is crucial to the flow rate of the pump because there is a long piece of capillary tubing inside the pump that restricts the flow. We wanted to show that removing or altering this piece of tubing could theoretically increase the flow rate to our desired dosing level. To do so, we called Medtronic to determine the specifications of the capillary tubing. They were able to provide us with the length of the tubing, but we had to estimate the radius. The results of these calculations are in the table below: As can be seen, by dramatically reducing the length of the capillary tubing and slightly increasing the radius, the flow rate of the IsoMed pump could be easily adjusted to meet our specifications. The other feasibility process we completed was to estimate the total energy

13 consumption of the device over ten years. By estimating the microcontroller s energy consumption during both sleep and run times and the energy draw of the two Lee valves, we were able to determine that over the course of 10 years the device would consume approximately 80,000 J. We believe this shows the device is feasible for a few reasons. First, these calculations were approximated with devices that are not optimal for long term low power consumption. Second, we think that a lithium battery could potentially provide this long term power source. Third, there are currently implantable devices such as the implantable pacemaker that consume similar amounts of energy and have roughly 10 year implantable lifespans. Costs: This project requires the use of a Medtronic IsoMed pump ($5900), two Lee company series 120 valves ($150/each), a parallax BS2 Microcontroller ($40) and various miscellaneous tubing (<$20), amounting to a total cost of $6220. In order to significantly cut costs we contacted medtronic and tried to convince them that we could use their technology to solve other worldly issues. Medtronic liked our hypothesis and sent us two IsoMed models, one new and one used. We used this same tactic when contacting The Lee Company, and to our surprise they sent us the valves for free. Additionally, Dr. Milam from Vanderbilt's Urological Center gave us a mechanical prosthesis ($7000) in order to demonstrate the benefits of our device. We received roughly $19,100 if you take into consideration all of the products that were sent to us for free.

14 Market Size and Potential Market Share Capture Treatments for erectile dysfunction (ED) fall under the healthcare sector of men s health, which in 2005 had a total world market size of $19.5 billion. Additionally, this market size is predicted to grow to $26.1 billion, or a 5.9% increase, by Factors such as a Table 1. Both the prevalence and incidence estimations for ED are promising for growth in the ED treatment market. It is also important to consider that there may be a general underreporting of ED both in the United States and worldwide. 18 generally increasingly older population, men s health awareness, and societal factors, may all play a role in this trend. Table 1 shows the estimated prevalence and yearly incidence of ED in the world and specifically the United States, and the figures are staggeringly large. Drug therapies such as Viagra, Cialis, and Levitra have dominated the ED treatment market, which in 2005 totaled $3.1 billion. This market size is expected to grow at a rate of 6.5% annually through With the three primary treatment methods currently in existence being oral pills, injection therapy, and penile implants, it is important to identify the market share that each of these treatments has in the ED treatment space. This will help us estimate what sort of market share our device could potentially capture. As of 2005, oral pills, specifically phosphodiesterase type V inhibitors (PDE 5 inhibitors) such as Viagra, Cialis, and Levitra, dominated the market. These PDE 5 inhibitors represent roughly 90% of the ED treatment market, or approximately $2.8 billion in However, as new therapies arise in ED treatment, this percentage is expected to decline, but these products still clearly dominate the market. In 2005, other

15 therapies such as injections and implants totaled only $339 million, and it is likely that injection therapies represent a larger portion of this than do penile implants. 33 As with any new product, the keys to capturing market share are implementation of bringing the product to market, marketing strategies, cost considerations, and competitive advantages. While we are not currently at a development stage where we can consider product implementation or marketing strategies, we can identify some cost considerations and our potential competitive advantages. In terms of cost considerations, our device will benefit from several things. First, gaining coverage from insurance companies and Medicare will likely increase the number implantations performed by reducing the costs to the consumer. Second, our product will see increased adoption of the total cost to the consumer of receiving the implant is less than the cost of paying for prescription PDE 5 inhibitors over the course of the lifetime of the implant. For example, if the yearly cost of a Viagra prescription is $500, and our device has a lifetime of 5 years, then ideally the cost for a consumer to receive the implant would be no greater than $2500 ($500 x 5 years). Obviously from this relationship, the longer the device lifetime can be extended, whether through increased reservoir size or easy refillable access, the more cost advantageous the device becomes. We do believe that our device, if it works as planned, offers several competitive advantages over all other treatment options. When compared to PDE 5 inhibitor pills, this implant would improve patient compliance by removing all patient responsibility to administer their dosage. Additionally, the implant would improve patient s experience compared to pills as erection is achieved without any preplanning. However, there is a major drawback with

16 transitioning from pill treatment to this implant in that implantation requires a significant surgical procedure. Transitioning from injection therapy to this implant would likewise improve patient compliance and reduce risk from injection injury. Still, there is the drawback of surgery. Current penile implants also require a surgical procedure, which is generally more invasive than our proposed implantation procedure. Additionally, our implant acts as a biomimetic therapy for ED, while current penile implants require mechanical manipulation to achieve erection. Thus, provided our implant works as designed, the only foreseeable drawback of our device compared to current penile implants is a possibly shorter device lifetime. In all cases, it is our belief that this implant will offer the most natural treatment of ED by internally using the body s nervous signals as input and outputting a local vasodilator that will cause erection. Under ideal circumstances, this device will be available to the consumer at cost advantageous prices compared to oral pill therapy, meaning roughly the same as the yearly cost of PDE 5 inhibitors multiplied by the yearly lifetime of the implant. If this is the case, we believe that this implant offers considerable advantages over all other therapies with the one major drawback being surgery. As such, it is our feeling that this device has the potential to capture market share from all competing therapies. Assuming the device is produced successfully, obtains FDA approval, and is adopted by surgeons as an acceptable treatment, we can estimate initial revenue streams. In order to capture just 2% of the market share from the PDE 5 inhibitor market, 120,000 implants would need to be performed. This comes from the assumption that a year s supply of PDE 5 inhibitor drug costs $500 and the total PDE 5 inhibitor drug market is approximately $3 billion. This makes for approximately 6 million patients, and 2% of 6 million is 120,000. A 2% market capture of the PDE 5 inhibitor drug market also

17 represents yearly revenues of roughly $300 million ($500 yearly cost of prescription drugs x 5 year device lifetime x 120,000 implants). If 10% of the remaining injection and current implant market, valued at roughly $400 million, can be captured, then this would translate to an additional revenue stream of approximately $40 million. The reason that we assume greater market capture in this part of the market is because the switch from injection or current implant to our implant is less dramatic than the switch from oral pills to a surgical implant. Hopefully over time though, the surgical technique will be perfected and shown to be minimally invasive and effective, and then the market capture of the PDE 5 inhibitor drug market will grow. References 1 National Institutes of Health Consensus Development Panel on Impotence: Impotence. JAMA, 270: 83, Robert C. Dean, MD and Tom F. Lue, MD. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am November ; 32(4): 379 v. 3 Sattar AA, Salpigides G, Vanderhaeghen JJ, et al. Cavernous oxygen tension and smooth muscle fibers: relation and function. J Urol 1995; 154: Human Anatomy. Gray s Anatomy on < anatomy/the_penis.html>. 5 Burnett AL, Tillman SL, Chang TS, et al. Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol 1993; 150: 73.

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