Patent Ductus Arteriosus Occlusion Device

Patent Ductus Arteriosus Occlusion Device

David Brogan, Darci Phillips and Daniel Schultz

Department of Biomedical Engineering

Vanderbilt University

April 22, 2002

Advisor: Dr. Thomas Doyle

Assistant Professor of Pediatrics, Pediatric Cardiology

Vanderbilt University Medical Center

Instructor: Dr. Paul King

Associate Professor Biomedical and Mechanical Engineering

Vanderbilt University

TABLE OF CONTENTS

21. ABSTRACT

32. INTRODUCTION

32.1 The Patent Ductus Arteriosus (PDA)

42.2 Current Treatments

82.3 Design Goals

93. METHODOLOGY

93.1 Background

103.2 Initial Work

123.3 Prototype Development

134. RESULTS

134.1 Preliminary Tests

144.2 Safety Analysis

164.3 Market Analysis

164.4 Device Patenting

174.5 Economic Analysis

195. CONCLUSIONS

206. FUTURE WORK AND RECOMMENDATIONS

207. ACKNOWLEDGEMENTS

208. REFERENCES

22Appendices

1. ABSTRACT

Patent ductus arteriosus is the persistence after birth of an in-utero shunt from the pulmonary artery to the aorta. To correct this deficiency, an elective procedure is performed at five to ten years of age to close the hole. Current treatment involves catheter insertion of fibrous coils into the duct, relying on endothelialization to completely occlude flow. This project sought to build on two previous groups’ efforts to design an alternative closure device. The final design involves a mushroom shaped foam device held rigid by the insertion of a Nitinol backbone. Biocompatible materials were investigated, specifically a polyurethane foam and resulting prototypes built out of silicone and foam. Both pressure and flow tests were performed on both prototypes to measure their efficacy at occluding flow. The foam device proved to be more compressible and easier to insert, but does not completely stop the flow of water. The silicone completely stopped the flow of water, but did not compress fully into the catheter. A polymer specialty firm (PTG) has been contacted to make a certified prototype out of a custom foam and initial steps have been taken in the application for a patent.

2. INTRODUCTION

2.1 The Patent Ductus Arteriosus (PDA)

The ductus arteriosus is a normal fetal structure, connecting the pulmonary artery and the aorta. Prior to birth the fetus receives oxygen through the mother’s placenta, as his/her lungs are not yet fully developed. Therefore, the ductus arteriosus allows blood to bypass the nonfunctioning pulmonary circulatory system and enters the systemic circulatory system. At birth the placenta is removed when the umbilical cord is cut, the baby begins to breathe on his/her own, and the blood supply to the ductus arteriosus decreases dramatically. As a result the ductus arteriosus closes within 15 hours of delivery [5]. However, if it fails to close within three months of birth, patent (open) ductus arteriosus (PDA) occurs and blood continues to flow from the aorta to the pulmonary artery (Fig. 1).

PDA accounts for 10-12% of all congenital defects and has an estimated incidence of more than 20,000 cases in the United States alone [3]. Additionally, PDA occurs twice as often in girls as in boys. Although the causes of PDA remain unknown, this condition is seen more often in premature infants and infants born to a mother who had rubella (German measles) during the first trimester of pregnancy [11]. Some congenital heart defects may have a genetic link, either occurring due to a gene defect, a chromosome abnormality, or environmental exposure, causing heart problems in certain families to increase [9]. However, PDA typically occurs sporadically, with no clear reason for its development.

Depending on the size and impact of the PDA on the circulatory system, this condition may result in many adverse effects. When the ductus arteriosus remains open, oxygenated blood passes from the aorta to the pulmonary artery, mixing with deoxygenated blood already flowing to the lungs. The effects of this altered circulation may be life-threatening due to pulmonary over-circulation, which may lead to an increased lung workload and fluid in the lungs [11]. Since the PDA creates a hole in the aorta, the pressure in the aorta decreases dramatically. Consequently, there is an increased workload on the heart and an increased risk of congestive heart failure over time [3]. Additionally, the PDA increases the volume load on the left atrium and ventricle of the heart [3]. Furthermore, because the blood is pumped at high pressure through the PDA, the lining of the pulmonary artery becomes irritated and inflamed. Bacteria in the bloodstream can easily infect this injured area, causing a serious illness known as bacterial endocarditis [9].

The size of the PDA (ranges from 2-8 mm, average of 3.1 mm) affects the type of symptoms noted and the severity of the symptoms. A child with a small PDA may reveal a continuous heart murmur, while infants with a larger PDA may exhibit different symptoms; the most common being fatigue, rapid, heavy or congested breathing, a lack of appetite, poor weight gain, and growth retardation [14].

2.2 Current Treatments

Multiple treatments for PDA have been developed, including drug therapy, surgery and implantable devices. Indomethacin is the most commonly used intravenous medication for treating PDA. A relative of aspirin and ibuprofen, indomethacin, works by stimulating the muscles inside the PDA to constrict, thereby closing the connection [6]. This is typically the first method physicians try. It is a safe alternative to the more invasive procedures, such as surgery and the use of implantable devices, especially for premature infants.

Surgical ligation, where the PDA is tied at both ends and cut in the middle, is another available treatment option. Although this method represents the “gold standard,” it is the most invasive option (performed thorascopically) and can therefore be traumatic for small children and infants. The mortality rate for this procedure is negligible; however, the morbidity of anesthesia and thoracotomy, scaring from the surgery and the expense ($20,000) are significant disadvantages [13]. A chest tube is required for at least 24 hours, and causes further discomfort. Additionally, the patient is generally hospitalized for a week, with an expected recovery period of six to eight months.

Non-surgical closure of PDA has become more common, as it is a less invasive intervention and can be done with local anesthetic and sedation. There has been an improvement in implantable devices over the past ten years, with devices now being delivered through catheters as small as 4 French (4F) [5],. As noted the anatomy of PDA varies considerably in size and configuration. Where a diameter is described, it arbitrarily refers to its narrowest segment, which is smaller than 4 mm in 78% of cases [4]. PDA’s have been classified into five types, the most common being Type A, where the ductus arteriosus is funnel shaped with a narrowing at the pulmonary artery junction. Type B is the next common, and is funnel shaped with an aortic ampulla (neck). Type C is tubular, Type D is oval shaped with aortic and pulmonary ampulla, and Type E refers to other rare forms [11]. These different types of PDA’s are identified by a chest x-ray, electrocardiogram or an echocardiogram [11].

Some forms of occlusion devices are more ideal than others for the various types and sizes of PDA. The first device to gain widespread popularity for the occlusion of PDA was developed by Dr. William Rashkind in the 1980s. Though never approved by the FDA for use in the United States, this device is still in use in foreign countries. The Rashkind double umbrella is made up of two tiny sponge umbrellas that are attached to one another. When positioned correctly, the device is astride the PDA, with one umbrella on the aortic side of the PDA and one on the pulmonary artery side. The size of each umbrella is larger than the orifice of the PDA, so the device cannot move. The umbrellas become coated with blood and quickly become non-porous. Eventually natural tissue lining of the blood vessels will grow to cover the device. The standard device size has a diameter of 12 mm. This device was quite successful in closing small PDA's (> 90% success rate), but was limited by the large catheter sizes (8F-11F) required for delivery [8]. This precluded its use in small children, and in 1992 it was removed from trials in the US. Furthermore, since this device is priced at $2500, its application is limited among low income families and less affluent countries.

The Porstmann Plug (or Ivalon plug) is a trans-catheter closure device invented and used around the same time as the Rashkind double umbrella. This device consists of a polyvinyl chloride plug on a stainless steel umbrella fame and is delivered via a catheter. Although clinically effective, an 18F catheter is required for delivery, preventing wide acceptance of the procedure.

Another device used for PDA closure is the Dideris buttoned device. This device consists of a 1-inch square of thin polyurethane foam on a flexible wire that patches holes in children’s hearts. The patch is inserted through the vein in the child’s groin, gently pushed into place by a catheter and secured by tiny buttons. The main advantage of this device is that it can be delivered via a 7F catheter, resulting in minimal vascular damage during delivery [4]. Unfortunately, 29% patients who received this method of treatment experienced a residual shunt [13]. An additional drawback of this device is that it is expensive to manufacture and deliver.

Figure 2

: Control release Cook coil.

The most common devices used at present are Cook coils and the Amplatzer Duct Occluder. Coils can be delivered through catheters as small as 1.3 mm in diameter (4F) [11]. This allows the procedure to be performed on smaller patients, including premature babies weighing less than 5 kg. Gianturco spring coils were the first coil system to be used. These coils are made of surgical steel that has thrombosing fibers interwoven between them, resulting in quick endotheliazation. Although successful, these coils are difficult to adjust or retrieve, increasing the chance of embolization (loss of coil into bloodstream). Currently controlled release coils—Cook coils—have improved the use of coils to occlude PDA’s. These Cook coils, made from stainless steel with Dacron fibers interwoven throughout, (Fig. 2) allow adjustment and positioning of the coil before release, avoiding protrusion of the coil into the vascular lumen that may otherwise result in turbulent flow of blood or obstruction. As the risk of embolization is lower, smaller coils can be used. Cook coils are manufactured with different diameters to fit different PDA sizes—3 mm, 5 mm, and 8mm diameters [10]. Another advantage of these coils is their cost: $65 per coil. Unfortunately, one coil is often not enough. If the PDA is large or oddly shaped, the patient may require 3 or 4 coils [12]. This can create a twisted knot in the vasculature of the patient. Furthermore, if the coils become dislocated, they must be completely removed and a second attempt can be performed once the patient has recovered.

The Amplatzer Duct Occluder (ADO) is a self-expanding mushroom shaped device made from nitinol wire mesh, with a thin aortic retention disc designed to secure positioning in the aortic ampulla (Fig. 3). Although percutaneous closure of PDA using ADO in pediatric patients appears to be a low risk procedure, it is not recommended for use in infants weighing less than 5kg [11]. This is substantiated by failures in implantation and reversion to surgery, reported by several authors [1, 4, 12]. An infant “normally” reaches 5kg by about two months of age, but an infant with PDA may grow slower, and will be older before use of ADO is recommended. Therefore, this device is not suitable for premature babies. Additionally, the ADO has a projected cost of $2500. Since this device is still in the clinical trial phase, no conclusions about its efficacy and safety can be made.

One major disadvantage of the Porstmann Plug, Cook coils, and Amplatzer Duct Occluder is that they are thick and rigid, forcing the PDA to conform to their shape. This causes undesirable stress and tension on the walls of the PDA. Thus, each device must be individually shaped according to the size and shape of the PDA it is meant to occlude.

Examination of the available PDA occlusion devices has established their disadvantages in terms of size, cost and the inability to conform to the shape of the PDA. Thus, the demand remains for a cost-effective device that can be delivered through a small catheter and successfully occlude the PDA.

2.3 Design Goals

Dr. Thomas Doyle, a pediatric cardiologist at Vanderbilt Medical Center and the advisor for this project, provided our group with specifications for a PDA occlusion device during our first meeting in October 2002. The minimal requirements for the device included the following:

· Made from biocompatible materials

· Conforms to the shape of the PDA and causes occlusion

· Be delivered via a catheter <2mm in diameter (6-7F)

· Provide an initial success rate of 100%

· Quick endotheliazation (~1 month)

· Can be easily repositioned

· Cost effective (<$200)

· Simple implantation system

· More patient friendly

The main objective of this project was to create a single device that would conform to a PDA of any shape and size. Therefore, a biocompatible, expandable foam was essential. Two past groups have attempted to create such a device. Neither of these groups was able to locate or create a potential foam that would result in occlusion. Although each group came up with a basic design for the device, we have modified it considerably based upon our new design ideas and experimental tests.

3. METHODOLOGY

Since this project is a continuation of two previous senior design projects at Vanderbilt, and as such, a great deal of the methodology of the project has been written and rewritten over time. Complete understanding of the current design progress requires a requisite knowledge of the efforts made in previous years, thus the progress of these groups will be discussed briefly.

3.1 Background

The first group to work on this device began the project in 1999 with the design of a tapered cylinder made of a biocompatible foam. The cylinder contained a metal core of stainless steel with a set of three feet on each end designed to dig into the surrounding tissue wall and provide stability. The purpose of the foam was to help conform the device to the varying shapes of PDA. Mock simulations of the device yielded encouraging results, increasing pressure in both the pulmonary artery and aorta after device insertion, similar to manual occlusion results in the same simulation [2].

A second group undertook the project in the fall of 2001, refining the design to a mushroom plug shape with surgical steel tubing forming the backbone of the device. Testing was done to determine if the device could withstand the pressure differential between the pulmonary artery and aorta. This prototype was found to provide adequate occlusion at the desired pressure differential. The evolution of the design resulted in the stainless steel coil being curled around the top of the plug to reinforce the foam. The major obstacle encountered by the group involved their inability to locate a suitable biocompatible foam. This obstacle prevented any true prototype development and blocked the hopes of clinical testing [7].

The development of the device throughout the previous three years resulted in a design challenge centered around the procurement of materials and the actual development of the device. Much thought and effort had been put into preliminary investigation and testing of in-vitro models, thus it was decided that the bulk of this year’s project should focus on the acquisition or development of biocompatible materials to implement the preliminary design ideas. To help focus the efforts of the group, a timeline was created outlining the objectives of the project and the estimated time for each. This timeline can be found in Appendix A. During the course of this project, numerous refinements have taken place. As a result, the Innovation Work Bench diagram for this occlusion device has no foreseeable conflicts (Appendix F).

3.2 Initial Work

The patch plug design seemed like a suitable overall shape, but a general brainstorming session still occurred. This resulted in a decision to increase the top of the plug device to make it more closely resemble a mushroom. It was also decided that the stainless steel should be replaced with Nitinol memory wire, a biocompatible wire that retains its shape after being straightened. Nitinol was chosen based on its strength, low cost and ability to squeeze through the catheter and still retain its original shape. The staple shown in previous designs was removed due to the problems associated with pushing it through the catheter. Instead of the staple, it was decided that the wire would be kinked inside the foam to hold the foam in position on the wire during times of high stress. A preliminary prototype was made out of clay and can be seen in Fig. 4.

With an initial design of the final device in mind, preliminary searches of biocompatible foams were performed. The most prevalent biocompatible foam makers seemed to be the manufacturers of epistaxis strips, used to stop nosebleeds. In particular, Shipper Medical manufactures an Expandacell foam that expands upon contact with water or blood. This was initially thought to be a desirable trait, thus efforts were made to obtain samples of the foam. After repeated email inquiries, Shippert stated that none of their products were made for implantation into the body, thus this foam was ruled out as a possibility. Other companies were contacted with little success.

Around this same time, the idea of an expanding foam was brought up to Dr. Doyle, who pointed out that an expanding foam could cause problems due to it’s inability to retract after initial deployment in the case of a misplacement. The idea of an encapsulated expanding foam was also discussed, so that the procedure could be performed with a slow expansion of the foam occurring as the encapsulation wore away (similar to the foam for bathtub toys). This was also eventually discarded due to the inherent problems of misplacement or expansion after the surgery was complete.

Since the possibilities of finding a suitable, commercial, biocompatible foam seemed to be diminishing, a biomaterials expert in Florida was contacted for assistance, at the suggestion of Dr. King. This expert, Dr. Len Pinchuk, gave us a chemical formula to develop a biocompatible polyurethane foam. A simple mixing of 3 primary ingredients, with water, would give us a foam similar to the one used in pacemaker leads. Dr. Pinchuk, also suggested that the mixing could occur in a catheter to allow creation of the foam inside the body. While the idea of creating a plug specifically molded to each individual PDA was attractive, the risks inherent with the possibility of foam leaking and becoming an embolus were far too great. After several attempts, chemicals were ordered to construct this foam. Unfortunately, though, the last component of the chemical was never delivered due to shipping problems. Instead, silicone was chosen as the suitable medium for the life size prototype. The ease of creating silicone, combined with its foam-like elasticity properties made silicone an excellent choice. Unfortunately, since silicone cannot be compressed like foam, it made it impossible to put into the catheter for testing. Instead, ordinary foam was used for the in-vitro simulations, as will be explained later.

3.3 Prototype Development

The next step in developing a prototype involved finding a suitable mold to place the liquid foam into. A trip to Home Depot provided suitable starting molds composed of metal hose connectors. A plan was developed for creating the prototype: the wire would be run through the center of the mold and the liquid foam poured into it. After hardening, the finished prototype would be removed. A batch of silicone was mixed and poured into the mold. After hardening, wire wrap was pulled through the center and formed into the shape of coils to form the finished product seen in Fig. 5.

In addition to developing a prototype for show, some simple tests were performed to determine the limitations of the device. The group obtained a glass PDA and simulation device from Dr. Doyle, shown in Fig. 3, to use in flow tests. Water was run through the simulated aorta with the device in position to determine if any liquid escaped into the pulmonary artery. Also, a pressure test was conducted with a column of water to discover whether the device could withstand the pressure difference between the pulmonary artery and aorta.

4. RESULTS

4.1 Preliminary Tests

The results of the flow test demonstrated that the foam could not completely occlude the flow of a non-ionic liquid such as water. At relatively small flows and pressure, water was still able to move through the ductus and into the pulmonary artery side of the simulator. The flow was reduced due to the insertion of the occluder and thus demonstrated promising results. Another encouraging point was that the occluder effectively filled the gap made by the ductus and conformed to the shape it was placed in, one of the major design criteria of the project.

One notable problem was the difficulty associated with squeezing the occluder into the 6F catheter for delivery purposes. Even with a small amount of foam (approximately 5 mm in diameter), the device required a great deal of pushing to put it into the catheter. This should change quite a bit when the generic wire used in the testing device is replaced with Nitinol, a much thinner wire. Still, this problem brings up the issue of compressibility a critical factor in the design and implementation of the device. The Nitinol is designed specifically to be able to straighten and then retake its shape. Care must be taken in the final manufacturing of the foam to ensure that it can be compressed into the 6F catheter.

The pressure test was conducted with a column of water calculated to simulate a pressure of 100 mmHg. The PDA occluder was placed at the bottom of the column in a 5 mm duct. A Matlab program was written to calculate the pressure in the device with any given width of tubing at any given height. The code for the program can be found in Appendix B, and for this setup, it determined that 96 cm of water would be necessary.

After placement of the device and creation of the water column, the device demonstrated that water could flow through the porous foam at a wide range of pressures. However, even at pressures greater than 100 mmHg, the device remained in place and showed no signs of deformation. When a silicone plug was inserted into the same setup, flow was completely blocked.

Overall, these simple tests showed that the design of the device is effective in causing it to stay in position within the duct and maintain its structural integrity. This particular foam did not stop the flow of water at any noticeable pressure, but did serve to dramatically slow it down. The thrombogenic effect of blood should easily stop the flow of blood once the device is implanted inside the body. Also, the actual foam used in the final device should be manufactured to certain specifications. In particular, the foam should be more dense than the regular foam used in testing, but more compressible than the silicone device.

To manufacture this device, a polymer specialty firm – Polymer Technology Group, Inc. (PTG) was contacted. Preliminary discussions and negotiations have been undertaken to build a prototype for use in beginning clinical trials. PTG maintains the certification and facilities necessary to build a suitable FDA approved prototype.

4.2 Safety Analysis

The central safety risks associated with the PDA occlusion device arise from the methods of delivery and placement of the device. Since extensive research and extreme caution was exercised while choosing proper biomaterials, primary safety risks do not involve the device itself or the body’s reactions to it. The risks and hazards associated with this device are summarized in Appendix C.

The first major concern is dislodgement of the device. A potential problem could occur if the coils of the device became entangled, making the device difficult to remove and perhaps creating sharp edges that would lead to stabbing or puncturing of the vasculature. Additionally, if the dislodged device entered the wrong area of circulation, such as the heart or the pulmonary artery, the blood pressure could force the device into circulation. Quick embolization may occur, cutting off blood flow to the heart. These risks may be reduced considerably by the physician. The physician should have a clear understanding of how to direct the catheter through the PDA to implant the device properly and reposition the device if necessary.

Another potential risk associated with this device is failure to preserve sterility. If a contaminated device was implanted into the vasculature, the entire area around the device may become infected. Such a mishap may result in strokes, heart attacks, and decreased blood flow to other vital organs. By placing the device within the catheter and putting proper instructions on the package, the chances of delivering a sanitary device will increase considerably.

Additionally, as the physician pushes the catheter up through the femoral artery and into the heart, the risk of puncturing the vasculature wall increases. Since the tip of the catheter has a large surface area and is curved, it is highly unlikely that this hazard would occur. By ensuring that a physician is properly trained in using a catheter, the possibility of puncturing the vascular walls will become negligible.

Although there are numerous safety hazards associated with this device, these risks are substantially less than those encountered with other occluders currently in use today. Furthermore, the safety hazards affiliated with this PDA occlusion device are minimal compared to the surgical ligation procedure, which is referred to as the gold standard.

4.3 Market Analysis

For the past decade, it was believed that PDA occurred among children from birth to the age of 15. All previous technology catered to this age group and, due to design limitations, was somewhat limited for other age groups. In previous years, cases have been seen in adults up to the age of 90. These new cases have expanded the market potential of this device. In addition to children, this device could also be implanted in adults suffering from this condition.

Each year the Vanderbilt University Medical Center performs 40 procedures, while another 20,000 procedures occur across the United States and an additional 10,000 procedures are performed in the rest of the world (Garson). The introduction of this device has the potential to increase worldwide as the price of the device decreases, allowing less developed countries access to this procedure. It is believed that approximately 85% of the population in the United States and another 52% of the rest of the world would use this device. The total number of devices sold in the first year would be roughly 22,200 (Garson). As the elderly population continues to need a device for their patent ductus, it is assumed that an additional 5,000 devices could be sold a year, bringing the total sales to 27,966. In addition to being cost effective, this device could sell above the existing devices due to features such as expandability, shape, and ease of placement by a physician. Other methods require time for positioning and repositioning that would not be necessary for this device.

4.4 Device Patenting

In order for manufacturing of a device to occur and the beginning of FDA approvals, a group must file their patent with the United States Patent Office. A meeting has occurred with Brian Cox from the Technology Transfer Office and steps have been taken to file a provisional patent. The costs associated with Patenting would be $15,000 to file with the United States Patent Office, an additional $2,000 for attorney fees and $3,000 for miscellaneous costs. This would cover additional patenting fees such as professional drawings and prototyping.

4.5 Economic Analysis

As shown by the market analysis of this device, there would be a greater demand for physicians to use the PDA over other existing devices. The main advantage of this device is that it conforms to the shape of the PDA as opposed to forcing the PDA to conform to the shape of the device. The selling price for this device would be $200.00 and a breakdown for the projected cost can be seen in Appendix D. The estimate of the polyurethane foam is about $3.25 per device and the cost of Nitinol wire needed is $0.90. The material cost associated with this device would be $4.15 and a third party company would assess an additional manufacturing cost of $12.00. Contact has been made with PTG to actually manufacture this device, and collaboration will continue upon patenting. An insurance fee of $36.00 would also be added to the cost of each device to provide any coverage needed for our device. The total manufacturing costs would be $52.15.

An additional charge of $84.45 would be included in the cost of the device in order to cover the costs associated with animal testing, FDA trials, and patenting. This cost will include all device needs for animal trials, the three phases, labor, and cost of additional materials. This additional charge will only be applied to the first and second year, which means that profits will be lower the first two years and will increase in the third year. The breakdown of these additional costs is defined in the following:

· Animal Trials

· 1,000 animals would be needed for testing, no charge would be assessed for these animals because it is assumed that most of these animals could either be donated or provided by Vanderbilt University Medical Center

· Graduate students would perform the procedures at $16 an hour and it is expected that each procedure would take a maximum of 30 minutes with a total of 550 hours (total of labor costs – $8,800)

· 1,000 devices would be purchased from our manufacturer at a price of $52.15 (total device costs – $52,150)

· 1,000 catheters would be purchased (total catheter costs – $130,000)

· Total costs for the animal testing would be $190,950

· The safety of each animal would be considered while placing this device. Animals would provide extensive insight into the effectiveness of this device.

· FDA Phase One

· 30 Human Patients would be used for this testing

· Physicians would perform the procedures at $3,100 a procedure and it is expected that each procedure would take a maximum of 30 minutes (total of labor costs – $93,000)

· 30 devices would be purchased from our manufacturer at a price of $52.15 (total device costs – $1,565)

· Since each patient uses one catheter, there would be 30 catheters purchased at $130 (total catheter costs – $3,900)

· Total costs for phase one testing would be $98,456

· FDA Phase Two

· 100 Human Patients would be used for this testing

· Physicians would perform the procedures at $3,100 a procedure and it is expected that each procedure would take a maximum of 30 minutes (total of labor costs – $310,000)

· Since each patient uses one catheter, there would be 100 catheters purchased at $130 (total catheter costs – $13,000)

· Total costs for phase two testing would be $328,215

· FDA Phase Three

· 1000 Human Patients would be used for this testing

· Physicians would perform the procedures at $3,100 a procedure and it is expected that each procedure would take a maximum of 30 minutes (total of labor costs – $3,100,000)

· Since each patient uses one catheter, there would be 1000 catheters purchased at $130 (total catheter costs – $130,000)

· Total costs for phase three testing would be $3,282,150

· The total costs associated with testing and development would be $3,899,780

· For the three FDA trials, patients would consent to this procedure and their insurance company would pay for their hospital expenses.

It is anticipated that there would not be any serious side effects to this device. Since the materials have been chosen carefully to ensure compatibility with the body, there would be no expected harm to the patient. If a problem arises, additional costs of this device over the lifespan of the patient may occur from follow up testing to ensure device placement. This would only be a precautionary measure and would not be required expected by a doctor’s request. These additional costs would include an X-Ray, ultrasound, or fees associated with detecting the position of the device to ensure that the device healed safely. The worst case would be surgery, but this is not expected with the design of this device.

Other devices currently on the market range from $65 to a couple of thousand dollars. The most common coil method costs about $65 a coil with the average patient needing two coils. This raises the total device cost per patient to $130. Another device, called the Amplatzer, is expected to cost approximately $2,500. The current price is not available because researchers are in the final phase of their FDA approval. This device is expected to be on the market in the next few years and will be competing with the current coil method. Catheters are used with both these devices so there would be no need to consider these costs in terms of deciding which device to use.

By proving to physicians that our device is better, estimated dollar sales for the first year would be $1,287,600. The profits for the first year would be $320,375 after accounting for the manufacturing costs of $358,350, marketing costs of $100,000, and preliminary costs of $3,899,780. The marketing costs are assumed to increase at a rate of 6% each year. This marketing fee would include publications in magazines and representatives attending conferences to advertise this device to the medical field. The cost of this device is less than the competitors and provides a more effective method for occluding the patent ductus. Once physicians become aware of this product, the competitors will lose sales due to lower product costs and a higher rate of effectiveness of this PDA occluder.

5. CONCLUSIONS

The current state of the design seems promising in its ability to occlude the flow of blood through the PDA. The low cost and versatility of the device should make it an attractive alternative to cardiologists, creating a large market potential.

Both the pressure and flow tests demonstrated that the device would remain in place, even at high pressures. While the current foam does not stop the flow, the occlusion should be adequate when placed in the body. Thus, the success of the device relies heavily on the availability of a suitable foam. This current design should need little further development before full-scale prototyping and production. In essence, the final stages of the project have been reached using the locally available resources.

6. FUTURE WORK AND RECOMMENDATIONS

Construction of a sterile device such as this requires the use of a clean room and a rigorous certification procedure. Also, a custom, biocompatible foam must be used which cannot be made locally. Thus, to move this product from design into implementation, a third party must be brought in with knowledge of polyurethane foam and the facilities to manufacture it. The Polymer Technology Group has adequate resources to undertake the next step of this project. After a suitable prototype is developed, IRB approval should be obtained to facilitate testing of the device in canines. Finally, additional drawings and plans of the occluder need to be submitted to the U.S. Patent Office in conjunction with the patent application

7. ACKNOWLEDGEMENTS

The authors would like to thank Dr. Robert Galloway and John Warmath for their assistance with the creation of the silicone devices. Also, they would like to acknowledge the contributions of Dr. Len Pinchuk for his expert advice in biomaterials, and Brian Cox for his help in filing the provisional application.

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[8] Neish, Steven. Patent Ductus Arteriosus. http://www.emedicine.com/PED/topic1747.htm

Accessed 3/02/2002.

[9] Nicholas, David G. et al. “Critical heat disease in infants and children.” St. Louis: Mosby, 1995.

pp 716-722.

[10] Patent Ductus Arteriosus (PDA): A Parent's Guide.

www.techin.org/resources/resorm/c_art?16a.htm Accessed 2/10/2003.

[11] Patent Ductus Arteriosus (PDA).

www.chw.org/templates/PPF/parentid/3048/nid/3048/pageid/3049/Greystone.asp Accessed 3/15/2003.

[12] Radhakrishnan S, Marwah A, Shrivastava S. “Non-surgical closure of large ductus arteriosus

using Amplatzer Duct Occluder feasibility and early follow-up results”. Indian Journal of Pediatrics 2001; 68(1):31-35.

[13] Rao PS, Sideris EB, Haddad J, Rey C, Hausdorf G, Wilson AD et al. “Transcatheter occlusion

of patent ductus arteriosus with adjustable buttoned device: Initial clinical experience”.

Circulation 1993; 88(3):-1126.

[14] Warnecke, I. Frank, J. Hohle, R. Lemm, W. Bucherl, E. “Transvenous double-balloon

occlusion of the persistent ductus arteriosus: an experimental study.” Pediatric Cardiology.

5(2). 1984. pp 79-84.

Appendix A

A timeline of events necessary to accomplish the objectives of this project.

ID

Task Name

Duration

Start

1

Meet with Dr. Doyle to discuss potential project

1 day?

Mon 10/28/02

2

Investigate disadvantages of other PDA occlusion

devices

21 days?

Mon 10/28/02

3

Inquire about materials: foam, memory wire and

delivery device

116 days?

Mon 10/28/02

4

Meet with Dr. Doyle; discuss findigs and set goals

1 day?

Mon 11/11/02

5

Draw up prelimary design (sketch)

7 days?

Fri 11/22/02

6

Refine design with Dr. Doyle

12 days?

Mon 12/9/02

7

Build prelimary prototype

3 days?

Mon 1/13/03

8

Refine design further based on basic strength and

pressure tests

6 days?

Mon 1/27/03

9

0btain proper materials: nitinol memory wire,

biocompatible foam chemicals, catheter

53 days?

Thu 2/6/03

10

Design test apparatus

4 days?

Tue 2/25/03

11

Completed basic strength and pressure testing

4 days?

Wed 3/12/03

12

Attend NCIIA Conference in Boston

2 days?

Thu 3/20/03

13

Make adjustments to design based on suggestions

received at conference

5 days?

Sun 3/23/03

14

Preliminary meeting to initiate patent process

1 day?

Tue 4/8/03

15

Correspondence with PTG corporation to develop

actual device

1 day?

Tue 3/18/03

16

Build adequate prototype

3 days?

Wed 4/9/03

17

File patent

1 day?

Tue 4/8/03

18

Sign non-disclosure agreements with PTG

1 day?

Tue 4/1/03

19

Run final strength and pressure tests

1 day?

Tue 3/25/03

20

Complete course requirements

141 days?

Mon 10/28/02

Oct

Nov

Dec

Jan

Feb

Mar

Apr

May

Jun

October

November

December

January

February

March

April

May

June

Appendix B

MATLAB code used to calculate height of water column necessary to simulate a given pressure.

P = 100; %Pressure in mmHg

P = P*101325/760;

syms F;

syms A;

syms H; %Height

density = .001; %kg/cm^3

rt = .6/2; %radius of tubing in cm

rd = .005/2; %radius of duct in m

A = pi*rd^2;

% P = F/A, so F = P * A

F = P *A;

%m = density*volume;

% F = m * g, so m = F/g, -> volume = m/density

g = 9.8;

m = F/g;

volume = m/density;

%volume = pi * H *rt*rt;, so rearrange

H = volume / (rt^2 * pi)

Appendix F

Ideation Process

Innovation Situation Questionnaire

1. Brief description of the problem

The Patent Ductus in abnormal infants does not endothelialize and blood passes through the Patent Ductus into the pulmonary artery.

2. Information about the system

2.1 System name

DDD PDAO (Patent Ductus Arteriosus Occlusion)

2.2 System structure

This device is composed of a mushroom shaped piece of foam connected to a wire plug on one side and a flexible coiling wire on the other side.

2.3 Functioning of the system

The primary function of this system is to serve as a closure to the opening of the Patent Ductus. This closure will stop the flow of blood from the aorta to the lungs. Once placed in the correct position, the device is held in place by the difference in pressure of the pulmonary artery and the aorta.

2.4 System environment

The other systems that would work with this device include the pulmonary artery and the rest of the circulation system. Oxygen is an important part of the process because if blood moves through the Patent Ductus, then the deoxygenated blood does not receive fresh oxygen.

3. Information about the problem situation

3.1 Problem that should be resolved

The Patent Ductus should be close to prevent inefficient pumping of the blood. A device needs to provide a solution for Patent Ductus to cover holes ranging from 2 mm to 8 mm.

3.2 Mechanism causing the problem

Inability of a patient's body to naturally close the hole after birth within a period of 3 months.

3.3 Undesired consequences of unresolved problem

Strain on the heart and inefficient blood flow to the body leading to reduced oxygen delivery to the systems.

3.4 History of the problem

This problem begins at birth and affects 1 in every 2500 to 5000 lives. The current method of treatment is a coiling device inserted by a catheter which stops blood flow through the Patent Ductus.

3.5 Other systems in which a similar problem exists

A tire with a hole in it. There is a pressure differential across a membrane.

3.6 Other problems to be solved

Material must be biocompatible and have a high tensile strength so as not slip through the hole and remain in tack throughout one's lifetime.

4. Ideal vision of solution

An inexpensive, sterile and biocompatible device that expands when inserted into the Patent Ductus and remains in place throughout the life of the patient.

5. Available resources

Dr. Thomas Doyle, Vanderbilt Cardiology Department, Erskin Biomedical Library, National Institute of Health, American Heart Association,

6. Allowable changes to the system

The allowable changes to the device would include a better biocompatible foam, a new metal material, a modified method of positioning this device and small changes to the overall shape.

7. Criteria for selecting solution concepts

8. Company business environment

The business environment includes companies that sell current coil devices.

9. Project data

DDD PDAO

To develop a device to close the Patent Ductus in the heart

To investigate better biocompatible materials and metals

October - April

David Brogan

david.m.brogan@vanderbilt.edu

Darci Phillips

darci.j.phillips@vanderbilt.edu

Daniel Schultz

daniel.j.schultz@vanderbilt.edu

Problem Formulation

1. Build the Diagram

2. Directions for Innovation

9/19/02 9:25:29 PM Diagram1

1. Find an alternative way to obtain [the] (Patent Ductus Occlusion) that does not require [the] (Biocompatible), (Inexpensive), (Permanent), (Durable), (100% Success Rate) and (Effective).

Since we are placing a device in the body it has to be biocompatible and permanent. In order to fix the ductus arteriosis, it must be effective. Our goal is obviously to have a 100% success rate and for this procedure to be inexpensive so that more individuals could receive this procedure.

2. Consider transitioning to the next generation of the system that will provide [the] (Patent Ductus Occlusion) in a more effective way and/or will be free of existing problems.

Attempt to design a procedure for in vivo modification of the device size and shape to close the ductus arteriosis. Look into advances of composite foam devices to eliminate need for nitinol wire.

3. Find an alternative way to obtain [the] (Biocompatible) that provides or enhances [the] (Patent Ductus Occlusion).

Investigate possible remedies using the growth of human tissue from the patient undergoing the procedure. Essentially a designer permanent valve would be crafted from stem cells of the patient.

4. Find an alternative way to obtain [the] (Inexpensive) that provides or enhances [the] (Patent Ductus Occlusion).

Elimination of the nitinol wire would decrease the cost of this device and the total number of components required to build it.

5. Find an alternative way to obtain [the] (Permanent) that offers the following: provides or enhances [the] (Patent Ductus Occlusion), does not require [the] (Durable).

Design a non toxic polymer foam to slowly break up into the blood over time. This foam would have coagulation properties such that thrombosis would occur at the site of the PDA rendering the implantable device unnecessary over a long period of time.

6. Find an alternative way to obtain [the] (Durable) that provides or enhances [the] (Patent Ductus Occlusion) and (Permanent).

Develop a method for adjusting the chemical properties of the foam to make it more durable and last longer. By making this more durable, it would make this device more permanent.

7. Find an alternative way to obtain [the] (100% Success Rate) that offers the following: provides or enhances [the] (Patent Ductus Occlusion), does not require [the] (Effective).

This question is irrelevant.

8. Find an alternative way to obtain [the] (Effective) that offers the following: provides or enhances [the] (Patent Ductus Occlusion) and (100% Success Rate), does not require [the] (Simple) and (Fast).

Design a device that is implantable that can hook into the side of the ductus arteriosis that could be surgically put into place that would close the existing hole.

9. Find an alternative way to obtain [the] (Simple) that provides or enhances [the] (Effective).

Perhaps the foam could have expansion properties to allow it to form a tighter seal on the duct. The properties could be delayed with the use of a dissolvable outer capsule to ease placement of the device.

10. Find an alternative way to obtain [the] (Fast) that provides or enhances [the] (Effective).

Provide several tests that can be done to determine the size of the ductus arteriosis in order to build a specific mold that would tightly fit. Find a way to change the size of the PDA in vivo. Perhaps the foam could have expansion properties to allow it to form a tighter seal on the duct. The properties could be delayed with the use of a dissolvable outer capsule to ease placement of the device.

Prioritize Directions

1. Directions selected for further consideration

The most effective method found was the combination of foam and Nitinol wire. The device would have a mushroom shape with a Nitinol backbone. While the elimination of the Nitinol from the design could be a long term goal, it is currently not feasible given the status of the foam technology. A mushroom shaped top gives strength to the sides to prevent them from folding in, while the slender core allows for deep penetration into a duct.

2. List and categorize all preliminary ideas

Wire Concepts - Nitinol is biocompatible and gives strength with great flexibility. Also, it is easy to feed into a catheter. A wire mesh is very easy to create, control and implant with a great deal of backbone. However, wire is not forgiving in its shape and cannot conform to the size or shape of the PDA.

Foam plug without wire - This idea is theoretically the best device, but not feasibly possible at the moment.

It was briefly considered to find a foam that expands when exposed to water or blood, however the problem with this idea is that an expansive foam would form a tight fit around the duct immediately, leaving little room for positioning error. An expansive foam would thus prove very difficult to remove if a problem was encountered when placing it.

Develop Concepts

1. Combine ideas into Concepts

The Nitinol wire will be used as a backbone for the foam device. Both materials are biocompatible, thus eliminating any concerns of rejection from the body. The mushroom shaped foam will be molded around the Nitinol coil; the mushroom shape serving as a plug and the coil serving as a support system.

2. Apply Lines of Evolution to further improve Concepts

This product is an evolution from current market devices which currently use Nitinol wire to serve as both structural and functional support. The closest product currently available maintains a similar shape to our design, but has no use for the foam, as ours does. Current technology is also much more rigid and less forgiving in its placement.

Evaluate Results

1. Meet criteria for evaluating Concepts

This device, as designed, currently meets all of the given criteria.

2. Reveal and prevent potential failures

One possible mode of failure could be a structural support failure, where the device would slip through the PDA. This is unlikely given the nature of the design, however. Another greater possibility for problems could come from the clotting of platelets around the outside of the device and potentially occluding the aorta. Also, if the foam material does not expand or seal properly, excess leakage could be a cause for concern.

3. Plan the implementation

Get prototype developed by PTG.

Test prototype for ability to withstand pressure differential in a simulated in-vivo environment.

Patent idea.

Plan animal trials for device.

Begin FDA approval process.

Questions:

Is this device safe?

Is it more effective than current technologies?

Is it cost effective?

Will it provide a better outcome for patients?

What are the long term effects of its use in patients?

Figure 1: Anatomy of the patent ductus arteriosus.

Fig. 4 Early clay prototype.

Figure 3: Amplatzer Duct Occluder.

Fig. 5 Final silicone prototype.

Fig. 6 In-vitro PDA simulation apparatus.

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