Example- FDA Proposal Final Junior Year

8/3/2019 Example- FDA Proposal Final Junior Year

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Document No.: Revised: 05/01/12 File Name: PLA based stents

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Design Verification ProposalFood and Drug Administration

Submitted under guidelines established by 21 CFR 820.30

Effectiveness of Polylactic Acid Polymers in Biodegradable Stents

for Use in Coronary Arteries

Team Woosa

1/28/11

David Baruela

Samyukta Gade

Jennifer Go

Alex Hussinger

Austin Schader


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Report Title:Effectiveness of Polylactic Acid Polymers in Biodegradable Stents for

Use in Coronary Arteries

Product: Biodegradable StentsSubject: Biodegradation, tensile strength and pH

1. EXECUTIVE SUMMARY

Stents have evolved from the simple bare metal design to the more complex, drug

eluting design. However, there are a few drawbacks to each of these products, such as

encouraging restenosis (re-narrowing) to occur or even thrombus formation; these serious

issues have prompted groups such as ours to find a solution to the problems presented.

The patient is at his or her greatest risk for restenosis in the first 6 months after the

angioplasty, but by leaving a stent in too long we would run the risk of dangerous blood clot

formation. We think that by creating completely biodegradable stents, we will be able to

reduce the risk of clot formation in the blood vessels by both removing the surfaces the

body perceives as foreign, and by eventually having the stents degrade away.

Our design will follow the ASTM standards and FDA regulations for bare metal stents in

order to compare the effectiveness of our product to stents currently used in industry. Our

stent will undergo tensile testing and degradation tests to simulate the environment found in

coronary arteries. Our samples will be tested for strength after being degraded in order to

verify that they maintain structural support to the artery after a minimum of six months.

Afterwards, we will analyze and extrapolate the data to simulate the ideal lifetime of the

stent, six to twelve months.


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2. DESIGN AND DEVELOPMENT PLANNING

2.1. Introduction

2.1.1. Medical Condition

81.1 million people were diagnosed with heart disease in 20061

. Of those, one inone hundred of them died. The main cause of heart disease is stenosis, or closing

of one or more of your arteries, due to buildup of plaque along the endothelial lining.

Stenosis has become one of the most common and dangerous internal injuries. As

a result of this problem doctors used angioplasty to unclog the blockages, although,

restenosis occurred in 40% of the cases within one year.

2.1.2. Current Technology

Together with doctors engineers created stents a small wire mesh frame

cylinders in order to reduce the chance of restenosis. Since their inception stents

have evolved from bare metal platforms, to drug eluding stents that further reduce

chances of restenosis. Eventually stents will transition to fully biodegradable stents

made from biodegradable polymers. The implantation of stents has grown to

become the most common surgical procedure and the industry has grown to multi-

billion dollar proportions.

2.1.3. Current Limitations

Bare metal stents and drug-eluding stents have greatly decreased the chance of

restenosis; however, they are not without their drawbacks. Bare metal stents trigger

and auto-immune response that can lead to restenosis as the body tries to destroy

the foreign object (stent). Drug-eluding stents emit drugs to prevent the auto-

immune response; however, this can lead to blood clots that may travel to the heart

or brain causing heart attack or stroke.

2.2. Problem Statement

2.2.1. Problem Statement

There currently is a necessity for a geometrically similar device that does notcause blood clots while maintaining the necessary strength to keep the artery open

and minimize the auto-immune response.

1Cardiovascular Disease Statistics. American Heart Association.


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2.3. Project Goals, Solution and Objectives

2.3.1. Team Goals

Polymers chosen for biodegradable stents must exhibit strength near those of the

metal stents and biodegrade with six months to one year (the ideal time frame to

prevent restenosis or collapse of the artery and allow the body to repair the

damaged artery).

2.3.2. Proposed Design Solution

The proposed design solution is a collapsible, biodegradable Polylactic acid

based stent that degrades fully within one year and maintains structural strength for

at least six months after the angioplasty.

2.3.3. Objectives

Our project seeks to test biodegradable polymers (Polylactic acid based) for the

rate of degradation and for the fall in strength vs. % degradation. These two

characteristics represent the most important factors for a biodegradable stent.

2.4. Testing Justification and Overview

2.4.1. Brief description

During our project will test seven PLA polymer strips approximately 4 inches in

length and 3/4 inch in width and 1/8 inch. These strips will be fabricated from plastic

biodegradable spoons and melted down in a furnace at 250 C then poured into

Styrofoam molds lined in aluminum foil, and will then be sanded into the ideal shape

as specified above.

After forming, the strips will be placed into a saline solution with a measured pH

using either pH probe or pH strips. This solution will be held at 37 2C. These

strips will then be tested one per day for seven days in the Instron Tensile Tester

and the hardness tester using the Vickers scale. Additionally they will be measured

using calipers and weighed on a balance.

2.4.2. Verification

These tests will be conducted to monitor the strength and amount of material lost

over time and to confirm the strength is adequate for the first six months of

implantation. Additionally, the amount of sample lost will be used to verify that the

sample will be completely biodegraded within the one year timeframe.


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2.4.3. FDA Approval

The FDA should approve PLA for use in stents if it meets or exceeds the tests

below (section 5) as it has demonstrated adequate strength and biodegradability for

the human body. Additionally, drug coatings may reduce chances of forming a

thrombus and further research need to be conducted into combinations of drug-

eluding biodegradable polymers.

2.5. Important Terminology

2.5.1. Technical or Medical Terms

Artery-blood vessels that carry blood away from the heart

Catheter-tube inserted into body cavity

Coronary-having to do with the heart

Endothelial-cells that line that inner walls of blood vessels

Endothelialization-when the endothelial cells grow over the implant and incorporate

it into the body

Macrophage-white blood cells that engulf and digest pathogens

Mitotic inhibitors-a drug that inhibits cell division

Plaque-in blood vessels consists of accumulation of ruptured macrophages,

calcium and cholesterol

Restenosis-formation of blockage after the artery has been treated with angioplasty

Stenosis-narrowing of blood vessel due to formation of plaque

Thrombus-blot clot formed within a blood vessel

2.6. Organizational Responsibilities

2.6.1. Team Member Responsibilities

The main project responsibilities were divided into four roles: the delegator,

budget analyst, Gantt chartist, and Computer Aided Designers. The delegator,

Jennifer Go, will be the liaison between the team and our coaches, Dr. Harding and

Dr. Vanasupa. She will ask questions on behalf of the team, and check in with the

coaches periodically as the project moves forward. David Baruela will do the

budget analysis and make sure that the team is within budget and that the rest of

the project can be completed with the remaining resources. He will keep an up to

date spreadsheet of bill of materials. Samyukta Gade will create a Gantt chart

detailing individual tasks for each team member, critical milestones, and associated

completion dates. She will also make sure all deadlines are met and update the


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Gantt chart if any obstacles arise. Austin Schader and Alex Hussinger are in charge

of computer aided design of stent.

In addition to the roles listed above, each team member will have an assigned

task to be completed every week. These tasks and their due dates are listed in

section 2.7.3.

2.7. Document Tracking, Deliverables and Timeline

2.7.1. Tracking and Maintaining Important Documents

A Google Groups page has been created to keep track of all documents related

to this project. Documents include the team contract, related articles, list of sources,

related terminology, and deliverables. The list of sources will be updated whenever

a new source is used in the project. Related terminology will be continuously

updated every time a team member comes across medical term needed forfundamental knowledge of stents. These documents can be read and altered by any

member of the team.

2.7.2. Publishing Test Results

Test results will be published as a newsletter and sent to all team members at

the end of the testing period. This is an effective way to distribute a summarized

report that the team members can review as well as the FDA.

2.7.3. Timeline

The project was broken

down into three parts: FDA

proposal, testing, analysis, and

presentation. We allocated one

week for gathering materials

and one week for testing. An

extra was set aside just in

case unforeseen delays or

obstacles occur during the

ordering or testing of material.

The list of tasks along with

tentative completion dates are

in figure 1 and a Gantt chart

depicting critical milestones is

shown in figure 2.

Figure 1: List of tasks along with tentative completion dates


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Figure 2: Gantt chart depicting several milestones and a critical path


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3. DESIGN INPUTS

3.1. User and Patient Needs

The surgeon needs a stent that is small enough to fit inside an artery, but will be

able to hold open the artery for six to twelve months. The patient needs a coronarystent that is strong enough to hold open an artery and stiff enough to keep its shape

for 6 to 12 months. The stent will need to fully degrade in 6 to 12 months.

3.2. Performance Requirements

3.2.1. Functional Requirements

The stent must be able to fit inside the coronary artery. The patient needs a stent

that is able to hold open the artery for 6 to 12 months. The stent must fully degrade

after 6 to 12 months. The stent must not be toxic to humans. The stent must be

able to keep its strength while undergoing degradation in the artery. However, the

stent must not degrade until it is fully deployed within the artery.

3.2.2. Service Environment

The stent will be inside a coronary artery. The stent will be exposed to blood,

oxygen, and plaque. The stent will not be exposed to a lot of motion, since it will be

placed in the heart. However, the stent will be subject to the cyclic pressure

changes normally seen in the heart.

3.2.3. Regulatory Requirements

There are currently mandatory FDA regulations and voluntary ASTM standards in

place for coronary stents. However, FDA regulations are not as strict as the ASTM

standards. The stent diameter must be measured to the nearest 0.25 or 0.5 mm. 2

The stent length must be measured to the nearest 1mm. Standard sizes for stents

undergoing tests are 8 or 24 mm long and 2.5 or 4 mm in diameter3. The stent

must not undergo a length change greater than 1% from the undeployed state to

the deployed state. However, stents that have been deemed clinically useful can

have a shortening of up to 20%. The strut thickness should be measured to the

nearest 0.013 mm. The average strut thickness is between 0.025 0.177 mm. The

2F2081 Standard Guide for Characterization and Presentation of the Dimensional Attributes of Vascular Stents

3 Guidance for Industry and FDA Staff Non-Clinical Engineering Tests and Recommended Labeling for

Intravascular Stents and Associated Delivery Systems


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stent must not be toxic to humans4. When undergoing a three-point bending test, a

stent that is 20-24 mm long cannot deflect more than 3.2 mm5.

3.3. Design Input Assessment Plan

Our design will be measured following the ASTM instructions for vascular stents,

and will follow the FDA regulations for stents. The design will undergo tests similar to

those found in ASTM standards for testing balloon expanded stents, bare metal

stents, and drug-eluting stents.

4 Guidance for Industry Coronary Drug-Eluting Stents Nonclinical and Clinical Studies5 F2606 Standard for Three-Point Bending of Balloon Expandable Vascular Stents and Stent Systems


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4. PROPOSED SOLUTION

4.1. Conceptual Design Description

Biodegradable stents are an attractive alternative to bare metal and drug eluting

stents which are often rejected by the users body or cause a thrombus which could

have a cascade of negative effects, respectively. Currently, there are many

biodegradable materials out on the market however the material which is most

appealing for use in our project is Polylactic acid (PLA) based polymers. As stated

previously, PLA polymers are completely biodegradable if given enough time and are

contained in an oxygen-rich environment. They are very biocompatible with the

human body (see section 4.3 below), and can serve as vectors for drugs to provide

the same function and benefits that a drug eluting stent does without the drawbacks.

Also, there are various forms of PLA polymers which give our experiment flexibility

when choosing our specific polymer. Overall, PLA polymers have strength

comparable to similar polymer, 6-8% ductility, and have a low modulus of elasticity,

which would provide enough support for a stent without being brittle. They also can

theoretically support a blood vessel which is undergoing constant pressure and

sometimes load deformation.

Based on the limited flexibility of PLA polymers, the traditional diamond shaped

strut stent design cannot be used. PLA is not suited to be put into place by plastic

deformation. Instead, a new stent design will be used in tandem with the old method

of stent implantation to get the stent into the stenotic artery. The PLA stent will be

made of square shaped struts which are overlapped onto one another when the stent

is collapsed. If the stent needs to be placed in a stenotic artery the collapsed stent

will be threaded onto a catheter and guided to the blockage, once the stent/catheter

has reached the blockage the balloon at the end of the catheter will expand, pushing

the rings out on the stent. The rings of the stent will lock into place with a latch

mechanism that catches once the stent struts fall into place, causing the stent to

maintain its expanded shape.

A PLA polymer stent will rectify the problems encountered with traditional stents

because over time the polymer and thus stent will biodegrade. The rate at which PLA

degrades is slow enough so that it is able to undergo endothelialization and be

integrated into the vessel wall to provide support for the surrounding vessel; but once


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the stents job is complete, it will degrade and not cause any long term lasting effects.

PLA polymers are biocompatible which means that for the majority of cases, unlike

bare-metal stents, the body will not reject the stent. Additionally, since the PLA stent

can be incorporated with a drug of some-sort, the rate of restenosis (re-narrowing),

which is a common occurrence in a bare metal stent, of the vessel in question can be

decreased dramatically. Also, unlike drug-eluting stents, thrombus formation with

PLA stents is minimized or completely absent 6.

As shown, a PLA stent would provide many, if not all, of the benefits that

traditional stents provide without all the negative drawbacks. Manufacturing a stent of

pure PLA polymer is still in the research stages but due to its beneficial properties,

PLA is an attractive option of stent use.

4.2. Design Performance

Our completely PLA polymer stent will be used in the same way traditional stents

are, although their design and method of expansion are novel. The completed stent

will be threaded onto the end of a catheter guide wire and led to the location of

implantation, typically where the blockage is located in one of the coronary arteries.

The balloon will be expanded and in doing so flatten the components of the blockage

against the sides of the vessel wall as well as expand the PLA stent and hold it into

place. Once the PLA stent is in place, it will start to release the drug which has been

integrated with the stent. These drugs can range from mitotic inhibitors which inhibit

macrophage multiplication, to immunosuppressants which prevent the body from

attacking and rejecting the stent. With the stent in place, the vessel wall will be less

likely to collapse and the vessel will be clear for blood to flow normally. Over the

course of the next two to three months, the stent will start to become endothelialized

and incorporated into the vessel. The stent will also start to degrade once implanted

which prevents thrombus formation. It will take the stent anywhere from six months,

to one year to fully biodegrade; this time frame is long enough to provide the

necessary support as well as short enough to not cause any long term effects from a

foreign object located within the body.

6Zamiri, P. Kuang, Y. Sharma, U. Ng, T.F. Busold, R.H. Rago, A.P. Core, L.A. Palasis, M. The biocompatibility of

rapidly degrading polymeric stents in porcine carotid arteries.

Biomaterials 8 August 2010


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4.3. Patient Safety Assurance

Polylactic acid polymers are biocompatible and are bioabsorbable under aerobic

conditions. Since we intend on placing the PLA stent in the coronary artery, which is

an oxygen-rich environment, we can expect the polymer to be able to degrade

naturally.

In studies performed on stenotic porcine carotid arteries, metal stents laced with

different forms of PLA polymer to observe the effects of this material in vivo, returned

very positive results. There was minimal inflammation at the site of implementation,

successful widening of the carotid artery, as well as complete endothelialization and

beginning stages of absorption by the time the study was complete7.

According to ASTM standards for PLA polymers, there is a potential for increase

in local acidity as the polymer degrades depending on implant form. However, since

the application is stents, which have a very low volume, and the material is not being

used for larger solid devices, the residual monomer may be acceptable8. To ensure

the device will not drastically increase the localized pH, we will monitor the pH of the

solution during testing.

7Zamiri, P. Kuang, Y. Sharma, U. Ng, T.F. Busold, R.H. Rago, A.P. Core, L.A. Palasis, M. The biocompatibility of

rapidly degrading polymeric stents in porcine carotid arteries.

Biomaterials 8 August 2010

8ASTM standard: F1925-09 Standard specification for Semi-crystalline Poly(lactide) Polymer and Copolymer

Resins for surgical Implants


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5. DESIGN VERIFICATION PLAN

5.1 Design of Experiment

5.1.1 DOEOur experiment will involve placing different samples of PLA into phosphorus-

buffered saline solution (PBS) designed to simulate the ph level of human blood. We

will measure both the strength and reduced dimensions of the PLA samples for one

week in order to identify whether a stent made completely out of PLA, that

biodegrades between 6-12 months in the bloodstream, will have enough strength to

function as a coronary stent. We will be using a pH level of 7.4, the same as human

blood, and subject PLA samples to it for up to one week, but we will be extrapolating

our data linearly up to a year.

5.1.2 Control variables

Our main control variables will be the ph of the PBS (7.4) and the temperature of

the mixture (37 Degrees Celsius). Other factors like air pressure, humidity, and

possible impurities may affect the experiment, but not enough to warrant direct

controls given our limited resources.

5.1.3 Response Variable

The Variables we will be measuring are mass of the part in grams (calculating

the change in dimensions), yield strength of the part in KPA (expected to be around

54 MPA), and tensile strength of the part in KPA (Expected to be around 97.5 MPA)

5.1.4 Number of Replications and Justification

We intend to only repeat the experiment one time, as we feel that our resources

and time is limited and that by the nature of the experiment, we wont need to average

multiple data sets to acquire a meaningful value. We intend to use at least 7 samples

in the one test however.

5.2 Sample Description

5.2.1 Materials

We intend to use Polylactic acid, to be supplied from either an independent

supplier (Ecoproducts) or from Splash in the form of the biodegradable plastic

utensils. The Phosphorus-buffered Saline solution will be created by simply adding


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purchased table salt (NaCl) to De-Ionized water along with phosphates acquired from

(the chemistry department), and will be measured by a Ph probe.

5.2.2 Sample Preparation

We intend to prepare the samples by mixing the salt and buffer with de-ionized

water gradually, measuring the ph until it reaches the levels we need (approximately

.1M of each). We also intend to melt the polylactic acid (which is a thermoplastic) in a

furnace and re-cast it using a Styrofoam mold into at least 7 rectangular blocks, 4

inches long by 3/4th inch wide by 1/8th inch deep (approximately 50 grams each) that

fits easily into the Instron tensile tester and into the beakers we will be using.

5.3 Test Procedures

5.3.1 ASTM or ISO standards

F1635 In vitro degradation of poly (L-Lactic acid) is the standard is being used as

it allows us to measure exactly what we need (both the rate of decomposition and

the resulting mechanical properties of the degraded material), and seems completely

feasible with the resources available to us9. We intend to change only three details

from the ASTM standard. We will only be using one sample per testing time (as

using three would be too burdensome and costly for our scale), and no microbial

agent and a lower solution to sample ratio (as we are only going to be testing over

one week, so the odds that significant changes in the pH of the solution or large-

scale microbial growth occurring and interfering with the data are minimal)

5.3.2 Procedure

For each test, we will mix the saline solutions and Phosphate buffer together

ahead of time to the desired ph level. We will then place the samples into a water

bath at 37 degrees Celsius (+/- 2 degrees Celsius), and once thermal equilibrium is

attained, we will insert the samples into separate beakers, making sure none of the

samples touch. Each day, we will remove one sample and measure the yield

strength and tensile strength via the Instron tensile tester while the part is still wet.

We will then dry it off and measure its mass by electric scale.

9 F1635 Standard test method for in vitro degradation testing of hydrolytically degradable polymer

resins and fabricated forms for surgical implants


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5.3.3 Assumptions

We are assuming that the material we are using is pure PLA (L-type) when in fact

it might be only mostly PLA. However, the cups are marketed as being completely

biodegradable, so even if the material is not pure PLA, it should be able to

biodegrade at roughly the same rate. We are assuming that the PLA will biodegrade

solely based on the pH of the solution. We are assuming that simply leaving the

sample wet will adequately simulate loading while still submerged in the blood, and

that mechanical loading of the actual stent does not greatly affect the rate of

degradation inside the bloodstream.

5.4 Equipment

5.4.1 Equipment

The equipment we intend to use is a hot plate supplied from the MATEdepartment, a water bath (2L Beaker and water), a furnace that can go up to 300C,

a pH meter, an electric scale that measures down to hundredths of a gram, and an

Instron tensile tester.

5.4.2 Expected data and level of accuracy

The data we expect to get from these tests are both the mechanical strength of

the PLA after exposure to the PBS, and the rate of degradation of the PLA as a

function of time. The accuracy for the former will be relatively high, as the Instron

tensile tester machine is able to very precisely calculate the force needed to both

break the part and cause the initial yield (% error of about 1%). The accuracy of the

latter however will be lower, as we will be calculating minute changes in the size of

the part using both mass and measured dimensions (%error of about 3%)

5.5 Analytical Techniques

5.5.1 Significance Level

For our linear regression test the p-value used will be


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5.5.3 Description of Data

Additionally, all strength measurements will be converted into percents of the

original strength and compared to data from CES for common Nickel-Titanium

Stents to see if the PLA based polymer will be adequate in maintaining the artery

from collapsing. The loss in mass of the PLA sample will also be regression tested

in Minitab to see if we can extrapolate, using the linear trend formula, whether or not

the polymer will biodegrade within one year completely.

5.6 Contingency Plan

If we cannot get the saline solution to the proper pH is that well use baking soda

(Sodium Bicarbonate) instead. If the samples do not all fit inside the beaker, we will

use a larger beaker. If the samples do not cast properly, we will either re-cast them. If

we think it was a simple mis-cast, and sand the part down to an acceptable alternative

size if not. If our testing results show no significant degradation after one week (less

than .01 g mass loss), then we will simply sand down the samples to different cross-

sectional areas. If our experiment is unsuccessful for any other reason, we will

attempt to find additional recorded values for the data we need and extrapolate a

conclusion based on that data. If we cant get phosphates we will attempt to run the

experiment without it.

Example- FDA Proposal Final Junior Year

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