Proposal 10/29/09
Group 2
Applicants: Paul Guillod, Vanderbilt University,
Andrew Jallouk, Vanderbilt University,
Principal Investigator: Dr. Hak-Joon Sung, Assistant Professor of Biomedical Engineering, Vanderbilt University,
Administrative Contact: Mary Judd
Design of Biodegradable Vascular Constructs
Abstract -
Cardiovascular disease is the highest cause of death in the U.S. Accordingly, it is important to be able to replace diseased vessels. We propose to use electrospinning techniques to generate a polymer scaffold for use as a vascular construct. The construct can be made of a wide range of shapes and sizes composed of fibers with diameters in the nanometer to micrometer range. We then plan to use load testing, burst pressure testing and compliance testing to assess whether the scaffold is able to withstand physiological vascular conditions. We will then incorporate growth factors into the polymer scaffold to further aid in the regeneration of vascular tissue. Following in vitro testing of the material, the material will be tested in vivo and followed by clinical trials.
GOAL: Design vascular construct composed of "smart" materials (We may want to redefine "smart" as materials that can facilitate cellular proliferation and utilize the process of inflammation to encourage angiogenesis) to:
· Withstand normal physiological vascular conditions
· Slowly degrade while being replaced by vascular tissue
· Utilize the process of inflammation to encourage angiogenesis
Introduction:
Cardiovascular disease was responsible for over 800,000 deaths in 2005 and is currently the leading cause of death in the United States. Many of these deaths are a result of coronary artery disease, which is often caused by the buildup of atherosclerotic plaques on the walls of the coronary arteries. These plaques cause narrowing of the artery lumen, leading to decreased blood flow to the heart. Complete occlusion of the artery lumen or rupture of the plaque may lead to a myocardial infarction and the death of large sections of heart tissue. In order to treat coronary artery disease, surgery is often performed to remove the sections of artery affected by plaque. These sections of the coronary artery have traditionally been replaced by grafts from either a human or animal donor; however, these grafts are not readily available and have been known to induce an immune response in some patients. More recently, synthetic grafts have been introduced to overcome some of the difficulties associated with arterial transplants. Unfortunately, while grafts made of poly(ethylene terephthalate) (Dacron) or extended polytetrafluoroethylene have shown some promise as replacements for larger blood vessels, there is currently no viable synthetic replacement for small-diameter vessels such as the coronary arteries. In addition to its biocompatibility, the ideal small vessel replacement would need to be durable, capable of withstanding the pressures normally experienced by the arterial wall, and easily manufactured in a variety of different sizes. Rather than continue to search for synthetic materials that exhibit these properties when exposed to an arterial environment, the field of tissue engineering has begun to focus on designing biodegradable polymer scaffolds that not only exhibit these properties in the short term, but also create an environment which encourages the proliferation of cells into the scaffold. As the scaffold degrades over time, cellular proliferation from the adjacent sections of the artery will serve to maintain the physical properties of the arterial wall and, eventually, completely regenerate the surgically removed section of the artery. Our goal is to design a biodegradable polymer scaffold that will enhance the rate of vascular regeneration through its interactions with the extracellular matrix (ECM) and its incorporation of cellullar growth factors. Prior research has also shown there to be a relationship between the biological processes of inflammation and angiogenesis. Our scaffold will take advantage of this relationship by utilizing the inflammatory response induced by implantation of the scaffold to encourage angiogenesis and facilitate regrowth of the blood vessel wall.
History and Context
To date, most discussions with Dr. Sung have focused on ways of manufacturing the implantable polymer scaffold and testing it to ensure that it is capable of withstanding the pressures and stresses that it will experience under physiological conditions. We have decided to use electrospinning to generate the polymer scaffolds. Electrospinning is a technique which can be used to create scaffolds of a wide range of shapes and sizes composed of fibers with diameters in the nanometer to micrometer range. The diameter and composition of each of these fibers may be carefully controlled by varying experimental parameters during the electrospinning process. As the main component of our polymer scaffolds, we plan to use a combination of poly(lactic-co-glycolic acid) (PLGA) and poly(e-caprolactone) (PCL), two biodegradable polymers commonly used in the field of tissue engineering. Since polymer scaffolds generated by electrospinning are porous, we will need to use another substance to stabilize the scaffold structure and prevent the escape of blood through the scaffold pores. We have decided to use synthetic collagen type IV to fulfill this purpose. Collagen may either be incorporated into the solution used to generate the polymer scaffold or may be applied to the scaffold following the electrospinning process. Incubation of the polymer scaffold in glutaraldehyde vapor will then crosslink the collagen, further stabilizing the polymer scaffold. Additionally, collagen is a primary component of the ECM and has been shown to facilitate cellular proliferation onto a foreign substrate. We then plan to use load testing, burst pressure testing and compliance testing to assess whether the scaffold is able to withstand physiological vascular conditions. The incorporation of growth factors into the polymer scaffold to further aid in the regeneration of vascular tissue will be discussed at a later date.
Team:
Andrew Jallouk - Senior Biomedical Engineering and Chemistry Major.
Paul Guillod - Senior Biomedical Engineering Major.
Andrew and Paul are the lead designers of the vascular construct and will work together through the entire process.
Dr. Hak-Joon Sung is the principal investigator and will be providing his knowledge, lab supplies, and services.
Work plan and outcomes:
· Use electrospinning to generate polymer scaffolds composed of PLGA and PCL
Incorporate collagen type IV into these scaffolds and crosslink to enhance physical properties of the scaffolds and facilitate cellular proliferation
· Test physical properties, including tensile strength, burst pressure strength, and compliance to assess whether the scaffold can withstand physiological vascular conditions.
Perform in vitro experiments to determine the degree of endothelial and smooth muscle cell proliferation onto the polymer scaffolds.
· Incorporate growth factors into the polymer scaffold to enhance cellular proliferation.
Perform in vitro experiments to assess the effect of inflammation on the polymer scaffold and on release of these growth factors. These experiments should also attempt to measure the level of angiogenesis occurring within the polymer scaffolds.
· Dr. Sung plans to continue this project at the end of the Senior Design period. The overall goal is to develop a commercializable vascular implant, which may aid in the regeneration of damaged or surgically excised vascular tissue.
Evaluation and Sustainability Plan
Our internal measures of success will primarily include the results of experiments designed to test both the physical properties of the electrospun polymer scaffolds, as well as the rate and degree of cellular proliferation and vascular tissue formation on the polymer scaffolds.
Appendix
Timeline
To be added to later:
October / 19 / Team meeting - overview26 / Team meeting - overview
29 / NCIIA Proposal Due
November / 3 / Web based progress report 1
4 / Web pages up
10 / Web progress 2
12 / Corrected NCIIA
17 / Web progress report 3 or oral report
19 / Electronic reference
23 / Thanksgiving break starts
29 / Break ends
December / 1 / Web report 3
8 / IWB with conflict map and expansion
12 / Winter break starts
January / 12 / Break ends
March / 6 / Spring break starts
14 / Break ends
April / 27 / Classes end and project presentation
Budget
· All equipment necessary is provided by the lab of Dr. Sung including:
o cell incubator
o sterile culture hood
o electrospinning aparatus
o tensometer
· Supplies will also be provided by the lab of Dr. Sung including:
o cells (various types/morphologies)
o polymers (PEG, PLGA, PCL)
o collagen (synthetic/natural)