progress report: development of a electrospun …rdf24/200910q1/team05.pdfteam 5: c. corbin...

DREXEL UNIVERSITY

Progress Report: Development of a Electrospun Nanofibrous Polurethane and Drug Eluting Microsphere Composite Scaffold

Advisors: Dr. Peter Lelkes and Dr. Anat Katsir

TEAM 5: C. Corbin Drescher, Priyanka Kasbekar, Phil Nelson, Veronica Rosa, and Ben Tweddale

3/2/2010

Table of Contents Executive Summary ............................................................................................................................. 1

Introduction ........................................................................................................................................ 2

Criteria ................................................................................................................................................ 3

Constraints .......................................................................................................................................... 5

Description of Prototype...................................................................................................................... 5

Preliminary Data .................................................................................................................................. 7

Societal and Environmental Impacts .................................................................................................. 10

Plan of Action for Spring Term ........................................................................................................... 12

Schedule ............................................................................................................................................ 12

Schedule Gantt Chart ......................................................................................................................... 13

Appendix I ......................................................................................................................................... 14

Works Cited ....................................................................................................................................... 15

Drescher, Kaskebar, Nelson, Rosa, & Tweddale 1

A Progress Report Team 5: Christopher C. Drescher, Priyanka Kasbekar, Phil Nelson, Veronica Rosa, and Ben Tweddale

Advisor: Dr. Peter Lelkes and Dr. Anat Katsir

Executive Summary An Electrospun Nanofibrous Polurethane and Drug Eluting Microsphere Composite Scaffold is

being developed by Christopher C. Drescher, Priyanka Kasbekar, Phil Nelson, Veronica Rosa, and Ben

Tweddale at Drexel University under the technical advice of Dr. Peter Lelkes and Dr. Anat Katsir of

Drexel University’s School of Biomedical Engineering. Each year, 1.2 million Americans suffer from

myocardial infarction and subsequent left ventricular remodeling (LVR), which leads to significant

decreases in cardiac output. Current treatments for this affliction are varied and research has indicated

that elastic mechanical support can reduce negative left ventricular remodeling and improve the

contractile function of the heart (Fujimoto, et al., 2009). Hepatocyte Growth Factor (HGF), a 70 kDa

protein, has shown promise as a therapeutic agent for slowing and reversing left ventricular remodeling

(Ueda, Nakamura, Sawa, Matsuda, & Nakamura, 2001); however, HGF is prohibitively expensive for

systemic drug delivery and is a potent mitogen with a large range of effects on many different tissues

(Nakamura, 1991). To harness the powerful therapeutic effects of the aforementioned treatments, a

device is needed that combines elastic mechanical support of the infracted region of the heart with

targeted, sustained delivery of a molecule comparable to that of HGF. The device will have mechanical

properties comparable to that of ventricular myocardium including tensile strength and elastic modulus.

It will elude a model protein similar in chemistry to that of Hepatocyte Growth Factor, within a

concentration range that HGF has been shown to produce cardioprotective effects, and over a time

period that these concentrations of HGF have been shown to be beneficial. This project aims to produce

a 4cm by 4cm by 100μm elastic, nanofibrous polyurethane mesh with entrapped biodegradable PLGA

microspheres capable of releasing 70 kDa Dextran, a model protein for HGF, labeled with Rhodamine

over a two-week time period with a release profile that would maintain a concentration of model

protein within the volume of the nanofibrous mesh that is within the range of concentrations that HGF

has been shown in studies to be cardioprotective. The immediate benefits of this deliverable will

include providing a platform capable of delivering a protein similar in chemistry to HGF to localized areas

of the left ventricular myocardium. In future work, a combination of this device with HGF protein will

provide a therapeutic option that minimizes adverse left ventricular remodeling to the 1.2 million

Americans that suffer myocardial infarctions each year. Currently the project is on-schedule and testing

of the independent parts of the design is underway. These tests include mechanical testing of the

nanofibrous polyurethane mesh and release profile studies of the PLGA-spheres loaded with model

protein. Finally, the device which will incorporate the spheres into the fibrous mesh is currently being

assembled. Finally, the business model projected to deliver this product to clients will follow a licensing

model.


Introduction In the United States, 1.2 million people have a myocardial infarction (MI) each year (American

Heart Association, 2008). After a MI, the heart undergoes a process called left ventricular remodeling

(LVR), which is a widespread remodeling of its geometry and structure. The first phase of LVR occurs in

the first two weeks after a MI and is characterized by expansion of the necrotic tissue via thinning and

stretching of the heart wall. The second phase of LVR occurs over a period of months to years and is the

same process as the first phase except it includes hypertrophy and affects non-necrotic tissue as well.

Late stage LVR is a result of natural responses to increased cardiac stress as the heart attempts to

increase cardiac output (Mann & Cain, 2003).

Current treatments are on the market and are FDA approved for the treatment of LVR. Left

ventricular assist devices have been used for decades and attempt to offload the increased stress on the

heart by pumping blood directly into the aorta. The goal of this reduction in cardiac stress is to reduce

the negative effects of LVR. Also on the market are ACE inhibitors, which reduce the secretion of

norepinephrine, a hormone that increases the heart’s workload. However, pharmaceuticals only slightly

improve long-term patient outlook, and approximately 23% of patients taking ACE inhibitors die over a

35 month post-infarct period (Flather, et al., 2000). Current surgical options include a cardiomyoplasty,

in which autologous skeletal muscle is taken from a patient and wrapped around their heart.

Cardiomyoplasty is an effective treatment in current clinical usage; however, this method is extremely

invasive and often requires repeat surgeries (Chachques, 2009). Another option is the usage of patches

for mechanical support. Patches have shown to ease the workload of the infarcted heart and improve

both systolic and diastolic cardiac function (Kochupara, et al., 2005), however there are no current

patches which include drugs as well. There is a need for a design combining the mechanical support of a

non-degradable patch with the application of certain drugs to improve cardiac function via the inhibition


of LVR. This treatment could allow for a reduced cardiac workload as well as direct pharmaceutical

treatment in order to improve survival rates in MI patients.

The solution to this problem will be presently discussed. A mechanically supporting patch with

drug eluting capabilities will be created. The patch will be composed of a polyurethane mesh. The mesh

will be non-degradable and permanent and will be created by electrospinning a polyurethane-containing

solution. It will be able to provide ample mechanical support for the post-MI heart. Microspheres will

also be incorporated throughout the patch. These microspheres will be made of PLGA in a 50:50 lactic

acid: glycolic acid ratio. According to the calculations attached to this document (See Appendix I), 306.5

spheres will be present per 100x100x100 µm volume. This figure was obtained because that density of

spheres is necessary to deliver the proper amount of drug to aid the heart. For this purpose, hepatocyte

growth factor (HGF) has been selected. The reasoning for this selection will be discussed later.

Criteria 1. The composite electrospun scaffold will have a final thickness between 100 and 150 μM.

a. The final thickness of the patch is constrained by the available area within the pericardial

space and research has shown that a patch up to 1.5mm thickness is acceptable (Wei, Chen,

Lee, Chiu, Hwang, & Lin, 2008)(Fujimoto, et al., 2009). Because this space is over tenfold

thicker than the device proposed in this document, this is not a constraint on the design and

this thickness has been chosen to reflect the projected mechanical properties necessary for

a successful device.

2. The mechanical strength of the final patch (combined mesh and microspheres) will have similar yield

strength and Young’s modulus as myocardial tissue.

a. The heart has been shown to have a young’s modulus that ranges from 10-20 kPa at the

beginning of diastole to 200-500 kPa at the end of diastole (Chen, et al., 2008). The yield

strength of infarcted myocardium is between 3-15 kPa (Chen, et al., Characterisation of a

soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of

myocardial tissue, 2008). The yield strength of mesh must be between these values to

ensure no plastic deformation occurs while allowing for mechanical support in the form of

resistance to deformation during diastole and subsequent aid during systole.


3. Fiber aggregation will be limited to fewer than three masses of fibers with diameters in excess of 10

µM in a 100 µM by 100 µM area.

a. In order to maintain uniformity of the final patch, the nanofibers and microspheres in the

mesh must be non-aggregated. Fiber aggregation is defined as a mass of fibers larger than

10 µM. This size of aggregation will create an area in which no microspheres can be

incorporated, thus affecting the uniform release of the final patch. No more than two of

these fiber aggregates will be allowed in a 100 x 100 µm area.

4. Microsphere aggregation will be limited to fewer than 30 spheres per 100 x 100 µM area, with a

target concentration of 18 spheres per 100 x 100 µM area.

a. Microsphere aggregation is defined as more than 30 spheres per 100 x 100 µm area. The

attached calculations show that about 18 spheres should be present in this area to allow for

the drug release to be distributed evenly throughout the mesh. 30 spheres in one area

would cause an area of high drug concentration in the final patch.

5. The final mesh must be able to elute 70 kDa Dextran, as a model for HGF, and maintain a

concentration between 0.3-30 ng/mL at any given time, with the optimal value being 3 ng/mL.

a. These concentrations of HGF have been shown to provide a cardioprotective role following

MI by reducing LVR (Ueda, Nakamura, Sawa, Matsuda, & Nakamura, 2001). It should be

noted that HGF will be modeled in the present design with a drug of nearly identical

molecular weight: 70 kDa Dextran. This is due to the prohibitively high cost of purchasing

HGF.

A successful design of this type to solve the problem must meet the preceding criteria.

Modulating the concentration of spheres and fiber aggregates will be done by optimizing the distance

from the spinneret tip to the collection plate in order to allow for complete solvent evaporation before

the fibers are collected on the plate. If the distance is too short, electrospraying of fibers occurs and the

fibers will form an aggregation in an area, with the solvent acting as a glue to hold fibers together.

Microsphere concentration will be regulated by modulating flow rate from the syringe pump, syringe tip

to target distance, and concentration of spheres in solution. Common distances used fall between the

range of 10-20 cm (Dror, et al., 2007)(Murugan & Ramakrishna, 2006). In addition, these spheres must

be incorporated into the mesh, which will be determined via SEM analysis of the fabricated product.


Criteria regarding sphere and fiber aggregation will be determined via SEM analysis. Ten 100x100

micron area samples will be measured: five from the top horizontal surface and five cross-sections.

These samples of the patch will be sufficient to determine if the overall patch meets these criteria for

uniformity. Proper release profiles will be determined by BCA analysis.

Constraints 1. Polyurethane must be used as the material to spin the nanofibers.

a. Polyurethane must be used as the fiber material for the design. This is due to the

relationship our client has with Biospan, a company which will provide polyurethane

reduced cost.

2. PLGA must be used to create the microspheres.

a. PLGA must be used due to its availability in the laboratory in which this project will be done.

Biocompatibility, applicable release profiles and common usage in the field are additional

reasons PLGA must be used. PLGA is defined by the ratio of lactic acid: glycolic acid. Only

three ratios will be explored due to a lack of time for conducting further experimentation:

90:10, 75:25, and 50:50. These three ratios have been heavily researched by other scientists,

so data is readily accessible. Due to the constraints of time, the project is limited to one of

these three ratios. As mentioned earlier, 50:50 PLGA has been selected for use in this

project.

3. A co-electrospinning device must be used to create the final patch.

a. This is due to the fact that the client is interested in a co-electrospinning device as well as

the final patch. Thus, in order to satisfy the client’s needs, no methods of making the mesh

will be explored other than electrospinning.

Description of Prototype The intended prototype is a polyurethane electrospun drug-eluting cardiac patch. It addresses

the problem statement by providing the mechanical support of a cardiac patch over the area of infarct,

while eluting drugs that locally inhibit cardiac remodeling. These goals and how the deliverable will

specifically address them will be discussed in detail below.

The intended prototype consists of two main components. One is the drug-eluting

microspheres and the other is the nanofibrous polyurethane mesh. The mesh component, also referred


to as a patch, is made from electrospun nanofibers. The nano scale of fibers allows the deliverable to

meet specifications by allowing the desired incorporation of microspheres among the fibrous mesh.

Additionally, the nano scale of the fibers contributes to the desired mechanical properties. The material

used to create the nanofibers is Biospan, a biocompatible polyurethane (DSM Biomedical, 2009). It has

high electrospinning capabilities. Additionally, it possesses superior mechanical properties to achieve

the design specifications. The volume density of the intended prototype will be 25%-50% fiber-to-void.

This design specification was set to achieve a Young’s modulus 70kPa-200kPa, with a target of 110kPa

(specification). These values represent the range of moduli from infracted myocardium to healthy

myocardium (Pedicini & Farris, 2003). The volume density on the intended prototype is specified also to

achieve a yield-strength greater than 15 kPa (specification), which is the maximum yield strength of

healthy ventricular myocardium (Chen, et al., 2008), (Berry, et al., 2006). The intended prototype will

possess a fiber thickness of 0.5-2 µm. This is specified to allow the mesh to possess the mechanical

properties similar to cardiac tissue (Pedicini & Farris), (Kenar, Kose, & Hasirci, 2009), (Rockwood, Akins,

Parrag, Woodhouse, & Rabolt, 2008). The physical dimensions of the patch will be 4cm x 4cm x 100 µm.

The 4cm x 4cm size is based on the average size of infarct of the left ventricle (Tamaki, et al., 1982). The

thickness was derived in consideration of the volume necessary to include enough drug-filled spheres.

The second main component of the intended prototype is the microspheres. They will be made

of PLGA, which is biocompatible and degrades in the body, releasing the drugs contained within it

(Agrawal, Niederauer, & Athanasiou, 1995). The drug contained within the microspheres will be

Hepatocyte Growth Factor (HGF). The drug will be released in a concentration release of 0.3ng – 30ng,

with a target concentration of 3ng. The drug exhibits cardio-protective effects by inhibiting cardiac-

remodeling in this concentration range (Ueda, Nakamura, Sawa, Matsuda, & Nakamura, 2001). The

drug will be released for two weeks, since cardiac remodeling takes place for 2 weeks after MI (Mann &

Cain, 2003). The PLGA will have a 50PLA:50PGA ratio since the degradation of PLGA of this ratio takes


place for 7-60 days, and this allows for a desirable release profile of 2 weeks. The sphere size of the

intended prototype will be 3um – 10um. The spheres need to be this size to fit into the voids between

fibers without affecting morphology of the mesh.

Currently, the two main components of the intended prototype, the nanofibrous mesh and

microspheres, have been made separately. Preliminary samples of Biospan have been electrospun into

patches. PLGA microspheres have been created, but they were loaded with water and created in the

interest of determining the exact protocol necessary to create to size spheres desired. The team has

successfully created spheres in the 3-10um range. The apparatus to allow for the microspheres to be

integrated into the electrospun mesh is still in production. When the apparatus is completed, final stage

prototypes can be created for testing.

One major change was made to the project after considering observations from the fall term

were considered. Originally, the intended prototype was going to be co-electrospun using an emulsion

electrospinning method, meaning that the microspheres would be suspended in the polyurethane

solution and the spheres and fibers would be electrospun at the same time. The team considered that

the spheres would have negative interactions with the solvent that is in the Biospan solution. Rather

than solving the solvent-sphere interactions, an alternative approach to creating the deliverable was

designed. The fibers will be electrospun horizontally to a spinning mandrel that will act as the collection

apparatus. The microspheres will be separately electrosprayed vertically, using an additional syringe

pump, onto the same spinning collection apparatus. The simultaneous electrospinning and spraying of

the fibers and spheres onto the same collection apparatus, while in different solutions, will allow for the

integration of the microspheres among the fibers. The method was roughly adapted from the method

proposed and used by Bill Wagner (Wagner, Stankus, Guan, & Fujimoto, 2006).

Preliminary Data


Electrospinning and microsphere preparation are necessary lab techniques for the production of

a co-electrospun scaffold. During the fall term, the team developed protocols for microsphere

preparation via a traditional w/o/w double emulsion method and became proficient in the technique

from October 26th, 2009 through October 30th, 2009. Electrospinning protocols and techniques were

developed by the team using a pre-arranged electrospinning setup. Electrospinning techniques were

developed using a 5% w/v poly(lactic-co-glycolic acid) (PLGA) in Hexafluoroisopropanol (HFP) solution.

Electrospinning protocols and techniques were acquired by the team from October 31, 2009 through

November 9th, 2009. Preliminary data were collected for both laboratory techniques including optical

and fluorescent microscopy, as well as SEM imaging; see Figure 1 and Figure 2 below.

Figure 1: PLGA Microsphere preparation preliminary data. Top left: 1.03 K X SEM magnification of FITC/BSA filled microspheres. Top right: 40x fluorescent magnification of FITC/BSA microspheres. Bottom left: 20x optical magnification of FITC/BSA filled microspheres against a measurement grid. One small white square has dimensions of 50µm by 50µm. Bottom right: control of water under a FITC fluorescent light at 20x magnification. This batch of PLGA microspheres spheres was prepared on 11/6/2009.


Additional lab techniques were developed between 9/21/2009 and 11/9/2009 and include

fluorescent microscopy, digital acquisition of microscope images, centrifugation, as well as general

orientation to the 5th floor laboratory run by Dr. Peter Lelkes at Drexel University’s New College Building.

Freeze drying techniques, which are necessary for preparation of microspheres for incorporation into

the final product, were acquired from 11/16/2009 to 11/20/2009.

Lab techniques have been developed in the Winter term that include release profile testing

methods for PLGA microspheres, polyurethane electrospinning techniques, and tensile testing

procedures for the polyurethane scaffolds. Additionally, the co-electrospinning apparatus has been

constructed and will be producing composite scaffolds by March 6, 2010. A diagram of the

electrospinning setup is included below Figure 3.

Figure 2: 20x optical magnification (left) and 9.93 K X SEM magnification (right) of an electrospun PLGA scaffold developed as the team acquired necessary laboratory techniques. This nanofibrous mesh was created on 11/9/2009 from 0.3mL of 5% w/v PLGA:HFP solution in an electrospinning apparatus in a 9kV electric field, 10cm distance from spinneret tip to target, and a flow rate of 0.7ml/hour.


Figure 3: 3D Model of the co-electrospinning apparatus used for the development of the proposed composite scaffold. Two perpendicularly positioned syringe tips are positioned surrounding a rotating aluminum target capable of concurrently co-electrospinning two 4x4cm composite scaffolds simultaneously. The box is constructed of all non-metallic materials (0.25in

acrylic and 100% Si-caulk) to prevent interference with the electric field generated by electrospinning apparatus.

Societal and Environmental Impacts There are a myriad of various societal and environmental impacts that need to be considered

when designing a biomedical device. The proposed composite scaffold is made of materials that are

biocompatible, therefore allowing this to function with little or no immunosuppressant medicines. There

are various advantages and disadvantage to this design. Since this scaffold will be directly on the heart

and would be eluting a drug, there would be minimal need for oral or intravenous medications. This

could lead to cheaper healthcare. Also, the proposed drug that will be used in this end product scaffold

is hepatocyte growth factor (HGF). The half of this drug is 4 minutes in the systemic circulation (Liu, et

al., 1992) and 4.6 hours in the pericardial space (Baek, et al., 2002). Due to the localized method in

which the drug will be delivered using this biomedical device, the amount of drug needed to achieve the

desired therapeutic effect will be significantly smaller thereby reducing costs, negative environmental

impact, and the potential side effects associated with systemic delivery of drugs. In order for this

composite scaffold to be placed or sutured onto the heart, surgery would be required. Also, this surgery


must be performed as soon as possible after an infarction occurs. This is due to the fact that the cardio

protective effects of HGF are most effective in the first two weeks after an infarction. Therefore this is

another disadvantage that sets a semi-urgent time requirement.

This composite scaffold would be composed of microspheres, which encapsulate the drug, and

nano-fibers that make up most of the mesh in the scaffold. The microspheres are made with small

amounts of methylene chloride and can be extremely toxic to the human body. However, toxicity is an

issue only if exposed to high amounts which can chronically be carcinogenic for humans. Extreme effects

would occur to those that have pre-existing skin disorders, impaired function of liver, kidney,

cardiovascular, or respiratory systems. (Material Safety Data Sheet, 2008). Polyurethane is the material

used for the nano-fibers of the scaffold. This material can cause some health effects as well. If there is

an acute exposure, it may cause liver damage and can lead to jaundice. This is only aggravated with

those who have pre-existing impairment of liver function (Biospan, 1993). Both methylene chloride and

polyurethane need to be closely regulated for the exposure in vivo as well as the amount being released

into the body. However, studies have shown that the amount of methylene chloride and polyurethane

used in this type of design is not enough to cause any in vivo complication (Mathur, et al., 1997)

(Galeska, et al., 2005).

The two materials that are of environmental concern when used in this scaffold are methylene

chloride and polyurethane. When methylene chloride is released in water, it will degrade or evaporate

quickly. When this is released in the air, it will photo-chemically react and produce hydroxyl radicals.

However this could be removed from the air via wet deposition (Material Safety Data Sheet, 2008).

Both methylene chloride and polyurethane are handled as hazardous waste and is disposed in an

approved waste facility (Material Safety Data Sheet, 2008), (Biospan, 1993). Overall, there are many


positive attributes to this design. With this design, many people with severe heart attack or tissue

damage can live a better life.

Plan of Action for Spring Term Within the spring term the group needs to continue testing of the nanofibrous polyurethane

mesh with incorporated spheres. The co-electrospinning system will continue to be used to electrospin

polyurethane and PLGA microspheres meshes. The prototype meshes will be measured for tensile

strength, yield strength, and elastic modulus. This will be done using an Instron on the University of

Pennsylvania’s campus. These mechanical properties will be determined to compare it to the

mechanical properties of healthy heart tissue and infracted tissue, which are available in literature.

Additionally, the composite meshes’ mechanical properties will be compared to the properties of

electrospun meshes that do not contain microspheres. This will be done to determine the effect of

microsphere incorporation on the mechanical properties of the mesh.

Another component of the design is the PLGA microspheres and their incorporation into the

polyurethane mesh. Release profile studies of Dextran from the meshes with incorporated

microspheres will be conducted to determine whether or not incorporation of spheres into the mesh

will affect degradation and release.

Depending on the results of these tests, electrospinning variables such as tip to target distance,

voltage applied to the syringe tips and target, flow rate from the syringe pump, and concentration of

spheres in solution will be varied to fine tune the characteristics of the composite scaffolds to meet

specification. Testing on these patches will be a continuous process during the spring term.

Schedule In fall 2009, the team acquired all the necessary techniques to complete the project. The

following skills were acquired: microsphere training using the homogenizer, electrospinning of

polyurethane and freeze-drying training. In January 2010, the co-electrospinning design and box


dimensions were drawn to scale. On February 5th, the Plexiglas box for the co-electrospinning enclosure

was completed and moved into the lab to begin the building of the co-electrospinning system. In

January 2010, the electrospinning of polyurethane to a 4cm by 4cm by 100um mesh, mechanical testing

and microsphere release profile was started. These tasks are still being performed are to be completed

the end of February to the beginning of March. Total encapsulation degradation and characterization of

the microsphere are to be completed by March. Co-electrospinning of polyurethane and microspheres

will be started in March and competed by the first week of April. When that is completed the

mechanical testing and release profiling of functional prototypes will be started and completed by May.

Attached is a copy of the team’s schedule.

Schedule Gantt Chart


Appendix I

Calculations

x=38.34 mg

Where 5 mg is the mass of BSA used to fill the spheres and x is the total amount of PLGA needed

to make the number of spheres which can contain the total volume of drug + BSA with 15% loading

(note that the actual drug will not be used in our studies, only BSA will be used, as discussed later).

Therefore, the total mass of the spheres will be 38.34 mg + 5 mg + 109 ng = 43.34 mg.

The volume of the average sphere, assuming an average diameter of 6 µM, is 1.13x10-10 cm3.

Therefore, the number of grams PLGA per sphere is 1.414x10-10 grams. From these numbers, the total

number of spheres can be determined:

If approximately 5 mg of BSA is encapsulated in all of the spheres, then about 1.634x10-8 mg of

BSA will be in each sphere.

The sphere density in the final deliverable can also be calculated. A simple conversion shows

that there are .000306 spheres per µM3. In a 100 µM3 area, there are 306.5 spheres on average.

However, analysis of an entire three dimensional 100 µM3 area cannot be done due to the limitations of

SEM imaging. Therefore, assuming that a single layer of spheres can be analyzed via SEM, which is

capable of visualizing 6 µM deep into, it has been determined that there will be about 18 spheres per

100x100x6 µM volume.


Works Cited Agrawal, M. C., Niederauer, G. G., & Athanasiou, K. A. (1995). Fabrication and Characterization of PLA-

PGA Orthopedic Implants. San Antonio, Texas: Mary Ann Liebert, Inc.

American Heart Association. (2008). Heart Disease and Stroke Statistics - 2008 Update. American Heart

Association.

Baek, S. H., Hrabie, J. A., Keefer, L. K., Hou, D., Fineberg, N., Rhoades, R., et al. (2002). Augmentation of

Intrapericardial Nitric Oxide Level by a Prolonged-Released Nitric Donor Reduces Luminal Narrowing

After Porcine Coronary Angioplasty. Circulation , 2779-2784.

Berry, M., Engler, A., Woo, J., Pirolli, T., Bish, L., Jayasankar, V., et al. (2006). Mesenchymal stem cell

injection after myocardial infarction improves myocardial compliance. American Journal of Heart and

Circulatory Physiology , 2196-2203.

Biospan. (1993, April 8). Material Safety Data Sheet. Retrieved November 2009, from

http://www.dsm.com/en_US/downloads/dbm/pdf005_-_BioSpan_Material_Safety_Data_Sheet.pdf

Chachques, J. C. (2009). Cardiomyoplasty: is it still a viable option in patients with end-stage heart

failure? European Journal of Cardio-Thoracic Surgery , 201-203.

Chen, Q.-Z., Bismark, A., Hansen, U., Junaid, S., Tran, M. Q., Harding, S. E., et al. (2008). Characterisation

of a soft elastomer poly(glycerol sebacate) designed to match the mecanical properties of myocardial

tissue. Biomaterials , 29, 47-57.

Chen, Q.-Z., Bismark, A., Hansen, U., Junaid, S., Tran, M. Q., Harding, S. E., et al. (2008). Characterisation

of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial

tissue. Biomaterials , 29, 47-57.

Dror, Y., Salalha, W., Avrahami, R., Zussman, E., Yarin, A., Dersch, R., et al. (2007). One-step production

of polymeric microtubes by co-electrospinning. Small , 1064-1073.

Flather, M., Yusuf, S., Kober, L., Pfeffer, M., Hall, A., Murray, G., et al. (2000). Long-term ACE-inhibitor

therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from

individual patients. The Lancet , 1575-1581.

Fujimoto, K., Tobita, K., Merryman, D., Guan, J., Momoi, N., Stolz, D., et al. (2009). An Elastic,

Biodegradable Cardiac Patch Induces Contractile Smooth Muscle and Improves Cardiac Remodeling and

Function in Subacute Myocardial Infarction. Journal of the American College of Cardiology .

Galeska, I., Kim, T., Patil, S., Bhardwaj, U., Chattopadhyay, D., Papadimitrakopoulos, F., et al. (2005).

Controlled release of dexamethason from PLGA microspheres embedded within polyacid-containing PVA

hydrogels. The AAPS Hournal , E231-E240.

Kenar, H., Kose, G. T., & Hasirci, V. (2009). Design of a 3D aligned myocardial tissue construct from

biodegradable polyesters. Journal of Material Science .


Kochupara, P. V., Azeloglu, E. U., Kelly, D. J., Doronin, S. V., Badylak, S. F., Krukenkamp, I. B., et al. (2005).

Tissue-Engineered Myocardial Patch Derived From Extracellular Matrix Provides Regional Mechanical

Function . Circulation , 144-149.

Liu, K., Kato, Y., Narukawa, M., Kim, D., Hanano, M., Higuchi, O., et al. (1992). Importance of the liver in

plasma clearance of hepatocyte growth factors in rats. Am J Physiol Gastrointest Liver Physiol , G642-

G649.

Mann, D. L., & Cain, G. (2003). Heart Failure: A Companion to Braunwald's Heart Disease . Philadelphia:

Saunders.

Material Safety Data Sheet. (2008, August 20). Retrieved November 2009, from

http://www.jtbaker.com/msds/englishhtml/M4420.htm

Mathur, A., Collier, T., Kao, W., Wiggins, M., Schubert, M., Hiltner, A., et al. (1997). In vivo

biocompatibility and biostabiloty of modified polyurethanes. Journal of Biomedical Materials Research ,

246-257.

Murugan, R., & Ramakrishna, S. (2006). Nano-featured scaffold for tissue engineering: A review of

spinning methodologies. Tissue Engineering , 435-447.

Nakamura, T. (1991). Structure and Function of Hepatocyte Growth Factor. Progress in Growth Factor

Research , 3, 67-85.

Pedicini, A., & Farris, J. R. (2003). Mechanical behavior of electrospun polyurethane. Polymer , 6857-

6862.

Rockwood, D. N., Akins, R., Parrag, I., Woodhouse, K., & Rabolt, J. (2008). Culture on electrospun

polyurethane scaffolds decreases atrial natriuretic peptide expression by cardiomyocytes in vitro.

Biomaterials , 4783-4791.

Tamaki, S., Murakami, T., Yui, Y., Kambara, H., Kadota, K., Yoshida, A., et al. (1982). Estimation of Infarct

Size by Myocardial Emission Computed Tomography with Thallium-201 and Its Relation to Creatine

Kinase-MB Release After Myocardial Infarction in Man. Circulation , 994-1001.

Ueda, H., Nakamura, K., Sawa, Y., Matsuda, H., & Nakamura, T. (2001). A potential cardioprotective role

of hepatocyte growth factor in myocardial infarction in rats. Cardiovascular Research , 41-50.

Wagner, W. R., Stankus, J. J., Guan, J., & Fujimoto, K. (2006). Microintegrating smooth muscle cells into a

biodegradable, elastomeric fiber matrix. Biomaterials , 735-744.

Wei, H., Chen, C.-H., Lee, W.-Y., Chiu, I., Hwang, S.-M., & Lin, W.-W. (2008). Bioengineered cardiac patch

constructed from multilayered mesenchymal stem cells for myocardial repair. Biomaterials , 3547-2556.

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