BME PhD Prospectus Defense - Eric Falde

Starts:
2:00 pm on Wednesday, May 15, 2013
Ends:
4:00 pm on Wednesday, May 15, 2013
Location:
44 Cummington St, Room 401
Title: Layered Superhydrophobic Meshes for Controlled Drug Release

Committee:
Prof. Mark Grinstaff (Advisor, Chair)
Prof. Yolonda Colson
Prof. Tyrone Porter
Prof. Béla Suki

Abstract:
Surgery is the most effective treatment for early stage cancer. However, surgeons must also preserve the function of surrounding healthy tissue while removing a tumor. Because of this balance, microscopic disease is often missed, leading to local recurrence. This is an especially significant issue for cancers in critical tissues such as non-small-cell lung cancer, where the 5-year recurrence rate is about 36%, more than half of which is local recurrence. A local source of chemotherapeutic applied at the resection site to kill remaining disease has the potential to significantly improve cancer treatment outcomes. Such a device needs to be biocompatible, resorbable, mechanically flexible, and able to deliver drug controllably over multiple cell cycles. Ideally, initial release would also be delayed to promote wound healing.
The primary objective of this thesis project is to develop and evaluate a layered mesh to deliver chemotherapeutic in a controlled manner to prevent local cancer recurrence using the principles of superhydrophobicity. Superhydrophobic materials are composed of an intrinsically low surface energy material that is processed to become rough, increasing both the effective surface area and resistance to wetting. Because of the large energy barrier to wetting, these materials form stable or metastable air-liquid interfaces. Electrospinning is a well-developed technique in which a large electric potential draws out a polymer solution into a micron- or nano-scale fiber that collects onto the grounded target in a nonwoven random mesh. When chemotherapeutics are mixed into the electrospinning solution, they are encapsulated into the fibers. This technique is scalable and creates flexible materials with high porosity. Our group has investigated electrospinning poly(ε-caprolactone) (PCL) with a more hydrophobic copolymer poly(ε-caprolactone-co-glycerol monostearate) (PGC) and has succeeded in creating materials with robust superhydrophobicity.
My preliminary studies with these materials under physiologic conditions have shown that complete wetting can take many weeks. Since wetting is sequential from the outside in, release of drug present only in a middle layer is delayed until water reaches the core. In further testing of layered meshes, drug release exhibited initial delay: after 6 days less than 5% total loading was released, followed by a more rapid release that exhausted by ~30 days.
I hypothesize that the superhydrophobic character of electrospun meshes can control the wetting rate and therefore chemotherapeutic release after implantation, allowing prevention of local cancer recurrence. This project has numerous potential benefits over existing treatment options: 1) The local nature of delivery limits systemic side effects; 2) The kinetics of release create a high local tissue drug level over several weeks; 3) A variety of drugs can be employed including those too hydrophobic to be injected intravenously. Thus, my three aims are:

Aim 1: Create, characterize, and tune superhydrophobic, layered, electrospun meshes. Meshes will be electrospun and tuned for desired release kinetics using different fiber diameters, mesh porosities, layer thicknesses and drug loadings. Meshes will be characterized using contact angle measurements, SEM imaging, computed tomography (CT) imaging, compression and tensile testing.

Aim 2: Determine release and in vitro toxicity, with mechanical and surfactant stresses. Drug release and cytotoxicity toward three lung cancer cell types (LLC, NCI-H460, and a patient sample) will be tested under physiologic conditions. Meshes will be incubated in a serum solution under sink conditions and subjected to mechanical agitation and tensile and compressive stresses.

Aim 3: Evaluate in vivo efficacy in preventing local recurrence of cancer. Following complete resection of Lewis Lung Carcinoma (LLC) tumors, meshes will be implanted in rats at the resection site to test prevention of recurrence. Endpoints will be local recurrence-free survival, overall survival, tumor size and weight, histological score, and wound healing score at the implant site.