Winblade, Natalie Dawn (2001) Blocking adhesion to cell and tissue surfaces via steric stabilization with graft copolymers containing poly(ethylene glycol) and phenylboronic acid. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-01202002-221541
Graft copolymers were designed to coat biological surfaces and thereby block subsequent adhesion and recognition events with other proteins, cells, and tissues. Inspired by polymeric steric stabilization of colloidal dispersions, the copolymers contain a backbone with affinity for biological surfaces and grafted side-chains that are resistant to adhesion of biological elements. Phenylboronic acid (PBA) moieties in the polymer backbone provided for binding, by forming reversible covalent complexes with cis-diols in oligosaccharides that are ubiquitous on cell surfaces and secreted macromolecules. The PBA moieties were conjugated to a poly-L-lysine (PLL) backbone via a secondary amine linker. Grafted poly(ethylene glycol) (PEG) side-chains provided for resistance of adhesion of proteins and cells. It was hypothesized that these PLL-g-(PEG;PBA) copolymers would spontaneously assemble on biological (e.g., cell or tissue) surfaces, where the PBA-containing backbone would bind to the surfaces and thereby anchor a dense PEG brush on the surface.
PLL-g-(PEG;PBA) copolymers were synthesized with varying degrees of PEG and PBA grafting. The pKa of the PBA groups was found to be circa 6, allowing for stronger binding at physiological pH than most PBA groups, which have pKas circa 8.8. The PLL-g-(PEG;PBA) copolymers were found to bind specifically to a mannan resin, where the PEG grafting ratio sterically controlled the binding. The copolymers coated red blood cells and blocked their agglutination by lectins and by blood group antibodies. The copolymers were also found to coat tissue culture polystyrene, adsorbed serum proteins, and extracellular matrix and to prevent the adhesion, spreading, and/or migration of rabbit lens epithelial cells on those surfaces. The copolymers displayed evidence of toxicity in vitro but no toxicity was seen when administered in vivo in models of posterior capsule opacification or peritoneal adhesion formation. PLL-g-(PEG;PBA) was found to interfere with the worsening of peritoneal adhesions following adhesiolysis. The efficacy of the copolymers was a function of the degree of PEG and PBA grafting, and PLL-g-(PEG;PBA) copolymers were found to be more effective than electrostatically-binding PLL-g-PEG copolymers. PLL-g-(PEG;PBA) copolymers have many possible clinical applications where blocking protein or cell interactions with cell, tissue, or biomaterial surfaces via a simple aqueous lavage is desired.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Subject Keywords:||cell adhesion; coatings; fibrin; in vitro; in vivo; interface; surface modification; tissue engineering; tissue interactions; wheat germ agglutinin|
|Degree Grantor:||California Institute of Technology|
|Division:||Chemistry and Chemical Engineering|
|Major Option:||Chemical Engineering|
|Thesis Availability:||Public (worldwide access)|
|Defense Date:||23 October 2000|
|Author Email:||natalie (AT) alumni.caltech.edu|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Imported from ETD-db|
|Deposited On:||20 Nov 2002|
|Last Modified:||26 Dec 2012 02:28|
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