Our overriding motivation is to produce biomimetic endothelial cell glycocalyx surfaces that provide biocompatibility of blood-contacting polymeric implants. The ability to biofunctionalize solid substrates by binding ultra thin films onto the surface makes possible the bioengineered construction of biomimetic membrane structures. Using novel synthetic and attachment chemistries, surfaces can be tailored to have a confluent layer of specific molecular structures such as oligosaccharides and glycoproteins, major constituents of the glycocalyx. These coatings can then also serve as a backbone for coupling different macromolecules selected to have specific binding capabilities or therapeutic activities, making the blood- contacting biomimetic surface suitable for biosensor or drug delivery applications. Considering the human vascular endothelial glycocalyx's vast surface area, it is an important structure for study in bioengineering and understanding the molecular basis of biocompatibility in vascular biology and medicine. An artificial glycocalyx will have direct, and broad, clinical application in cardiovascular medicine and will also serve as a powerful research tool in the cardiovascular sciences. For example, the creation of a biomimetic glycocalyx confers the ability to study molecular function of circulating cells and proteins in vitro or to manufacture a truly nonreactive extracorporeal circulation circuit for use in cardiopulmonary bypass surgery. In our proposed application, particular attention is paid to nano-scale structure-function relationships that govern the biomimetic glycocalyx's contribution to responses to contact with blood and its derivatives. Our global hypothesis is that the chemical composition and nano-scale surface structure features of coated biomaterials contacting blood control adverse physiological responses and thus determine the functional limits of bio- or hemo-compatibility. We will test this hypothesis via three Specific Aims. We will derivatize and coat planar and tubular surfaces with biological and synthetic macromolecules selected to impart biocompatibility and therapeutic function to implantable devices. We will characterize the derivatized surface nano-scale structure, including its electrostatic profile. We will use experimental methods to identify specific molecular pathways governing pathophysiological responses, including thrombogenic and inflammatory responses, to blood contact with derivatized surfaces. We will assess surface durability and rheology. We will incorporate findings from these aims to make functional correlates of hemo- and bio- compatibility corresponding to specific nanoscale surface structural features. Use of these preclinical studies will enable identification of biomaterial surface constructs having interventional and therapeutic potential. Narrative Blood contact with artificial surfaces such as dialysis and cardiac bypass tubing, vascular catheters, stents, grafts and other implantable causes blood clotting and inflammatory responses. This research will evaluate biomimetic surface coatings made from biomacromolecules and quantify responses of blood and blood products contacting those artificial surfaces. The development of biomimetic surface coatings is a powerful method to increase medical device biocompatibility.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060230-11
Application #
7790728
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Moore, Timothy M
Project Start
1998-12-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$437,278
Indirect Cost
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lee, Hyun-Su; Dastgheyb, Sana S; Hickok, Noreen J et al. (2015) Targeted release of tobramycin from a pH-responsive grafted bilayer challenged with S. aureus. Biomacromolecules 16:650-9
Kandel, Judith; Lee, Hyun-Su; Sobolewski, Peter et al. (2014) Chemically grafted fibronectin for use in QCM-D cell studies. Biosens Bioelectron 58:249-257
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Coll Ferrer, M Carme; Eckmann, Uriel N; Composto, Russell J et al. (2013) Hemocompatibility and biocompatibility of antibacterial biomimetic hybrid films. Toxicol Appl Pharmacol 272:703-12
Lee, Hyun-Su; Stachelek, Stanley J; Tomczyk, Nancy et al. (2013) Correlating macrophage morphology and cytokine production resulting from biomaterial contact. J Biomed Mater Res A 101:203-12
Lee, Hyun-Su; Tomczyk, Nancy; Kandel, Judith et al. (2013) Hemocompatibility of Chitosan/poly(acrylic acid) Grafted Polyurethane Tubing. J Mater Chem B 1:
Eckmann, David M; Tsai, Irene Y; Tomczyk, Nancy et al. (2013) Hyaluronan and dextran modified tubes resist cellular activation with blood contact. Colloids Surf B Biointerfaces 108:44-51

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