5 research outputs found
Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.
The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials
Biocompatible polymer microarrays for cellular high-content screening
The global aim of this thesis was to study the use of microarray technology for the
screening and identification of biocompatible polymers, to understand physiological
phenomena, and the design of biomaterials, implant surfaces and tissue-engineering
scaffolds. This work was based upon the polymer microarray platform developed by the
Bradley group.
Polymer microarrays were successfully applied to find the best polymer supports for:
(i) mouse fibroblast cells and used to evaluate cell biocompatibility and cell
morphology. Fourteen polyurethanes demonstrated significant cellular adhesion.
(ii) Analysis of the adhesion of human erythroleukaemic K562 suspension cells onto
biomaterials with particular families of polyurethanes and polyacrylates identified. A
DNA microarray study (to access the global gene expression profiles upon cellular
binding) demonstrated that interactions between cells and some polyacrylates induced a
number of transcriptomic changes. These results suggested that, during these
interactions, a chain of cellular changes is triggered, most notably resulting in the downregulation
of membrane receptors and ligands.
(iii) Identification of polymers with potential applications in the field of stem cell
biology. Polymers were identified that showed attachment, promotion and stabilisation
of hepatocyte-like cells. A polyurethane support (PU-134) was pinpointed, which
significantly improved both hepatocyte-like cell function and âlifespanâ. A second
project investigated biomaterials that promoted adhesion, growth and function of
endothelial progenitor cells. A new polymer matrix was identified which contained the
necessary signals to promote endothelial phenotype and function. This has potential
application in the creation of blood vessels and the endothelialisation of artificial vessel
prostheses and stent coatings for improving angioplasty therapy.
(iv) The study of bacterial adhesion, focusing on the adhesion of food-borne pathogenic
bacterium Salmonella enterica serovar typhimurium, strain SL1344, and the commensal
bacterium Escherichia coli, strain W3110. Several polymers were found to support
selective bacterial enrichment, as well as others that minimised bacterial adhesion