Control of collagen gel mechanical properties through manipulation of gelation conditions near the sol-gel transition.

The ability to control the mechanical properties of cell culture environments is known to influence cell morphology, motility, invasion and differentiation. The present work shows that it is possible to control the mechanical properties of collagen gels by manipulating gelation conditions near the sol gel transition. This manipulation is accomplished by performing gelation in two stages at different temperatures. The mechanical properties of the gel are found to be strongly dependent on the duration and temperature of the first stage. In the second stage the system is quickly depleted of free collagen which self assembles into a highly branched network characteristic of gelation at the higher temperature (37 °C). An important aspect of the present work is the use of advanced rheometric techniques to assess the transition point between viscoelastic liquid and viscoelastic solid behaviour which occurs upon establishment of a sample spanning network at the gel point. The gel time at the stage I temperature is found to indicate the minimum time that the gelling collagen sample must spend under stage I conditions before the two stage gelation procedure generates an enhancement of mechanical properties. Further, the Fractional Maxwell Model is found to provide an excellent description of the time-dependent mechanical properties of the mature collagen gels.

A semi-empirical computational model for the inhibition of porcine cholesterol esterase.

Cholesterol esterase significantly contributes to cell membrane structure. It also facilitates transfer of cholesterol and phospholipids across membranes. Inhibition of this enzyme by a number of xenobiotics has been reported. This research sought to confirm if a widely used methacrylate monomer, bisphenol A dimethacrylate, inhibits porcine cholesterol esterase since this and other methacrylates are known to leach from various biomaterial preparations. A quantum mechanically developed computational chemistry model is presented. Specific chemical information linking potential mechanisms of cholesterol esterase inhibition to chemical structure is shown. Model chemical descriptors identified the importance of maximum oxygen valency and molecular shape/size to cholesterol esterase inhibition. A porcine cholesterol esterase inhibition mechanism is inherent in bisphenol A dimethacrylate which mimics chemical properties of reported cholesterol esterase inhibitors. This predictive semiempirical quantum mechanical model can be used to design new cholesterol esterase non-inhibitors for biocompatible biomaterials used in an aqueous environment.

Quantum mechanical quantitative structure activity relationships to avoid mutagenicity in dental monomers.

The objective of this study was to identify through quantum mechanical quantitative structure activity relationships (Q-QSARs) chemical structures in dental monomers that influence their mutagenicity. AMPAC, a semiempirical computer program that provides quantum mechanical information for chemical structures, was applied to three series of reference chemicals: a set of methacrylates, a set of aromatic and a set of aliphatic epoxy compounds. QSAR models were developed using this chemical information together with mutagenicity data (Salmonella TA 100, Ames Test). CODESSA, a QSAR program that calculates quantum chemical descriptors from information generated by AMPAC and statistically matches these descriptors with observed biological properties was used. QSARs were developed which had r2 values exceeding 0.90 for each study series. These QSARs were used to accurately predict the mutagenicity of BISGMA. a monomer commonly used in dentistry, and two epoxy monomers with developing use in dentistry, GY-281 and UVR-6105. The Q-QSAR quantum mechanical descriptors correctly predicted the level of mutagenicity for all three compounds. The descriptors in the correlation equation pointed to components of structure that may contribute to mutagenesis. The QSARs also provided 'dose windows' for testing mutagenicity, circumventing the need for extensive dose exploration in the laboratory. The Q-QSAR method promises an approach for biomaterials scientists to predict and avoid mutagenicity from the chemicals used in new biomaterial designs.

Evaluation of quantitative structure property relationships necessary for enantioresolution with lambda- and sulfobutylether lambda-carrageenan in capillary electrophoresis.

Lambda-carrageenan, a linear, high molecular weight sulfated polysaccharide, was successfully employed in both its native and sulfobutyl derivatized form as a chiral selector in capillary electrophoresis for the separation of enantiomers of basic pharmaceutical compounds. In order to characterize the chiral selectivity properties of this chiral selector, various structurally related racemic compounds were analyzed for enantiomeric interactions using capillary electrophoresis. The results of these studies were then rationalized and analyzed utilizing a general quantitative structure-property relationship (QSPR) evaluation in order to predict critical analyte structural requirements for successful enantiomeric separation. Important structural components of the analytes were found to include the aromatic content, the type of substitution on the aromatic ring, presence of a primary or secondary protonated amine, and an overall positive charge to the molecule.

Semiempirical and ab initio conformational analysis of 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane with application of GIAO-SCF methods to NMR spectrum interpretation.

The GIAO-SCF method for calculating isotropic nuclear magnetic shielding values has been utilized to explain certain features in the 1H-NMR spectrum of 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane. Population distributions of the low-energy conformers based on their ab initio energies were used to produce weighting factors for the individual calculated shielding values to calculate the weighted average of the shielding values for a complete set of conformers. The differences in 1H chemical shifts between the hydrogens of the two methyl groups and between the axial and equatorial hydrogens in 2-methylene-8,8-dimethyl-1,4,6,10-tetraoxaspiro[4.5] decane were shown to be due to energy differences between the chair and boat orientations of the six-membered ring and contribution from a twist-boat conformation. Results suggest a hypothesis that intramolecular differences in chemical shift might be calculated to a greater degree of accuracy than chemical shifts calculated relative to a standard.

A semiempirical computational investigation of the antipsoriatic drug anthralin.

A series of computational studies was carried out, by using the highly successful Austin Model 1 (AM1) semiempirical method, to illuminate more completely the fundamental, molecular-level forces that affect the function and utility of the antipsoriatic drug anthralin. First, examination of the keto-enol tautomeric equilibrium by AM1 showed that the keto tautomer of the drug is 9.5 kcal/mol more stable than the enol form. Strong electrostatic forces involving the hydrogens on the hydroxy groups (a partial charge of +0.25 in both forms) and the keto oxygen (a partial charge of -0.40) apparently overcome the effects of the increased aromatic stabilization present in the enol form. Second, AM1 was applied to the degradation products of anthralin, 1,8-dihydroxy-9,10-anthraquinone, 1,8,1',8'-tetrahydroxy-10,10'-dianthrone, and a further oxidized form of the dimer. These molecules have been implicated in some of the unpleasant side effects of anthralin. Third, AM1 was used to predict the preferred site of ionization of anthralin.