Ph.D Thesis

Ph.D StudentHecht Hadas
SubjectStructural Investigation of Ca-Alginate Physical Gelation
Using Molecular Dynamics Simulation
DepartmentDepartment of Polymer Engineering
Supervisor ASSOCIATE PROF. Simcha Srebnik


Calcium alginate is a natural occurring gel composed of two basic monomer units: guluronic (G) and mannuronic (M) acid residues. The G monomers are known to form specific strong physical cross-links with the calcium ions to form a gel. Calcium alginate gel is a very popular material for novel medical applications such as matrix device for drug delivery systems. The physical properties of alginate depend strongly on the sequence of the monomer blocks: GG, MM and alternating GM. The main objective of this research was to develop molecular model for theoretical prediction and better understanding of the alginate gelation mechanisms, gel nanostructure and physical properties relationships.

Molecular Dynamics simulation was used to study the influence of different G/M sequences and alginate ion concentrations on the association of chains and the mesoscopic structure formation. Physical characterizations of the resulting structures were fitted to known polymer gel models. Ion-monomer and monomer-monomer binding preferences and degree of association were measured using coarse-grained representation on the monomeric scale. The nano-structure properties of the chains were evaluated using measures such as the chains persistence length, gyration radius, end-to-end distance, contour length and calculation of the system particles radial distribution function and scattering curves.

Persistence length measurements of alginate chains showed chain stiffness to reduce in the following composition order: GGG>MMM>GGM>GMM>GMGM.  Fits to known polymer models revealed that GGG chains behave as rod like chains, MMM and GGM chains as semi-flexible worm like chains and GMGM and GMM chains as flexible chains. Alternating G/M sequences are more flexible, with GGM chains being stiffer relative to GMGM/GMM chains. Chain gyration radius (Rg) follows MMM>GGG>GGM>GMM>GMGM. Ca2 concentration didn't have a pronounced effect on any of the measured alginate chain dimensions.

Visual quantification of chain association number in Ca2-alginate solutions revealed chain association preference to be in the following order GMM>GMGM>MMM>GGM>GGG, indicating that M monomers operate as elasticity moderators and therefore promote chain association. MMM chains associate through rapid dimerization followed by lateral association of the dimers, while GGG chains associate in a slower dimerization stage through a gradual zipper mechanism. The three alternating G/M compositions form stiff zones connected by flexible zones, where the stiff zones are larger in the following order GGM>GMGM>GMM.

Structural properties of chain association in Ca2-alginate solution were investigated using radial distribution function (RDF) between monomers. It was found that MMM chains have higher order, while GGG chains have more specific binding. Heteropolymer G/M compositions show significantly less order. RDF measurements of monomer-ion association showed Na ions to favor specific association with MMM chains while Ca2 ions favors specific association with GGG chains.

Scattering curves of Ca2-alginate gel from atomic coordinates, according to Debye formula had good agreement with the broken-rod SAXS model. The broken-rod radius increased with increasing alginate concentration, caused by broader lateral associations of a growing number of alginate chains. The radius decreased with increasing Ca2 concentration, for most alginate compositions, due to the association of the chains in denser narrower rods with increasing number of Ca2 binding sites.