Hydrogel Chemistry and Crosslinking Mechanisms – Part 2
Some of the earliest hydrogels used for cell encapsulation were, (not ironically) naturally derived, ionically crosslinked materials, such as alginate, chitin and agarose. Although somewhat low-tech, these were a natural place to start. Alginate is a polysaccharide found in the cell walls of brown algae, and produced commercially by refining wild seaweed. Solutions of alginate are reversibly crosslinked by divalent cations, such calcium (Ca2+), barium (Ba2+) or magnesium (Mg2+) – most commonly Ca2+. After the hydrogel has crosslinked, the crosslinks can be removed by adding a chelating agent (eg EDTA, ethylenediaminetetraacetic acid), which competitively bind and remove the Ca2+.
Benefits of Alginates
Alginate, like all polysaccharides, does not have cell adhesion domains, so encapsulated cells generally have a rounded morphology. It is not cell degradable, meaning that in the absence of a chelating agent, the gels generally retain their shape and structure for long periods. This can be beneficial in certain applications – for example, in new treatments being developed for diabetes. People with type I diabetes regularly check their blood sugar and inject insulin as required.
Are Pancreatic Islets the solution?
A fundamentally different approach is to transplant the cells that normally produce insulin, pancreatic islet cells, into the pancreas of the patient. Clearly there is a limited number of human donors from which these pancreatic islets can be derived, so an alternative is to use animal cells. Living Cell Technologies (http://www.lctglobal.com/) is developing a treatment in which pancreatic islet cells from a disease-free pig population are encapsulated in alginate and implanted into type I diabetes patients. The encapsulated cells produce insulin as required, and the alginate barrier shields the insulin-producing cells from the immune response that would otherwise be triggered by implanting pig-derived cells into the body.
Gellan Gum as an alternative
Gellan gum is another polysaccharide hydrogel that can be ionically crosslinked. Like alginate, it is negatively charged, so is crosslinked by cations (such as Ca2+). It is produced by bacteria, and used as a gelling agent or thickener in foods. It has also been used in medical research – for example as a biomaterial for intervertebral disc repair (Silva-Correia et al. 2011).
Chitosan facilitates negative crosslinking
Chitosan is derived from the exoskeletons of crustaceans, but unlike alginate and gellan gum, chitosan is a positively charged polymer, and is crosslinked by negatively charged ions, such as molybdenum ions (Mb(VI)) or platinum ions (Pt(II)). In addition, chitosan can also form ionically crosslinked polyelectrolyte complexes (PECs) by mixing with negatively charged polymers, such as chondroitin sulfate. Natural polymers certainly have their advantages, and ionic crosslinking is just one way that these hydrogels can be crosslinked. The next topic will be looking at another option – thermal crosslinking.
Silva-Correia, J., J. M. Oliveira, S. G. Caridade, J. T. Oliveira, R. A. Sousa, J. F. Mano and R. L. Reis. 2011. “Gellan gum-based hydrogels for intervertebral disc tissue-engineering applications.” Journal of Tissue Engineering and Regenerative Medicine 5: 97-107.