A new scaffold material based on a biocompatible silk-alginate hydrogel, which can be made soft or stiff, could provide the just right environment to culture stem cells for regenerative medicine, say researchers.

Stem cells could provide powerful new treatments for intractable autoimmune diseases, cancer, and other conditions. But the use of stem cells in the clinic requires a robust and reliable culture system that mimics the natural microenvironment of the cell. This microenvironment provides crucial direction to the function and viability of stem cells but is tricky to recreate artificially.

The complex make-up of the microenvironment, which includes a network of proteins like collagen or elastins forming an extracellular matrix (ECM), decides the fate of stem cells through a number of different, complementary mechanisms. For example, the stiffness of the matrix, determined by the orientation and elasticity of the fibers making up the ECM, as well as its fluid handling properties, the presence of signaling molecules and the creation of cytokine gradients all have a profound effect on the growing stem cells.

The new silk-alginate biocomposite developed by researchers at Stanford University and Queen’s University in Canada could provide a simple solution to tackle these complex problems. The hydrogel is formed from a mixture of alginate and silk in solution, which rapidly gels when immersed in CaCl2 [Ziv, et al., Biomaterials 35 (2014) 3736-3743, http://dx.doi.org/10.1016/j.biomaterials.2014.01.029]. But crucially, the stable hydrogel can be made soft and flexible or stiff by controlling the silk-alginate ratio and the concentration of crosslinking ions. Varying the silk-alginate ratio during fabrication changes the elasticity of the hydrogel, which can determine the yield of a particular differentiation path. The elasticity can be further fine-tuned in vitro by varying the CaCl2 concentration. Being able to modify the stiffness of the scaffold material to such a degree gives researchers a powerful means of guiding stem cell survival and differentiation.

“The ability to change the elasticity [of the silk-alginate hydrogel] helps mimic the natural process that is happening in the stem cell niche and improves the stem cell commitment into desired differentiation paths,” explain Keren Ziv and Harald Nuhn, of the Molecular Imaging Program at Stanford.

Using the protein laminin to enhance cell adhesion and promote cell growth, the researchers cultured mouse embryonic stem cells in the new scaffold material and transplanted samples into live mice. The silk-alginate hydrogel appears to be better at maintaining the survival of stem cells once transplanted than the best current alternative, matrigel.

But there is a long way to go until the new scaffold material could be used in the clinic for stem cell applications, cautions Ziv and Nuhn. Ideally, such applications would require the injection of the hydrogel in liquid form followed by gelation but this is currently unfeasible in vivo. The long-term stability of the hydrogel also needs to be scrutinized, along with its effect on other cell types. These issues are tractable, however, say the researchers, and are the focus of on-going efforts.