Control of the electromechanical properties of alginate hydrogels via ionic and covalent cross-linking and microparticle doping.

Many tissues in the human body consist of cells embedded in an extracellular matrix that has an abundance of charged macromolecules. Examples of such tissues include tendon, bone, cartilage, and corneal stroma. Motions of the body impose on these tissues solid and fluid mechanical stimuli, such as compression, tension, and viscous shear due to fluid flow. Mechanical stimuli may influence cell behavior by activating cell signaling cascades that modulate gene expression or protein activity. Mechanical stimuli may act on cells directly (e.g., by perturbing stretch sensitive membrane proteins) or indirectly through electric fields (e.g., by perturbing voltage-sensitive ion channels), which are generated as a consequence of mechanical perturbation of the highly charged tissues. Understanding such mechanotransduction processes is important to enable design of tissue scaffolds that send appropriate regulatory signals to cells when mechanically stimulated. In general, tissue engineering seeks (at the microscale) to mimic a cell’s native chemical and mechanical environment and (at the macroscale) to mimic the function of tissue. Many macromolecular materials have been implemented for this purpose, including natural polymers such as chitosan, alginate, collagen, and fibrin, as well as synthetic polymers such as PEG-diacrylate and PLGA. Chemical biocompatibility is typically assessed in terms of binding, toxicity, degradability, and so on, and mechanical compatibility is assessed in terms of the similarity of the material’s bulk mechanical properties to those of native tissue, as well as the material’s ability to support phenotypic behavior, morphology, and gene expression. While the chemical and mechanical properties of tissue scaffolds have received considerable attention, the electrical (and, in particular, electromechanical) properties of scaffolds have been less thoroughly explored. Descriptive work exists in native tissues, including detailed measurements and modeling of the electromechanics of cartilage and bone. Additionally, techniques have been investigated that use electrical stimulation to enhance healing of bone, tendon, and ligament. However, the electromechanical properties of hydrogels remain largely unmeasured and have not been manipulated for tissue engineering applications. Chondrocytes are an example of a cell type in which tissuespecific cell behavior has been observed to change as a function of electromechanical environment. Dynamic compression of cartilage tissue and chondrocyte-seeded tissue scaffolds stimulates chondrocytes to increase biosynthesis of glycosaminoglycans (GAG), which are primarily responsible for the compressive strength of cartilage. Coupled mechanical, physicochemical, and electrical stimuli are thought to play a role in controlling chondrocyte response to mechanical loading. In particular, the concentration of glycosaminoglycans in dynamically compressed samples is positively correlated with fluid velocity, indicating that the stimulus is related to fluid transport. This points toward hydrodynamic shear, flowenhanced nutrient transport, and flow-induced electric fields, which are all coupled to the intrinsic electromechanical properties of the tissue, as possible mechanotransduction stimuli. An understanding of the relative importance of these phenomena in regulating chondrocyte metabolism would be a significant achievement for cartilage tissue engineering and instruct better scaffold design.