pH-sensitive and thermosensitive hydrogels as stem-cell carriers for cardiac therapy.pdf

Stem-cell therapy has the potential to regenerate

damaged heart tissue after a heart attack. Injectable hydrogels may be

used as stem-cell carriers to improve cell retention in the heart tissue.

However, current hydrogels are not ideal to serve as cell carriers because

most of them block blood vessels after solidification. In addition, these

hydrogels have a relatively slow gelation rate (typically >60 s), which

does not allow them to quickly solidify upon injection, so as to

efficiently hold cells in the heart tissue. As a result, the hydrogels and

cells are squeezed out of the tissue, leading to low cell retention. To

address these issues, we have developed hydrogels that can quickly

solidify at the pH of an infarcted heart (6−7) at 37 °C but cannot

solidify at the pH of blood (7.4) at 37 °C. These hydrogels are also

clinically attractive because they can be injected through catheters

commonly used for minimally invasive surgeries. The hydrogels were

synthesized by free-radical polymerization of N-isopropylacrylamide, propylacrylic acid, hydroxyethyl methacrylate-cooligo(

trimethylene carbonate), and methacrylate poly(ethylene oxide) methoxy ester. Hydrogel solutions were injectable

through 0.2-mm-diameter catheters at pH 8.0 at 37 °C, and they can quickly form solid gels under pH 6.5 at 37 °C. All of the

hydrogels showed pH-dependent degradation and mechanical properties with less mass loss and greater complex shear modulus

at pH 6.5 than at pH 7.4. When cardiosphere-derived cells (CDCs) were encapsulated in the hydrogels, the cells were able to

survive during a 7-day culture period. The surviving cells were differentiated into cardiac cells, as evidenced by the expression of

cardiac markers at both the gene and protein levels, such as cardiac troponin T, myosin heavy chain α, calcium channel

CACNA1c, cardiac troponin I, and connexin 43. The gel integrity was found to largely affect CDC cardiac differentiation. These

results suggest that the developed dual-sensitive hydrogels may be promising carriers for cardiac cell therapy.