title: A Diels-Alder modulated approach to control and sustain the release of dexamethasone and induce osteogenic differentiation of human mesenchymal stem cells.
abstract: We report a new approach to controlled drug release based upon exploiting the dynamic equilibrium that exists between Diels-Alder reactants and products, demonstrating the release of a furan containing dexamethasone peptide (dex-KGPQG-furan) from a maleimide containing hydrogel. Using a reaction-diffusion model, the release kinetics were tuned to achieve sustained concentrations conducive to osteogenic differentiation of human mesenchymal stem cells (hMSCs). Efficacy was first demonstrated in a 2D culture model, in which dexamethasone release induced significant increases in alkaline phosphatase (ALP) activity and mineral deposition in hMSCs compared to a dexamethasone-free treatment. The results were similar to that observed with a soluble dexamethasone treatment. More dramatic differences were observed in 3D culture, where co-encapsulation of a dexamethasone releasing hydrogel depot within an hMSC-laden extracellular matrix mimetic poly(ethylene glycol) hydrogel resulted in a local and robust osteogenic differentiation. ALP activity reached levels that were up to six times higher than the dexamethasone free treatment. Interestingly, at 5 and 10 day time points, the ALP activity exceeded the dexamethasone positive control, suggesting a potential benefit of sustained release in 3D culture. After 21 days, substantial mineralization comparable to the positive control was also observed in the hydrogels. Collectively, these results demonstrate Diels-Alder modulated release as an effective and versatile new platform for controlled drug delivery that may prove especially beneficial for sustaining the release of low molecular weight molecules in hydrogel systems.
authors: University of Colorado - Boulder, Department of Chemical and Biological Engineering, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA. Electronic address: kckoehler@gmail.com.
authors: Kenneth C
authors: KC
authors: Koehler
authors: University of Colorado - Boulder, Department of Chemical and Biological Engineering, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA; University of Colorado - Boulder, Howard Hughes Medical Institute, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA.
authors: Daniel L
authors: DL
authors: Alge
authors: University of Colorado - Boulder, Department of Chemical and Biological Engineering, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA; University of Colorado - Boulder, Howard Hughes Medical Institute, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA.
authors: Kristi S
authors: KS
authors: Anseth
authors: University of Colorado - Boulder, Department of Chemical and Biological Engineering, 3415 Colorado Avenue UCB 596, JSC Biotech Building 530, Boulder, CO 80303-0596, USA. Electronic address: christopher.bowman@colorado.edu.
authors: Christopher N
authors: CN
authors: Bowman
mesh_terms: D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D003198:Computer Simulation; D061565:Cycloaddition Reaction; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003692:Delayed-Action Preparations; D010455:Peptides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D003907:Dexamethasone