Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 4, Issue 10, Pages 3561-3569Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.8b00775
Keywords
dual gradient; hydrogels; biochemical; mechanical; zonal organization; cartilage
Categories
Funding
- NIH [R01DE024772]
- NSF CAREER award [CBET-1351289]
- California Institute for Regenerative Medicine Tools and Technologies Award [RT3-07804]
- Stanford Chem-H Institute
- Stanford Bio-X Interdisciplinary Initiative Program
- Stanford Child Health Research Institute Faculty Scholar Award
- Alliance for Cancer Gene Therapy Young Investigator award grant
- Stanford Graduate Fellowship
- Stanford Bio-X Interdisciplinary Program SIGF Fellowship
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Articular cartilage is characterized by zonal organizations containing dual gradients of biochemical cues and mechanical cues. However, how biochemical gradient interacts with the mechanical gradient to drive the cartilage zonal development remains largely unknown. Here, we report the development of a dual-gradient hydrogel platform as a 3D niche to elucidate the relative contributions of biochemical and mechanical niche gradients in modulating zonal-specific chondrocyte responses and cartilage zonal organization. Chondroitin sulfate (CS), a major constituent of cartilage extracellular matrix, was chosen as the biochemical cue. Poly(ethylene glycol), a bioinert polymer, was used to create the stiffness gradient. Dual-gradient hydrogels upregulated cartilage marker expressions and increased chondrocyte proliferation and collagen deposition in a zonal-dependent manner. Hydrogels with CS gradient alone exhibited poor mechanical strength and degraded prematurely after 1 week of culture. While CS gradient alone did not support long-term culture, adding CS gradient to mechanical-gradient hydrogels substantially enhanced cell proliferation, glycosaminoglycan production, and collagen deposition compared to mechanical gradient hydrogels alone. These results suggest that biochemical and mechanical gradient cues synergize to enhance cartilage zonal organization by chondrocytes in 3D. Together, our results validate the potential of dual-gradient hydrogels as a 3D cell niche for cartilage regeneration with zonal organization and may be used to recreate other tissue interfaces.
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