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Abstract
Cell laden biomaterials are archetypically seeded with individual cells and steered into the desired behavior using exogenous stimuli to control growth and differentiation. In contrast, direct cell-cell contact is instructive and even essential for natural tissue formation. Namely, microaggregation and condensation of mesenchymal progenitor cells triggers chondrogenesis and thereby drives limb formation. Yet a biomimetic strategy translating this approach into a cell laden biomaterial-based therapy has remained largely unexplored. Here, we integrate the microenvironment of cellular condensation into biomaterials by encapsulating microaggregates of a hundred human periosteum-derived stem cells. This resulted in decreased stemness-related markers, up regulation of chondrogenic genes and improved in vivo cartilage tissue formation, as compared to single cell seeded biomaterials. Importantly, even in the absence of exogenous growth factors, the microaggregate laden hydrogels outperformed conventional single cell laden hydrogels containing supraphysiological levels of the chondrogenic growth factor TGFB. Overall, the bioinspired seeding strategy described herein represents an efficient and growth factor-free approach to efficiently steer cell fate and drive tissue formation for biomaterial-based tissue engineering strategies.
Highlights
We recently have reported on the development of a high throughput platform for highly controlled production of cellular microaggregates of 50 to 250 cells[13]
We report on the effects of microaggregating human periosteum-derived progenitor cells on chondrogenic differentiation and cartilage formation both in vitro and in vivo
We investigated whether microaggregation improved in vivo chondrogenesis and subsequent cartilage formation
Summary
We hypothesize that seeding biomaterials with cellular microaggregates of a few dozen cells, instead of dispersed progenitor cells, will enable cell specification and subsequent augmentation of the implants’ chondrogenic capacity. A microaggregate based approach will allow for a more homogenous cell seeding within the biomaterial as compared to the conventional micromasses It has remained largely unknown if microaggregates of a few dozen cells behave distinctly from micromasses of ~200.000 cells. We recently have reported on the development of a high throughput platform for highly controlled production of cellular microaggregates of 50 to 250 cells[13] This platform enables the facile production of high quantities of stem cell microaggregates, which can be incorporated within the biomaterials using standard single cell seeding techniques. We demonstrate that microaggregation can be used as an easy biomimetic stimulatory pre-treatment prior to induce cartilage formation in a growth factor free manner
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