Hypoxia mimicking hydrogels to regulate the fate of transplanted stem cells.

Controlling the phenotype of transplanted stem cells is integral to ensuring their therapeutic efficacy. Hypoxia is a known regulator of stem cell fate, the effects of which can be mimicked using hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors such as dimethyloxalylglycine (DMOG). By releasing DMOG from mesenchymal stem cell (MSC) laden alginate hydrogels, it is possible to stabilize HIF-1α and enhance its nuclear localization. This correlated with enhanced chondrogenesis and a reduction in the expression of markers associated with chondrocyte hypertrophy, as well as increased SMAD 2/3 nuclear localization in the encapsulated MSCs. In vivo, DMOG delivery significantly reduced mineralisation of the proteoglycan-rich cartilaginous tissue generated by MSCs within alginate hydrogels loaded with TGF-ß3 and BMP-2. Together these findings point to the potential of hypoxia mimicking hydrogels to control the fate of stem cells following their implantation into the body. STATEMENT OF SIGNIFICANCE: There are relatively few examples where in vivo delivery of adult stem cells has demonstrated a true therapeutic benefit. This may be attributed, at least in part, to a failure to control the fate of transplanted stem cells in vivo. In this paper we describe the development of hydrogels that mimic the effects of hypoxia on encapsulated stem cells. In vitro, these hydrogels enhance chondrogenesis of MSCs and suppress markers associated with chondrocyte hypertrophy. In an in vivo environment that otherwise supports progression along an endochondral pathway, we show that these hydrogels will instead direct mesenchymal stem cells (MSCs) to produce a more stable, cartilage-like tissue. In addition, we explore potential molecular mechanisms responsible for these phenotypic changes in MSCs.

3D finite element model of meniscectomy: changes in joint contact behavior.

The goal of this study is to quantify changes in knee joint contact behavior following varying degrees of the medial partial meniscectomy. A previously validated 3D finite element model was used to simulate 11 different meniscectomies. The accompanying changes in the contact pressure on the superior surface of the menisci and tibial plateau were quantified as was the axial strain in the menisci and articular cartilage. The percentage of medial meniscus removed was linearly correlated with maximum contact pressure, mean contact pressure, and contact area. The lateral hemi-joint was minimally affected by the simulated medial meniscectomies. The location of maximum strain and location of maximum contact pressure did not change with varying degrees of partial medial meniscectomy. When 60% of the medial meniscus was removed, contact pressures increased 65% on the remaining medial meniscus and 55% on the medial tibial plateau. These data will be helpful for assessing potential complications with the surgical treatment of meniscal tears. Additionally, these data provide insight into the role of mechanical loading in the etiology of post-meniscectomy osteoarthritis.