The long-term success of surgical repair of rotator cuff tears is largely dependent on restoration of a functional tendon-to-bone interface. We implemented micro-precise spatiotemporal delivery of growth factors in three-dimensional printed scaffolds for integrative regeneration of a fibrocartilaginous tendon-to-bone interface. Sustained and spatially controlled release of tenogenic, chondrogenic and osteogenic growth factors was achieved using microsphere-based delivery carriers embedded in thin membrane-like scaffolds. In vitro, the scaffolds embedded with spatiotemporal delivery of growth factors successfully guided regional differentiation of mesenchymal progenitor cells, forming multiphase tissues with tendon-like, cartilage-like and bone-like regions. In vivo, when implanted at the interface between the supraspinatus tendon and the humeral head in a rat rotator cuff repair model, these scaffolds promoted recruitment of endogenous tendon progenitor cells followed by integrative healing of tendon and bone via reformation of strong fibrocartilaginous interfaces. Our findings demonstrate the potential of in situ tissue engineering of tendon-to-bone interfaces by endogenous progenitor cells. The in situ tissue engineering approach shows translational potential for improving outcomes after rotator cuff repair
Tendons injuries frequently result in scar-like tissue with poor biochemical structure and mechanical properties. We have recently reported that CD146 + perivascular originated tendon stem/progenitor cells (TSCs), playing critical roles in tendon healing. Here, we identified highly efficient small molecules that selectively activate endogenous TSCs for tendon regeneration. Methods : From a pool of ERK1/2 and FAK agonists, Oxo-M and 4-PPBP were identified, and their roles in tenogenic differentiation of TSCs and in vivo tendon healing were investigated. Controlled delivery of Oxo-M and 4-PPBP was applied via PLGA µS. Signaling studies were conducted to determine the mechanism for specificity of Oxo-M and 4-PPBP to CD146 + TSCs. Results : A combination of Oxo-M and 4-PPBP synergistically increased the expressions of tendon-related gene markers in TSCs. In vivo , delivery of Oxo-M and 4-PPBP significantly enhanced healing of fully transected rat patellar tendons (PT), with functional restoration and reorganization of collagen fibrous structure. Our signaling study suggested that Oxo-M and 4-PPBP specifically targets CD146 + TSCs via non-neuronal muscarinic acetylcholine receptors (AChR) and σ1 receptor (σ1) signaling. Principal conclusions : Our findings demonstrate a significant potential of Oxo-M and 4-PPBP as a regenerative therapeutics for tendon injuries.
Summary Studies have indicated significant pubertal-related differences in hormonal stress reactivity. We report here that prepubertal (30d) male rats display a more protracted stress-induced corticosterone response than adults (70d), despite showing relatively similar levels of adrenocorticotropic hormone (ACTH). Additionally, we show that adrenal expression of the ACTH receptor, melanocortin 2 receptor (Mc2r), is higher in prepubertal compared to adult animals, and that expression of melanocortin receptor accessory protein (Mrap), a molecule that chaperones MC2R to the cell surface, is greater in prepubertal males following stress. Given that these data suggest a pubertal shift in adrenal sensitivity to ACTH, we directly tested this possibility by injecting prepubertal and adult males with 6.25 or 9.375 μg/kg of exogenous rat ACTH and measured their hormone levels 30 and 60 min post-injection. As these doses resulted in different circulating levels of ACTH at these two ages, we performed regression analyses to assess the relationship between circulating ACTH and corticosterone concentrations. We found no difference between the ages in the correlation between ACTH and corticosterone levels at the 30 min time point. However, 60 min following the ACTH injection, we found prepubertal rats had significantly higher corticosterone concentrations at lower levels of ACTH compared to adults. These data suggest that prolonged exposure to ACTH leads to greater corticosterone responsiveness prior to puberty, and indicate that changes in adrenal sensitivity to ACTH may, in part, contribute to the protracted hormonal stress response in prepubertal rats.
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