In situ tissue engineering of the tendon-to-bone interface by endogenous stem/progenitor cells

Abstract

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

Effect of local anesthetics on viability and differentiation of various adult stem/progenitor cells

“…These findings may have a substantial clinical impact as LAs are frequently applied during the procedures to isolate stem/progenitor cells from adult tissues for regenerative medicine [3,11,16]. Moreover, the long-lasting side effect of LAs can be detrimental to the emerging in situ regeneration application that requires LAs administration during surgical procedures for delivering bioactive cues to recruit and/or stimulate endogenous stem/progenitor cells [14,[20][21][22][23].…”

“…Picrosirius Red (PR) staining was completed to evaluate collagen deposition, whereas Alcian Blue (AB) staining to evaluate chondrogenic differentiation. Alizarin Red (AR) staining and Oil Red O (ORO) staining were used to evaluate osteogenesis and adipogenesis, respectively, following our protocols [19,20,22]. The collagen deposition, AR-stained calcification, AR-stained proteoglycan, and ORO-positive lipid droplets were indirectly quantified guided by the previously validated digital imaging processing protocol [28,29].…”

“…The procedure for isolating adult stem/progenitor cells mostly requires the administration of LAs [14][15][16][17][18]. Moreover, we and others have made promising progress in an emerging field of in situ regeneration which is to guide the regeneration of various tissues by recruiting and activating endogenous stem/progenitor cells [19][20][21][22][23]. In situ regeneration approaches, mostly requiring delivery of bioactive cues with or without scaffolds, necessitate administration of LAs during the surgical and non-surgical procedures [14,15,[19][20][21][22][23].…”

“…Moreover, we and others have made promising progress in an emerging field of in situ regeneration which is to guide the regeneration of various tissues by recruiting and activating endogenous stem/progenitor cells [19][20][21][22][23]. In situ regeneration approaches, mostly requiring delivery of bioactive cues with or without scaffolds, necessitate administration of LAs during the surgical and non-surgical procedures [14,15,[19][20][21][22][23]. Accordingly, it is important to understand the potential effects of LAs not only on short-term cell viability but also on multilineage differentiation afterward.…”

Implementation of Endogenous and Exogenous Mesenchymal Progenitor Cells for Skeletal Tissue Regeneration and Repair

“…Over the years, regenerative approaches for treating tendon and ligament injuries have been explored. These include: (i) cell based therapies [180][181][182] (ii) gene therapy [24,183] (iii) orthobiologics/platelet rich plasma injections (PRP) [119,120,184], and recently, (iv) cell free strategies that implement sustained released growth factors to recruit endogenous stem cell that promote healing [121]. Biochemical factors such as cytokines (IL-6, IL-10, IL-1β,TNF-α) [185][186][187] and growth factors (transforming growth factor (TGF)-β, basic fibroblast growth factor (bFGF), IGF-1, PDGF) play a crucial role in maintaining tissue homeostasis [152,188].…”