Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis

Abstract

Significance It has been previously reported that hypertrophic cartilage tissues engineered from human mesenchymal stromal cells can efficiently remodel in vivo into bone organs, recapitulating developmental steps of endochondral ossification. We have here demonstrated that the extracellular matrix (ECM) of such engineered cartilage, even in the absence of a living cell component, retains frankly osteoinductive properties. The use of an apoptosis-driven devitalization technique revealed the importance of preserving the ECM integrity and, in particular, the embedded factors to trigger the regenerative process. Although exemplified in a skeletal context, our work outlines the general paradigm of cell-based but cell-free off-the-shelf materials capable of activating endogenous cells toward the formation of specific tissues.

Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing

“…ECM from various sources have been studied previously as biomaterials for tissue regeneration, as ECM has a number of obvious advantages for tissue engineering applications [17,35,43,44]. The data presented in this study add to the body of work demonstrating the utility of different cell and native tissue-derived ECM to be used as scaffolds in orthopaedic medicine [21,25,[45][46][47][48][49][50][51][52].…”

“…Indeed, other studies have demonstrated that ectopic bone formation within growth factor delivery scaffolds also occurs through this endochondral pathway [40]. In contrast, recent studies have suggested that bone formation induced by devitalized cartilaginous ECM cannot be defined as being of the endochondral origin [21]. Further work is required to track the fate of progenitor cells that are recruited into devitalized ECM derived scaffolds in vivo.…”

“…To the best of our knowledge, this study is the first to investigate the use of a decellularized engineered hypertrophic cartilage matrix as a scaffold for orthotopic bone repair, demonstrating the potential of this approach. It builds on a body of work demonstrating the use of devitalized engineered ECM for tissue regeneration, including a recent study using death inducible MSCs to deposit a hypertrophic cartilage ECM that was subsequently shown to promote ectopic bone formation [21]. With all of these strategies, including that proposed in this study, scaling-up the manufacture of engineered tissues will be a significant challenge, and will be hampered by the difficulties involved with culturing the very large numbers of cells required to engineer cartilaginous grafts.…”

“…Furthermore, 'off-the-shelf' availability may well determine the extent to which any new therapy achieves widespread clinical adaption. This has led to increased interest in the use of decellularized extracellular matrix (ECM) derived scaffolds for the regeneration of different tissue types [17][18][19][20][21][22], based on the premise that such biomaterials contain structural and functional molecules to facilitate tissue regeneration. The ECM can be harvested from native tissue or from cell-derived matrix deposited during in vitro culture [23][24][25][26][27][28].…”

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

“…Indeed, implantation of a chondrogenic construct can spontaneously induce the subsequent formation of mineralized tissue, reminiscent of what is seen during endochondral bone formation (Harada et al, 2014;Tam et al, 2014;van Gastel et al, 2014;Weiss et al, 2012). Moreover, endochondral ossification can also be induced using cell-free implants obtained by devitalizing chondrogenic constructs, especially when matrix characteristics and the presence of growth factors to attract host cells are preserved (Bourgine et al, 2014). Furthermore, while the effect of hypoxia on osteogenic differentiation is not yet fully clear, the activation of hypoxia signalling in chondrocytes (Pfander et al, 2004) leads to higher expression of cartilage markers during in vitro culture (Shi et al, 2015;Strobel et al, 2010;Zhou et al, 2015), as well as improved collagen cross-linking during matrix synthesis (Makris et al, 2014) despite lowering of the proliferation of chondrocytes.…”