Bone fracture healing: Cell therapy in delayed unions and nonunions

Abstract

Bone fracture healing impairment related to mechanical problems has been largely corrected by advances in fracture management. Better protocols, more strict controls of time and function, and hardware and surgical technique evolution have contributed to better prognosis, even in complex fractures. However, atrophic nonunion persists in clinical cases where, for different reasons, the osteogenic capability is impaired. When this is the case, a better understanding of the basic mechanisms under bone repair and augmentation techniques may put in perspective the current possibilities and future opportunities. Among those, cell therapy particularly aims to correct this insufficient osteogenesis. However, the launching of safe and efficacious cell therapies still requires substantial amount of research, especially clinical trials. This review will envisage the current clinical trials on bone healing augmentation based on cell therapy, with the experience provided by the REBORNE Project, and the insight from investigator-driven clinical trials on advanced therapies towards the future. This article is part of a Special Issue entitled Stem Cells and Bone.

Autologous Bone Marrow Stem Cells combined with Allograft Cancellous Bone in Treatment of Nonunion

“…As is widely accepted, the "diamond concept" of bone fracture healing is applied to treating nonunion (Fayaz et al, 2011;Giannoudis et al, 2007;Gómez-Barrena et al, 2015). A triangular-shaped complex of interactions between the potent osteogenic cell populations, the osteoinductive stimulus and the osteoconductive matrix scaffolds are extensively studied and applied in search for the optimal grafting material (Giannoudis et al, 2007;Khan et al, 2011;Virk and Lieberman, 2012).…”

“…It is the only graft capable of providing all 3 elements of bone regeneration including osteogenic and osteoinductive as well as osteoconductive properties (Giannotti et al, 2013a;Hatzokos et al, 2011;Tressler et al, 2011). However, a bone autograft is limited in quantity and its harvesting represents an additional surgical intervention and donor site morbidity (Gómez-Barrena et al, 2015). Therefore, investigations are needed to provide a safe and effective alternative.…”

“…According to the above mentioned "diamond concept", BM-MSCs provide the most appropriate cells for inducing bone repair, as they have a strong osteogenic potential and are easily obtained by culturing iliac crest aspirates (Akram et al, 2014;Gómez-Barrena et al, 2015). But the graft of BM-MSCs should be seen as the catalyst for bone healing and not the only determining factor for the resolution of the disease.…”

“…Various alternative treatment modalities to stimulate bone healing, including tissue engineering, have been investigated all with the aim of minimizing patient morbidity (Dimitriou et al, 2011;Fox and Genever, 2014;Gómez-Barrena et al, 2015;Kim and Cho, 2013). Embedding viable cells within the biological scaffolds appears to be extremely promising since it allows osteocompetent cells to generate new bone tissue and contribute to the improved tissue healing (Connolly et al, 1989;Gamie et al, 2012;Giannotti et al, 2013a).…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…According to the diamond concept [12,[124][125][126][127], the biological elements of these therapies should involve MSCs and growth mediators including those promoting the new vasculature formation. Whether MSCs are delivered within concentrated or not-concentrated mononuclear bone marrow cells [128,129] or as culture-expanded pure population and loaded on matrices [130] or injected subcutaneously [131], their therapeutic use still needs further optimisation. The inflammation status could affect considerably the effectiveness of the regenerative treatments at least in part via their effect on MSCs [132].…”