Make no bones about it: cells could soon be reprogrammed to grow replacement bones?

Abstract

Recent developments in nuclear reprogramming allow the generation of patient-matched stem cells with broad potential for applications in cell therapies, disease modeling and drug discovery. An increasing body of work is reporting the derivation of lineage-specific progenitors from human-induced pluripotent stem cells (hiPSCs), which could in the near future be used to engineer personalized tissue substitutes, including those for reconstructive therapies of bone. Although the potential clinical impact of such technology is not arguable, significant challenges remain to be addressed before hiPSC-derived progenitors can be employed to engineer bone substitutes of clinical relevance. The most important challenge is indeed the construction of personalized multicellular bone substitutes for the treatment of complex skeletal defects that integrate fast, are immune tolerated and display biofunctionality and long-term safety. As recent studies suggest, the merging of iPSC technology with advanced biomaterials and bioreactor technologies offers a way to generate bone substitutes in a controllable, automated manner with potential to meet the needs for scale-up and requirements for translation into clinical practice. It is only via the use of state-of-the-art cell culture technologies, process automation under GMP-compliant conditions, application of appropriate engineering strategies and compliance with regulatory policies that personalized lab-made bone grafts can start being used to treat human patients.

Engineering human bone grafts with new macroporous calcium phosphate cement scaffolds

“…Human MSCs derived from adult tissues display differentiation potential towards the mesodermal lineages (Pittenger et al, 1999), play a major role in bone development and regeneration (De Bruyn & Kabish, 1955), and have already been used in the clinic for dental and orthopaedic applications (Egusa, Sonoyama, Nishimura, Atsuta, & Akiyama, 2012;Gómez-Barrena et al, 2015). However, they display limited regenerative potential (Bonab et al, 2006;de Peppo, Sjovall, et al, 2010;de Peppo, Svensson, et al, 2010) and may not be available in sufficient amounts for every patient (de Peppo & Marolt, 2014;Zhou et al, 2008). On the other hand, human iPSCs can be easily derived, proliferate indefinitely, and give rise to all cells constituting the bone tissue (Takahashi et al, 2007), opening the possibility to grow Inclusion of multiple cell lines also increases the validity of this comparison and suggests that similar outcomes would arise when using different cell lines (i.e.…”

“…New strategies are therefore required to develop future treatments that are safer and display higher therapeutic potential. Human bone engineering opens the possibility to grow large amount of personalized bone for basic and applied research and for the clinic (de Peppo & Marolt, 2014). Successful engineering of functional bone tissue relies on combining osteocompetent cells with compliant biomaterials (Griffith & Naughton, 2002;Morishita et al, 2006).…”

Cellularizing hydrogel-based scaffolds to repair bone tissue: How to create a physiologically relevant micro-environment?

“…They maintain their pluripotent property during this amplification step, and only afterward can they be induced toward the osteoblastic differentiation pathway. 195,196 Besides, it is possible to generate different specialized cell types from a single source of iPSCs, enabling the design of more complex TEPs. For instance, Jeon et al 197 have shown that co-implanting osteoblasts and osteoclasts obtained from iPSCs in a HA-coated poly(lactic-co-glycolic acid)/poly( l -lactic acid) scaffold matrix elicited enhanced ectopic bone formation.…”

Bioreactor Systems for Human Bone Tissue Engineering

“…In this view, the development of proper manufacturing and clinical procedures that meet international regulatory requirements is paramount for future clinical translation. The prevention of microbial contamination using environmentally controlled areas, process standardization and validation and quality control testing are among some of the most important challenges that must be addressed before bioreactor-engineered bone substitutes can be used in clinical settings [88]. Production time and cost of customized bioreactor systems will also play a role in enabling the production of replacement bone substitutes for the treatment of complex skeletal defects.…”