Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration

Abstract

Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or extrinsic ones coming from external insults such as trauma or surgery. Although bone tissue has an intrinsic capacity of self-repair, large bone defects often require anabolic treatments targeting bone formation process and/or bone grafts, aiming to restore bone loss. The current bone surrogates used for clinical purposes are autologous, allogeneic, or xenogeneic bone grafts, which although effective imply a number of limitations: the need to remove bone from another location in the case of autologous transplants and the possibility of an immune rejection when using allogeneic or xenogeneic grafts. To overcome these limitations, cutting edge therapies for skeletal regeneration of bone defects are currently under extensive research with promising results; such as those boosting endogenous bone regeneration, by the stimulation of host cells, or the ones driven exogenously with scaffolds, biomolecules, and mesenchymal stem cells as key players of bone healing process.

Keywords: MSCs; bone regeneration; cell therapy; composite; hydrogel; scaffold; tissue engineering.

Figure 1

Regulation of cell fate and induction of osteogenic differentiation of MSCs by supplemented scaffolds. Surface modifications of the scaffolds by the attachment of a bioactive domain (Left), with the aim of improving adhesion, proliferation, and osteogenic differentiation of MSCs. Addition of bioactive molecules or drugs (Right) regulates bone homeostasis to emulate the complex network of biochemical and physiological signals that are representative in bone ECM.

Figure 2

Schematic representation of different strategies for bone regeneration described in this review. The strategies are divided into two main categories; the ones promoting the response of endogenous cells to form new bone (a–c); and the ones that rely on the addition of MSCs or their derivatives (extracellular vesicles) to induce the bone healing (d–f). (a) Scaffolds can be obtained from bone grafts (autographs, allografts, or xenografts) or made of different natural and synthetic materials that promote bone regeneration. The properties of these scaffolds can be enhanced by the addition of surface modifications or soluble molecules such as proteins or GFs that improve their osteogenic effect (b). Macrophages polarization of pro-inflammatory M1 into anti-inflammatory M2 is a key step not only for bone healing but also for the osteointegration of bone tissue engineered grafts (c). Regarding strategies that depend on exogenous cells, MSCs from many origins (adipose tissue, BM, umbilical cord and placenta), must be harvested and expanded in order to obtain the needed amount of cells. Cells pretreatment prior its implantation in the patient could enhance their effectiveness. Likewise, the secretome of MSCs can also be used in the so-called “cell free” therapy (d). Other strategies that combine MSCs and composites try to promote a more efficient response by introducing genetic modifications into the cells by gene delivery systems (e). Lastly, bioreactors provide a better control of physical parameters to achieve the maximum osteogenic potential (f).