Fracture Healing Research-Shift towards In Vitro Modeling?

Abstract

Fractures are one of the most frequently occurring traumatic events worldwide. Approximately 10% of fractures lead to bone healing disorders, resulting in strain for affected patients and enormous costs for society. In order to shed light into underlying mechanisms of bone regeneration (habitual or disturbed), and to develop new therapeutic strategies, various in vivo, ex vivo and in vitro models can be applied. Undeniably, in vivo models include the systemic and biological situation. However, transferability towards the human patient along with ethical concerns regarding in vivo models have to be considered. Fostered by enormous technical improvements, such as bioreactors, on-a-chip-technologies and bone tissue engineering, sophisticated in vitro models are of rising interest. These models offer the possibility to use human cells from individual donors, complex cell systems and 3D models, therefore bridging the transferability gap, providing a platform for the introduction of personalized precision medicine and finally sparing animals. Facing diverse processes during fracture healing and thus various scientific opportunities, the reliability of results oftentimes depends on the choice of an appropriate model. Hence, we here focus on categorizing available models with respect to the requirements of the scientific approach.

Keywords: bone tissue engineering; fracture healing; in vitro models; in vivo models.

Figure 1

Schematic description of the four phases of fracture healing: The first phase is characterized by the formation of the fracture hematoma and a local inflammation. Immune cells, such as peripheral multinucleated cells (PMN), T- and B-cells, monocytes and MSCs, are activated and recruited towards the fracture gap via autocrine and paracrine pathways (e.g., by the release of cytokines such as interleukin (IL-1), IL-6 or tumor necrosis factor (TNFα)). Activation of, for instance, vascular endothelial growth factor (VEGF) also paves the way for revascularization in this early phase. In the following phase, chondroprogenitor cells differentiate into chondroblasts and start to build an early fibrocartilaginous bridging area, while angiogenic processes are also upheld. The third phase is characterized by endochondral ossification, thereby substituting cartilage with primitive bone tissue. In the last phase bone structure and function is completely restored by the constrict interplay of bone-forming and bone-resorbing cells. Figure was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License.