Abstract
Anatomically, bone consists of building blocks called osteons, which in turn comprise a central canal that contains nerves and blood vessels. This indicates that bone is a highly innervated and vascularized tissue. The function of vascularization in bone (development) is well-established: providing oxygen and nutrients that are necessary for the formation, maintenance, and healing. As a result, in the field of bone tissue engineering many research efforts take vascularization into account, focusing on engineering vascularized bone. In contrast, while bone anatomy indicates that the role of innervation in bone is equally important, the role of innervation in bone tissue engineering has often been disregarded.
For many years, the role of innervation in bone was mostly clear in physiology, where innervation of a skeleton is responsible for sensing pain and other sensory stimuli. Unraveling its role on a cellular level is far more complex, yet more recent research efforts have unveiled that innervation has an influence on osteoblast and osteoclast activity. Such innervation activities have an important role in the regulation of bone homeostasis, stimulating bone formation and inhibiting resorption. Furthermore, due to their anatomical proximity, skeletal nerves and blood vessels interact and influence each other, which is also demonstrated by pathways cross-over and joint responses to stimuli.
Besides those closely connected sytems, the immune system plays also a pivotal role in bone regeneration. Certain cytokines are important to attract osteogenic cells and (partially) inhibit bone resorption. Several leukocytes also play a role in the bone regeneration process.
Overall, bone interacts with several systems. Aberrations in those systems affect the bone and are important to understand in the context of bone regeneration. This crosstalk has become more evident and is taken more into consideration. This leads to more complex tissue regeneration, but may recapitulate better physiological situations.
