Skeletal growth is a tightly controlled phenomenon. In general, it is difficult to correct for skeletal malformations that develop during growth. One of the tissues that are proposed to be of major importance in regulating long bone growth is the periosteum. Previously, it was proposed that periosteum regulates growth via a direct mechanical feedback mechanism where pressure in growing cartilage, balanced by tension in the periosteum, modulates growth processes of chondrocytes. The presence of this tension is attributed to the periosteal collagen. We support the existence of a load-dependent feedback mechanism between cartilage pressure and periosteum tension by showing that the global orientation of collagen in perichondrium and periosteum concurs with the assessed growth directions of cartilage. Nevertheless, the absolute magnitude of periosteum tension determines the extent to which regulation by this mechanical feedback mechanism is present. From measurements described in this thesis, it is concluded that residual periosteum force does not directly dominate modulation of cartilage growth. Hence, a mechano-biological feedback mechanism must prevail. We demonstrate this mechano-biological feedback loop between growing cartilage and tension in the periosteum, whereby the expression of soluble growth-inhibiting factors by periosteum cells is dependent on intracellular tension. Because cartilage growth lengthens the periosteum at a very high rate, a mechanism of fibrous tissue adaptation that preserves low periosteum tension is required. We show that this mechanism is through adaptation towards a state of equilibrium, characterized by a residual tissue strain that corresponds to the strain in between the pliant and stiffer region of the force-strain curve. This process is cell-mediated and involves a structural organization of the collagen network, determining the tissue stiffness, which is not directly coupled to the collagen or HP crosslink density. This thesis takes us closer towards understanding the regulation of bone growth, by not only demonstrating the critical involvement of the periosteum, but also demonstrating mechanisms for the interaction between periosteum and growing cartilage, and for periosteum adaptation
