**2. Cellular aspects of fracture healing**

From the histological point of view, restitution of the bone continuity proceeds due to accumulation and activation of mesenchymal stem cells (MSCs) that, transforming into osteoblasts and maturating into osteocytes, synthesize and release proteins forming the extracellular matrix (ECM).

In the vast majority of cases, MSCs that settle hematoma differentiate into chondrocytes. But revascularization, due to the ingrowth of blood vessels from the vasculature of the adjacent tissues, improves local oxygenation enabling the transformation of newly inflowing progenitors into osteoblasts that, maturating into osteocytes, initiate ossification forming bone cuff around the fracture gap. Starting from its periphery, it moves toward the center replacing the soft callus with woven bone [1, 2]. Later on, it's remodeling rebuilds the microarchitecture to the mature bonecancellous or compact, depending on the type of the bone that was primarily at the fracture gap.

The described above process, the endochondral ossification, proceeds in ca. 97–98% of all fractures, whereas remaining 2–3% heal due to the direct osteonal growth in the process called primary bone healing basing on the intramembranous ossification [3]. The latter one is possible, when the volume of the fracture's gap is minimal, thus in non-displaced or impacted fractures only. In those cases, the short distance between bone fragments enables osteonal remodeling toward the fracture gap restoring its vascularization and mineralizing it.

MSCs residue several tissues, including bone marrow, endosteum, and periosteum. They are abundantly represented in adipose tissue surrounding the extremity with subcutaneous fat and form a subpopulation of its leukocytes in peripheral blood as well [4]. Thus, extravasated into posttraumatic hematoma and recruited from adjacent tissues they form a population of precursors for reparative processes.

Their accumulation proceeds due to chemotactic stimulation. Stromal-derived factor-1 (SDF-1; also known as CXC-motif chemokine 12: CXCL12) is one of the most potent attractants of MSCs. Widely distributed in bone marrow, it splits in-between neighboring tissues, when bone continuity is broken, recruiting progenitors that accumulate at the sites of its highest concentration, the fracture gap. Inflowing cells multiply under the mitogenic stimulation of platelet-derived growth factor (PDGF) [5].

MSCs are precursors of various cells of mesenchymal origin, including chondrocytes, fibroblasts, adipocytes, neurons, and myocytes. The direction of their differentiation depends upon molecular regulation and local physicochemical conditions. When stimulated improperly or under unfavorable conditions, they may differentiate into, unwanted from the point of view of the fracture healing, cellular population forming cartilaginous or fibrous pseudoarthrosis.

Hypoxia, hypercapnia, and acidosis that characterize deprived of vasculature posttraumatic hematoma, promote their differentiation into chondrocytes, whereas higher oxygen tension and reduced acidosis-into osteoblasts [6].
