05/08/2023
Overview of Fracture Healing 🦴 🦴
👉Bone fracture healing is an intricate and fluent regenerative process that aims at restoring the damaged bone to its pre-injury state and cellular composition. https://pubmed.ncbi.nlm.nih.gov/25266456/
👉A fracture is a breach in the structural continuity of the bone cortex, with a degree of injury to the surrounding soft tissues. Following the fracture, secondary healing begins, which consists of four steps: (s. illustration) https://www.ncbi.nlm.nih.gov/books/NBK551678/
1⃣ Hematoma formation: (Immediately after the fracture)
This forms the key step in fracture healing. The blood vessels supplying the bone and periosteum are disrupted during the fracture, causing a hematoma to form at the fracture site, which is rich in hematopoietic cells. The hematoma clots and forms the temporary frame for subsequent healing. An adequate number of mesenchymal stem cells (MSCs) is recruited at the fracture site from the nearby tissues and the circulation. https://pubmed.ncbi.nlm.nih.gov/20830500/, https://pubmed.ncbi.nlm.nih.gov/21489527/
Macrophages, neutrophils, and platelets release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), bone morphogenetic proteins (BMPs), platelet-derived growth factors (PDGF), transforming growth factor beta (TGF-Beta), vascular endothelial growth factor (VEGF) and interleukins. These cytokines further stimulate essential cellular biology at the fracture site.
2⃣ Granulation tissue formation: (primary or fibrocartilaginous callus, within two weeks. This provides provisional stability)
Platelets, mesenchymal cells and inflammatory cells are recruited to the fracture site, such as fibroblasts and endothelial cells, with resultant fibrin-rich granulation tissue formation and angiogenesis. Mesenchymal stem cells begin to differentiate (driven by BMPs). As a result, chondrogenesis begins to occur, laying down a collagen-rich fibrocartilaginous network spanning the fracture ends, with a surrounding hyaline cartilage sleeve. The release of cytokines such as VEGF and TGF B induces angiogenesis at the fracture site. https://pubmed.ncbi.nlm.nih.gov/10494799/
3⃣ Bony Callus Formation: (If bone ends are not in contact, then a soft bridging callus forms)
The endosteum and periosteum serve as primary sources for the fibroblasts involved in fracture healing. [https://pubmed.ncbi.nlm.nih.gov/20049593/] The fibroblasts play a pivotal role by secreting the matrix constituents such as collagen, elastic and mesh fibers, and glycoproteins.
The cartilaginous (soft) callus begins to undergo endochondral ossification, and a medullary callus further supports the bridging soft callus. RANK-L is expressed, stimulating further differentiation of chondroblasts, chondroclasts, osteoblasts, and osteoclasts. As a result, the cartilaginous callus is resorbed and begins to calcify. Subperiosteally, woven bone continues to be laid down. The newly formed blood vessels continue to proliferate, allowing further migration of mesenchymal stem cells. At the end of this phase, a hard, calcified callus of immature bone forms.
4⃣ Bone remodeling (Continues for months to years after clinical union)
Osteoclasts have the capacity for bone matrix resorption, while osteoclasts' differentiation and activity are coordinated by osteoblasts. https://pubmed.ncbi.nlm.nih.gov/17308163/, https://pubmed.ncbi.nlm.nih.gov/6809295/
With the continued migration of osteoblasts and osteoclasts, the hard callus undergoes repeated remodeling - termed 'coupled remodeling.' This 'coupled remodeling' is a balance of resorption by osteoclasts and new bone formation by osteoblasts. The center of the callus is ultimately replaced by compact bone, while the callus edges become replaced by lamellar bone. Substantial remodeling of the vasculature occurs alongside these changes. The process of bone remodeling lasts for many months, ultimately resulting in the regeneration of the normal bone structure. https://pubmed.ncbi.nlm.nih.gov/28377988/, https://pubmed.ncbi.nlm.nih.gov/27743449/, https://pubmed.ncbi.nlm.nih.gov/2680203/
📸 Illustration: https://link.springer.com/chapter/10.1007/978-3-030-36790-9_10
