Fracture healing is a complex physiological process involving a coordinated interaction of hematopoietic and immune cells within the bone marrow, in conjunction with vascular and skeletal cell precursors.
During the repair process, the pathway of normal embryonic development is repeated with coordinated participation from several cell types :
- the cortex,
- the periosteum,
- the bone marrow,
- the external soft tissues.
Each component depends by level of growth factors, hormones, nutrients, pH, oxygen tension, the electrical environment, and the mechanical stability of the fracture.
Histologically, fracture healing has been divided:
- direct (primary) healing
- when rigid internal fixation anatomically reduces the fracture fragments
- involves by the cortex to reestablish new Haversian systems by forming discrete remodeling units known as “cutting cones”
- Vascular endothelial cells and perivascular mesenchymal cells produce the osteoprogenitor cells that differentiate into osteoblasts
- little or no periosteal response is noted (no callus formation)
- indirect (secondary) healing
- majority of fractures heal by indirect fracture healing, which involves callus formation through a combination of intramembranous and endochondral ossification
- Intramembranous ossification forms bone directl without first forming cartilage from committed osteoprogenitor and undifferentiated mesenchymal cells that reside in the periosteum, situated away from the fracture site ("hard callus")
- six identifiable stages:
- an initial stage of hematoma formation and inflammation,
- angiogenesis and formation of cartilage,
- cartilage calcification,
- cartilage removal, bone formation
- bone remodelling
Fracture healing promoting molecules
- the pro-inflammatory cytokines (IL-1, IL–6, TNF-α)
- the TGF-β superfamily and other growth factors (transforming growth factor-beta,(TNF–β1,TNF–β2,TNF–β3), bone morphogenetic proteins,(BMPs 1-8), growth differentiation factors,(GDFs-1,5,8,10) )
- metalloproteinases and angiogenic factors.
Sequential molecular events during fracture healing:
Fracture healing, like all other repair responses, is initiated by activation of the immune system; peak expressions of IL-1 and IL-6 one day after fracture, followed by a rapid decline to near undetectable levels by day three. Over the following days, mesenchymal stem cells (MSCs) proliferate and differentiate into a chondrogenic or osteogenic lineage. During this early phase the vascular ingrowth into the developing callus is regulated by FGF, VEGF, and angiopoietins 1 and 2.
- Intramembranous bone formation
- Within 24 hours of fracture, the cells from the bone marrow differentiate into an osteoblastic phenotype.
- day three, osteoblasts from the cortex and committed osteoprogenitors derived from the periosteal cambium divide and differentiate, forming woven bone (hard callus).
- day seven and ten proliferation peaks,
- day 14 proliferation deceases, although the osteoblastic activity continues.
Experiments on rat fracture-healing models showed increased levels of BMP-2, 4, and 7 expression during the early stages of intramembranous ossification.
- Endochondral bone formation
- days one-three after fracture MSCs are recruited and begin to proliferate
- Days 7−21 MSCs subsequent differentiation into chondroblasts (chondrogenesis) (synthesize and secrete cartilage-specific matrix, including type II collagen and proteoglycans), the proliferation of these new chondrocytes and results in soft callus formation
- As vasculature begins to invade, the calcifying hypertrophic chondrocytes are removed by chondroclasts and woven bone formation occurs;the stage of endochondral hypertrophy and mineralization is the final stage of a genetically programmed process that results in apoptotic chondrocyte death
Although the cellular events during fracture healing seem to be predominantly regulated by local factors and cytokines, systemic hormones (parathyroid/ thyroid hormone, growth hormone, 1,25 dihydroxyvitamin D, and the sex steroids) may also modulate these events.
Bone has a substantial capacity for repair and regeneration in response to injury or surgical treatment. Repair simply restores the continuity of the injured tissues, without necessarily increasing bone volume. Regeneration, in contrast, involves the differentiation of new cells and the formation.
Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment of new bone tissue that results in an overall increase in volume of new skeletal tissues.
more factors involved in fracture healing...