Biology of fracture healing


Keita Ito, Stephan M Perren

Biology of fracture healing

Fracture healing can be divided into two types:

  • primary or direct healing by internal remodeling;
  • secondary or indirect healing by callus formation.

The former occurs only with absolute stability and is a biological  process of osteonal bone remodeling. The latter occurs with relative stability (flexible fixation methods). It is very similar to the process of embryological bone development and includes both intramembraneous and endochondral bone formation. In diaphyseal fractures, it is characterized by the formation of callus.

Bone healing can be divided into four stages:

  • inflammation;
  • soft callus formation;
  • hard callus formation;
  • remodeling.

Although the stages have distinct characteristics, there is a seamless transition from one stage to another; they are determined arbitrarily and have been described with some variation.



After fracture, the inflammatory process starts rapidly and lasts until fi brous tissue, cartilage, or bone formation begins (1–7 days postfracture). Initially, there is hematoma formation and inflammatory exudation from ruptured blood vessels. Bone necrosis is seen at the ends of the fracture fragments. Injury to the soft tissues and degranulation of platelets results in the release of powerful cytokines that produce a typical inflammatory response, ie, vasodilatation and hyperemia, migration and proliferation of polymorphonuclear neutrophils, macrophages, etc. Within the hematoma, there is a network of fibrin and reticulin fibrils; collagen fibrils are also present. The fracture hematoma is gradually replaced by granulation tissue. Osteoclasts in this environment remove necrotic bone at the fragment ends.


The inflammation stage. Formation of hematoma resolving into granulation tissue with the typical inflammatory cascade.

Soft callus formation

Eventually, pain and swelling decrease and soft callus is formed. This corresponds roughly to the time when the fragments are no longer moving freely, approximately 2–3 weeks postfracture.

The soft callus stage. Intramembraneous ossification forming bone cuffs away from the fracture gap. Replacement of the granulation tissue elsewhere in the callus by fibrous tissue and cartilage, and ingrowth of vessels into the calcified callus. This starts at the periphery and moves towards the center.

  • At the end of soft callus formation, stability is adequate to prevent shortening, although angulation at the fracture site may still occur.

The soft callus stage is characterized by the growth of callus. The progenitor cells in the cambial layer of the periosteum and endosteum are stimulated to become osteoblasts. Intramembraneous, appositional bone growth starts on these surfaces away from the fracture gap, forming a cuff of woven bone periosteally, and filling the intramedullary canal. Ingrowth of capillaries into the callus and increased vascularity follows. Closer to the fracture gap, mesenchymal progenitor cells proliferate and migrate through the callus, differentiating into fibroblasts or chondrocytes, each producing their characteristic extracellular matrix and slowly replacing the hematoma [17].


Hard callus formation

When the fracture ends are linked together by soft callus, the hard callus stage starts and lasts until the fragments are firmly united by new bone (3–4 months). As intramembraneous bone formation continues, the soft tissue within the gap undergoes endochondral ossification and the callus is converted into rigid calcified tissue (woven bone). Bone callus growth begins at the periphery of the fracture site, where the strain is lowest. The production of this bone reduces the strain more centrally, which in turn forms bony callus. Thus, hard callus formation starts peripherally and progressively moves towards the center of the fracture and the fracture gap. The initial bony bridge is formed externally or within the medullary canal, away from the original cortex. Then, by endochondral ossification, the soft tissue in the gap is replaced by woven bone that eventually joins the original cortex.

The hard callus stage. Complete conversion of callus into calcified tissue through intramembraneous and endochondral ossification.



The remodeling stage begins once the fracture has solidly united with woven bone. The woven bone is then slowly replaced by lamellar bone through surface erosion and osteonal remodeling. This process may take anything from a few months to several years. It lasts until the bone has completely returned to its original morphology, including restoration of the medullary canal.

The remodeling stage. Conversion of woven bone into lamellar bone through surface erosion and osteonal remodeling.

Differences in healing between cortical and cancellous bone

As opposed to secondary healing in cortical bone, healing in cancellous bone occurs without the formation of significant external callus. After the inflammatory stage, bone formation is dominated by intramembraneous ossification. This has been attributed to the tremendous angiogenic potential of trabecular bone as well as the fixation used for metaphyseal fractures, which is often more stable. In unusual cases with substantial interfragmentary motion, intermediary soft tissue may form in the gap, but this is usually fibrous tissue, which is soon replaced by bone.


Mechanobiology of indirect or secondary fracture healing

Interfragmentary movement stimulates the formation of a callus and accelerates healing [19–21]. As the callus matures, it becomes stiffer, reducing the interfragmentary movement sufficiently, so that bridging by hard bony callus can occur.

Typical course of interfragmentary movement monitored for human tibial shaft fractures. The initial postoperative interfragmentary movements under 300 N axial load (normalized to 100% at the outset) decrease with the passage of time. After about 13 weeks, healing by callus has stabilized the fracture.

Perren’s strain theory.

In the early stage of healing, when mainly soft tissue is present, the fracture tolerates a greater deformation or higher tissue strain than in a later stage when the callus contains mainly calcified tissue. The manner in which mechanical factors influence fracture healing is explained by Perren’s strain theory.


Strain is the deformation of a material (eg, granulation tissue within a gap) when a given force is applied. Normal strain is the change in length (Δ l) in comparison to original length (l)when a given load is applied. Thus, it has no dimensions and is often expressed as a percentage. The amount of deformation that a tissue can tolerate and still function varies greatly. Intact bone has a normal strain tolerance of 2% (before it fractures), whereas granulation tissue has a strain tolerance of 100%. Bony bridging between the distal and proximal callus can only occur when local strain (ie, deformation) is less than the forming woven bone can tolerate. Thus, hard callus will not bridge a fracture gap when the movement between the fracture ends is too great [22]. Nature deals with this problem by expanding the volume of soft callus. This results in a decrease in the local tissue strain to a level that allows bony bridging. This adaptive mechanism is not effective when the fracture gap has been considerably narrowed so that most of the interfragmentary movement occurs at the gap, producing a high-strain environment. Thus, overloading of the fracture with too much interfragmentary movement later in the healing process is not well tolerated [23].


At the cellular level, where the fundamental process of bone regeneration and tissue differentiation occurs, the situation is more complex. The biomechanical conditions, such as strain
and fl uid pressure, have an inhomogeneous distribution within the callus. The mechanoregulation of callus cells is a feedback loop in which the signals are created by the applied load and modulated by the callus tissue. Mechanical loading of the callus tissue produces local biophysical stimuli that are sensed by the cells. This may regulate cell phenotype, proliferation, apoptosis, and metabolic activities. With alteration of the extracellular matrix, and the associated changes in tissue properties, the biophysical stimuli caused by mechanical loading are modulated, producing different biophysical signals even with the same load. In normal fracture healing this feedback process reaches a steady state when the callus has ossifi ed and the original cortex has regenerated. The biophysical signals themselves and the way they interact to produce the biological response are still being investigated. Several mechanoregulation algorithms have been postulated and have been shown to be consistent with some aspects of fracture healing, but they require further corroboration. Transduction of these stimuli into intracellular and extracellular messenger systems are being investigated; so both physical and molecular methods of treatment
may be developed to treat delayed union and nonunion.

When fractures are splinted, movement of the fragments in relation to each other depends on the

  • amount of external loading;
  • stiffness of the splints;
  • stiffness of the tissues bridging the fracture.

The same deforming force produces more strain at the site of a simple fracture than at that of a multifragmentary fracture.

Multifragmentary fractures tolerate more motion between the two main fragments because the overall movement is shared by several fracture planes, which reduces the tissue strain or deformation at the fracture gap. Today there is clinical experience and experimental proof that flexible fixation can stimulate callus formation, thereby accelerating fracture healing [20, 24]. This can be observed in diaphyseal fractures splinted by intramedullary nails, external fixators, or bridging plates.

  • If the interfragmentary strain is excessive (instability), or the fracture gap is too wide, bony bridging by hard callus is not obtained in spite of good callus formation, and a hypertrophic nonunion develops [25].

The capacity to stimulate callus formation seems to be limited and may be insufficient when large fracture gaps are to be bridged. In such cases dynamization (unlocking of the intramedullary nail or external fixator) may permit bony bridging by allowing the fracture gap to consolidate and increase its stiffness.

  • Callus formation requires some mechanical stimulation and will not take place when the strain is too low. A low-strain environment will be produced if the fixation device is too stiff, or if the fracture gap is too wide [22]. Delayed healing and nonunion will result.

Again, dynamization may be the solution to the problem. If a patient is too immobile to load the operated leg, an externally applied load might be the way to stimulate callus formation [26].


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