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Biology of fracture healing

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Authors

Keita Ito, Stephan M Perren


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 bothintramembraneous 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 fromone stage to another; they are determined arbitrarily and have been described with

some variation.

Inflammation

After fracture, the inflammatory process starts rapidly and lasts until fi brous tissue,

cartilage, or bone formation begins (17 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

de ranulation of latelets results in the release of owerful c tokines that roduce a
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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

23 weeks postfracture.

The soft callus stage. Intramembraneous ossification forming bone cuffs away from


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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 (34 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.


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The hard callus stage. Complete conversion of callus into calcified tissue through

intramembraneous and endochondral ossification.

Remodeling

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.


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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 [1921]. 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.


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Perrens 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 Perrens 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 ( 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


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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 thisfeedback 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 treatmentmay 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

ex erimental roof that flexible fixation can stimulate callus formation thereb


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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].

Bibliography

[1] Farouk O, Krettek C, Miclau T, et al (1999) The topography of the perforating

vessels of the deep femoral artery. Clin Orthop Relat Res; (368):255259.

[2] Gautier E, Cordey J, Mathys R, et al (1984) Porosity and remodeling of plated

bone after internal fixation: Result of stress shielding or vascular damage?

Amsterdam: Elsevier Science Publishers, 195200.

[3] Perren SM (1991) The concept of biological plating using the limited contact-

dynamic compression plate (LC-DCP). Scientic background, design and application.

Injury; 22(Suppl 1):141.

[4] Grundnes O, Reikeras O (1992) Blood flow and mechanical properties of

healing bone. Femoral osteotomies studied in rats.Acta Orthop Scand; 63(5):487

491.

[5] Kelly PJ, Montgomery RJ, Bronk JT (1990) Reaction of the circulatory system

to injury and regeneration. Clin Orthop Relat Res; (254):275288.

[6] Brookes M, Revell WJ (1998). Blood Supply of Bone. Scientic aspects. London:

Springer-Verlag.

[7] Rhinelander FW (1974) Tibial blood supply in relation to fracture healing. Clin

Orthop Relat Res; (105):3481.[8] Eckert-Hbner K, Claes L (1998) Callus tissue differentiation and


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International Society for Fracture Repair.

[9] Danckwardt-Lilliestrom G, Lorenzi GL, Olerud S (1970) Intramedullary

nailing after reaming. An investigation on the healing process in osteotomized rabbit

tibias.Acta Orthop Scand Suppl; 134:178.

[10] Smith SR, Bronk JT, Kelly PJ (1990) Effect of fracture fixation on cortical

bone blood flow.J Orthop Res; 8(4):471478.

[11] Klein MP, Rahn BA, Frigg R, et al (1990) Reaming versus nonreaming in

medullary nailing: interference with cortical circulation of the canine tibia.Arch

Orthop Trauma Surg; 109(6):314316.

[12] Pfister U (1983) [Biomechanical and histological studies following

intramedullary nailing of the tibia]. Fortschr Med; 101(37):16521659.

[13] Claes L, Heitemeyer U, Krischak G, et al (1999) Fixation technique

influences osteogenesis of comminuted fractures. Clin Orthop Relat Res; (365):221

229.

[14] Perren SM, Buchanan JS (1995) Basic concepts relevant to the design and

development of the point contact fixator (PC-Fix). Injury; 26(Suppl 2):14.

[15] Tepic S, Perren SM (1995) The biomechanics of the PC-Fix internal fixator.

Injury; 26 (Suppl 2):510.

[16] Farouk O, Krettek C, Miclau T, et al (1999) Minimally invasive plate

osteosynthesis: does percutaneous plating disrupt femoral blood supply less than the

traditional technique?JOrthop Trauma; 13(6):401406.

[17] Sarmiento A, Latta LL (1995) Functional Fracture Bracing. Berlin Heidelberg

New York: Springer-Verlag.

[18] Schandelmaier P, Krettek C, Tscherne H (1996) Biomechanical study of nine

different tibia locking nails.J Orthop Trauma; 10(1):3744.

[19] Claes LE, Augat P, Suger G, et al (1997) Infl uence of size and stability of the

osteotomy gap on the success of fracture healing.J Orthop Res; 15(4):577584.

[20] Claes LE, Wilke HJ, Augat P, et al (1995) Effect of dynamization on gap

healing of diaphyseal fractures under external fixation. Clin Biomech; 10(5):227234.

[21] Claes LE, Heigele CA, Neidlinger-Wilke C, et al (1998) Effects of mechanical

factors on the fracture healing process. Clin Orthop Relat Res; (355 Suppl):132147.

[22] Perren SM, Cordey J (1980) The concept of interfragmentary strain. Berlin

Heidelberg New York: Springer-Verlag.

[23] Claes LE, Heigele CA (1999) Magnitudes of local stress and strain along bony

surfaces predict the course and type of fracture healing.J Biomech; 32(3):255266.

[24] Goodship AE, Kenwright J (1985) The influence of induced micromovement

upon the healing of experimental tibial fractures.J Bone Joint Surg Br; 67(4):650655.


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Page 10 of 10https://www2.aofoundation.org/wps/portal/!ut/p/c1/04_SB8K8xLLM9Mfx_heal.jsp&soloState=true&popupStyle=diagnosis&printPopup=true

, ,

contribution to the development and treatment of pseudarthrosis]. Hefte Unfallheilkd;

94:1524.

[26] Kenwright J, Goodship AE (1989) Controlled mechanical stimulation in the

treatment of tibial fractures. Clin Orthop Relat Res; (241):3647.

[27] Perren SM, Huggler A, Russenberger M, et al (1969) The reaction of cortical

bone to compression.Acta Orthop Scand Suppl; 125:1929.

[28] van Frank Haasnoot E, Mnch TW, Matter P, et al (1995) Radiological

sequences of healing in internal plates and splints of different contact surface to bone.

(DCP, LC-DCP and PC-Fix). Injury; 26 (Suppl 2):2836.

[29] Schenk R, Willenegger H (1963) [On the histological picture of socalled

primary healing of pressure osteosynthesis in experimental osteotomies in the dog.]

Experientia; 19:593-595.

[30] Rahn BA, Gallinaro P, Baltensperger A, et al (1971) Primary bone healing.

An experimental study in the rabbit.J Bone Joint Surg Am; 53(4):783786.

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