Bone healing, or fracture healing, is a proliferative

physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...

process in which the body facilitates the repair of a

bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a ' ...

. Generally, bone fracture treatment consists of a doctor reducing (pushing) displaced bones back into place via relocation with or without anaesthetic, stabilizing their position to aid union, and then waiting for the bone's natural healing process to occur. Adequate nutrient intake has been found to significantly affect the integrity of the fracture repair. Age, bone type, drug therapy and pre-existing bone pathology are factors that affect healing. The role of bone healing is to produce new bone without a scar as seen in other tissues which would be a structural weakness or deformity. The process of the entire regeneration of the bone can depend on the angle of dislocation or fracture. While the bone formation usually spans the entire duration of the healing process, in some instances, bone marrow within the fracture has healed two or fewer weeks before the final remodelling phase. While immobilization and surgery may facilitate healing, a fracture ultimately heals through physiological processes. The healing process is mainly determined by the

periosteum The periosteum is a membrane that covers the outer surface of all bones, except at the articular surfaces (i.e. the parts within a joint space) of long bones. Endosteum lines the inner surface of the medullary cavity of all long bones. Structu ...

(the connective tissue membrane covering the bone). The periosteum is one source of precursor cells that develop into

chondroblasts Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongiou ...

and

osteoblasts Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functi ...

that are essential to the

healing With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells ...

of bone. Other sources of precursor cells are the bone marrow (when present),

endosteum The endosteum (plural endostea) is a thin vascular membrane of connective tissue that lines the inner surface of the bony tissue that forms the medullary cavity of long bones. This endosteal surface is usually resorbed during long periods of m ...

, small

blood vessels The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...

, and

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

Primary healing

Primary healing (also known as direct healing) requires a correct anatomical reduction which is stable, without any gap formation. Such healing requires only the remodeling of lamellar bone, the Haversian canals and the blood vessels without

callus A callus is an area of thickened and sometimes hardened skin that forms as a response to repeated friction, pressure, or other irritation. Since repeated contact is required, calluses are most often found on the feet and hands, but they may o ...

formation. This process may take a few months to a few years.

Contact healing

When the gap between the bone ends is less than 0.01 mm, and interfragmentary strain is less than 2%, contact healing can occur. In this case, cutting cones, which consists of osteoclasts, form across the fracture lines, generating cavities at a rate of 50–100 μm/day. Osteoblasts fill up the cavities with the Haversian system. This causes the formation of lamellar bone that orients longitudinally along the long axis of the bone. Blood vessels form that penetrate the Haversian system. Remodelling of

lamellar bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...

results in healing without

formation.

Gap healing

If the fracture gap is 800 μm to 1 mm, the fracture is filled by osteoblasts and then by lamellar bone oriented perpendicular to the axis of the bone. This initial process takes three to eight weeks. Perpendicular orientation of lamellar bone is weak, thus a secondary osteonal reconstruction is required to re-orient the lamellar bone longitudinally.

Secondary healing

Secondary healing (also known as indirect fracture healing) is the most common form of bone healing. It usually consists of only

endochondral ossification Endochondral ossification is one of the two essential processes during fetal development of the mammalian skeletal system by which bone tissue is produced. Unlike intramembranous ossification, the other process by which bone tissue is produced, c ...

. Sometimes,

intramembranous ossification Intramembranous ossification is one of the two essential processes during fetal development of the gnathostome (excluding chondrichthyans such as sharks) skeletal system by which rudimentary bone tissue is created. Intramembranous ossification i ...

occurs together with endochondral ossification. Intramembranous ossification, mediated by the periosteal layer of bone, occurs with the formation of

. For endochondral ossification, deposition of bone only occurs after the mineralised cartilage. This process of healing occurs when the fracture is treated conservatively using orthopaedic cast or immobilisation,

external fixation External fixation is a surgical treatment wherein rods are screwed into bone and exit the body to be attached to a stabilizing structure on the outside of the body. It is an alternative to internal fixation, where the components used to provide s ...

, or

internal fixation Internal fixation is an operation in orthopedics that involves the surgical implementation of implants for the purpose of repairing a bone, a concept that dates to the mid-nineteenth century and was made applicable for routine treatment in the m ...

Reaction

After bone fracture, blood cells accumulate adjacent to the injury site. Soon after fracture, blood vessels constrict, stopping further bleeding. Within a few hours, the extravascular blood cells form a clot called a

hematoma A hematoma, also spelled haematoma, or blood suffusion is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillaries. A hematoma is ...

that acts as a template for callus formation. These cells, including

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cell ...

s, release inflammatory mediators such as cytokines (

tumor necrosis factor alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

(TNFα),

interleukin-1 family The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

(IL-1),

interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoot ...

(IL-6), 11 (IL-11), and 18 (IL-18)) and increase blood capillary permeability. Inflammation peaks by 24 hours and completes by seven days. Through

tumor necrosis factor receptor 1 Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα). Function The protein encoded b ...

(TNFR1) and

tumor necrosis factor receptor 2 Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα). Like its counterpart, tumor necro ...

, TNFα mediates the differentiation of

mesenchymal stem cell Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ce ...

(originated from the bone marrow) into

osteoblast Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functio ...

and

chondrocyte Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteo ...

Stromal cell-derived factor 1 The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the ''CXCL12'' gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. S ...

(SDF-1) and

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemok ...

mediate recruitment of mesenchymal stem cells. IL-1 and IL-6 are the most important cytokines for bone healing. IL-1 promotes formation of callus and of blood vessels. IL-6 promotes differentiation of osteoblasts and

osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pr ...

s. All cells within the blood clot degenerate and die. Within this area, the

fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

s replicate. Within 7–14 days, they form a loose aggregate of cells, interspersed with small blood vessels, known as

granulation tissue Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...

. Osteoclasts move in to reabsorb dead bone ends, and other necrotic tissue is removed.Nyary Tamas, Scamell BE. (2015). Principles of bone and joint injuries and their healing. ''Surgery(Oxford)''. 33 (1), p 7-14.

Repair

$Scaphoid fracture with a radiolucent line after 12 days$ Seven to nine days after fracture, the cells of the periosteum replicate and transform. The periosteal cells proximal to (on the near side of) the fracture gap develop into

chondroblast Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spong ...

s, which form

hyaline cartilage Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has ...

. The periosteal cells distal to (at the far end of) the fracture gap develop into osteoblasts, which form woven bone through

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nucle ...

of calcified cartilage and recruitment of bone cells and osteoclasts. The fibroblasts within the granulation tissue develop into chondroblasts which also form hyaline cartilage. These two new tissues grow in size until they unite with each other. These processes culminate in a new mass of heterogeneous tissue known as a fracture callus Callus formation peaks at day 14 of fracture. Eventually, the fracture gap is bridged The next phase is the replacement of the hyaline cartilage and woven bone with

. The replacement process is known as

with respect to the hyaline cartilage and bony substitution with respect to the woven bone. Substitution of woven bone happens before substitution of hyaline cartilage. The lamellar bone begins forming soon after the collagen matrix of either tissue becomes mineralized At this stage, the process is induced by IL-1 and TNFα. The mineralized matrix is penetrated by

microvessel The microcirculation is the circulation of the blood in the smallest blood vessels, the microvessels of the microvasculature present within organ tissues. The microvessels include terminal arterioles, metarterioles, capillaries, and venules ...

and numerous osteoblasts. The osteoblasts form new lamellar bone upon the recently exposed surface of the mineralized matrix. This new lamellar bone is in the form of

trabecular bone A trabecula (plural trabeculae, from Latin for "small beam") is a small, often microscopic, tissue element in the form of a small beam, strut or rod that supports or anchors a framework of parts within a body or organ. A trabecula generally has ...

. Eventually, all of the woven bone and cartilage of the original fracture callus is replaced by trabecular bone, restoring most of the bone's original strength

Remodelling

Remodeling Renovation (also called remodeling) is the process of improving broken, damaged, or outdated structures. Renovations are typically done on either commercial or residential buildings. Additionally, renovation can refer to making something new, ...

begins as early as three to four weeks after fracture and may take 3 to 5 years to complete. The process substitutes the trabecular bone with

compact bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...

. The trabecular bone is first resorbed by osteoclasts, creating a shallow resorption pit known as a "Howship's lacuna". Then osteoblasts deposit compact bone within the resorption pit. Eventually, the fracture callus is remodelled into a new shape which closely duplicates the bone's original shape and strength. This process can be achieved by the formation of electrical polarity during partial weight bearing a long bone; where electropositive convex surface and electronegative concave surface activates osteoclasts and osteoblasts respectively. This process can be enhanced by certain synthetic injectable biomaterials, such as Cerament, which are osteoconductive and promote bone healing

Obstructions

# Poor blood supply which leads to the death of the osteocytes. Bone cell death also depends on degree of fracture and disruption to the Haversian system. # Condition of the soft tissues. Soft tissue between bone ends restricts healing. # Nutrition and drug therapy. Poor general health reduces healing rate. Drugs that impair the inflammatory response impede healing also. # Infection. Diverts the inflammatory response away from healing towards fighting off the infection. # Age. Young bone unites more rapidly than adult bone. # Pre-existing bone malignancy. # Mechanical factors such as the bone not being aligned, and too much or too little movement. Excess mobility can disrupt the bridging callus, interfering with union; but slight biomechanical motion is seen to improve callus formation.

Complications

Complications of fracture healing include: # Infection: this is the most common complication of fractures and predominantly occurs in open fractures. Post-traumatic wound infection is the most common cause of chronic osteomyelitis in patients. Osteomyelitis can also occur following surgical fixation of a fracture. # Non-union: no progression of healing within six months of a fracture occurring. The fracture pieces remain separated and can be caused by infection and/or lack of blood supply (Ischaemia) to the bone. There are two types of non-union, atrophic and hypertrophic. Hypertrophic involves the formation of excess callus leading to bone ends appearing sclerotic causing a radiological "Elephants Foot" appearance due to excessive fracture ends mobility but adequate blood supply. Atrophic non-union results in re-absorption and rounding of bone ends due to inadequate blood supply and excessive mobility of the bone ends. # Mal-union: healing occurs but the healed bone has 'angular deformity, translation, or rotational alignment that requires surgical correction'. This is most common in long bones such as the femur. # Delayed union: healing times vary depending on the location of a fracture and the age of a patient. Delayed union is characterised by 'persistence of the fracture line and a scarcity or absence of callus formation' on x-ray. Healing is still occurring but at a much slower rate than normal.

Gallery

File:Woven bone matrix.jpg, Collagen fibers of woven bone File:Osteoclast.jpg, Osteoclast displaying many nuclei within its "foamy" cytoplasm. File:Active osteoblasts.jpg, Light micrograph of decalcified cancellous bone displaying osteoblasts forming new bone tissue, containing two osteocytes, within a resorption pit.

Radiologic timeline in young children

medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to rev ...

, secondary bone healing displays the following features over time in young children:

Footnotes

References

*Brighton, Carl T. and Robert M. Hunt (1986), "Histochemical localization of calcium in the fracture callus with potassium pyroantimonate: possible role of chondrocyte mitochondrial calcium in callus calcification", ''

Journal of Bone and Joint Surgery ''The Journal of Bone and Joint Surgery'' is a biweekly peer reviewed medical journal in the field of orthopedic surgery. It is published by the non-profit corporation The Journal of Bone and Joint Surgery, Inc. It was established as the ''Transact ...

'', 68-A (5): 703-715 *Brighton, Carl T. and Robert M. Hunt (1991), "Early histologic and ultrastructural changes in medullary fracture callus", ''

'', 73-A (6): 832-847 *Brighton, Carl T. and Robert M. Hunt (1997), "Early histologic and ultrastructural changes in microvessels of periosteal callus", ''Journal of Orthopaedic Trauma'', 11 (4): 244-253 * Ham, Arthur W. and William R. Harris (1972), "Repair and transplantation of bone", ''The biochemistry and physiology of bone'', New York: Academic Press, p. 337-399 {{Bone/cartilage physiology

Physiology Anatomical pathology