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Bones fracture frequently and often result in significant impairments, functional limitations, and disabilities, especially when the hand is involved. When fractures occur, there is a disruption of the skeletal tissue organization and a loss of mechanical integrity. The goal of fracture healing is to regenerate mineralized tissue in the fracture area and restore mechanical strength to the bone. Of equal importance is the reconstitution of the normal soft tissue gliding and movement about the fracture site. This article briefly reviews the history of fracture healing and the advances in mechanics and cellular and molecular biology, which should help the reader better understand the current mechanisms related to bone healing (primarily and secondarily). Fracture fixation modes also are described along with the temporal sequencing as to when to protect or move the fractured region.
Fracture healing was studied in male, adult Sprague-Dawley rats. Closed bilateral tibial fractures were observed to be clinically stable after 3 weeks. Parathyroidectomy (PTX) resulted in impaired fracture healing and several delayed unions. Fracture tensile strength, elastic stiffness and failure energy were significantly lower at the beginning of the healing period compared to that of control fracture rats. Treatment with low doses (60 ng/kg/day) of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) increased early fracture bone formation and mineralization. However, these events did not result in a corresponding increase of tensile strength or failure energy compared with that of the controls. Increased bone turnover seemed to be the dominant characteristic and resulted in early resorption of periosteal callus. Toward the end of the healing period, fracture strength measured as tensile strength and failure energy actually decreased compared to that of the control rats. Elastic stiffness initially rose above control values due to increased mineralization, but declined later to control values.
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Fracture healing is a complex physiologic process that involves the coordinated participation of several cell types. By using a reproducible model of experimental fracture healing in the rat, it is possible to elucidate the integrated cellular responses that signal the pathways and the role of the extracellular matrix components in orchestrating the events of fracture healing. Histologic characterization of fracture healing shows that intramembranous ossification occurs under the periosteum within a few days after an injury. Events of endochondral ossification occur adjacent to the fracture site and span a period of up to 28 days. Remodeling of the woven bone formed by intramembranous and endochondral ossification proceeds for several weeks. Spatial and temporal expression of genes for major collagens (Types I and II), minor fibrillar collagens (Types IV and XI), and several extracellular matrix components (osteocalcin, osteonectin, osteopontin, fibronectin and CD44) are detected by in situ hybridization. Immunohistochemical studies show that expression of proliferating cell nuclear antigen is both time and space dependent and differentially expressed in the callus tissues formed by the intramembranous and endochondral processes. Chondrocytes involved in endochondral ossification undergo apoptosis (programmed cell death), and early events in fracture healing may be initiated by the expression of early response genes such as c-fos. Additional characterization and elucidation of fracture healing will lay the foundation for subsequent studies aimed at identifying mechanisms for enhancing skeletal repair.
Fracture healing is largely controlled by local regulatory interactions among cells and tissues near the site of injury; however, many systemic hormones including insulin, the glucocorticoids, and the gonadal steroids also can influence the course of tissue repair, particularly in the case of pathologic hormone excess or deficiency. Using well-defined animal models, recent studies have established that deficiencies in insulin and estrogen impair fracture healing, but data from this type of experiment are limited. Still, the similarities between morphogenetic events in fracture healing and those found in normal bone development and remodeling suggest that testable predictions can be made concerning hormonal effects on the progress of fracture healing. One concept that has received some direct experimental support in fracture healing model studies is that systemic hormones exert pleiotropic effects on callus tissue by regulating the expression and activity of local growth factors. Further verification of this and other predicted hormone effects should increase our understanding of the fundamental mechanisms underlying fracture repair, and may aid development of means to improve fracture healing in states of altered endocrine function.
Fracture healing may take place in the form of direct repair by laminar bone with a little callus, and it is called the third type of fracture healing or an optimal form of fracture healing. The results of stress analysis of electric measurements on the femoral shaft after osteotomy, which is fixed with plates, in simulation to load tests demonstrated that if the design of the plate is reasonable, even the load is added over twice of the body weight, the compression stress subjected to osteotomy site may be greater than that or nearly the same as that in the intact bone. In another animal experiment, a model of the third type of fracture healing of the canine tibial shaft osteotomy fixed with trapezoid compression plate (TCP) was established with polychromatic sequential labeling. The results of 3-point bending tests indicated that the strength and the rigidity of the healing bone may be greater than normal region. The mechanical and biological bases of the third type of fracture healing are provided by these experiments.
Fracture healing is a specialized postnatal repair process that recapitulates many aspects of embryological skeletal development. While many of the molecular mechanisms that control cellular differentiation and growth during embryogenesis recur during fracture healing, these processes take place in a postnatal environment that is unique and distinct from those which exist during embryogenesis. A number of the central biological processes that are believed to be crucial in the embryonic differentiation and growth of skeletal tissues and play a functional role in fracture healing are reviewed. The functional modification of these various developmental processes of fracture healing is discussed in the context of how different pharmacological agents might alter fracture healing.
Fracture healing is a unique postnatal repair process in which the events of endochondral and intramembranous bone formation follow a definable temporal sequence. The temporal patterns of messenger RNA (mRNA) expression for members of the transforming growth factor beta (TGF-beta) superfamily were examined over a 28-day period of fracture healing in mouse tibias. Bone morphogenetic protein 2 (BMP-2) and growth and differentiation factor 8 (GDF8) showed maximal expression on day 1 after fracture, suggesting their roles as early response genes in the cascade of healing events. Restricted expression of GDF8 to day 1, in light of its known actions as a negative regulator of skeletal muscle growth, suggests that it may similarly regulate cell differentiation early in the fracture healing process. GDF5, TGF-beta2, and TGF-beta3 showed maximal expression on day 7, when type II collagen expression peaked during cartilage formation. In contrast, BMP-3, BMP-4, BMP-7, and BMP-8 showed a restricted period of expression from day 14 through day 21, when the resorption of calcified cartilage and osteoblastic recruitment were most active. TGF-beta1, BMP-5 and BMP-6, and GDF10 were constitutively expressed from day 3 to day 21. However, during the same time period, GDF3, GDF6, and GDF9 could not be detected, and GDF1 was expressed at extremely low levels. These findings suggest that several members of the TGF-beta superfamily are actively involved in fracture healing and although they are closely related both structurally and functionally, each has a distinct temporal expression pattern and potentially unique role in fracture healing.
Fracture healing involves a complex interaction of many local and systemic regulatory factors. Recently, the presence of several bone morphogenetic proteins and their receptors in the fracture healing process has been described. During the early stages of fracture healing, only a minimum number of primitive cells are expressing bone morphogenetic proteins in the fracture callus. As the process of endochondral ossification proceeds, the presence of bone morphogenetic proteins and their receptors increases dramatically, especially in the primitive mesenchymal and chondrocytic cells. While the cartilaginous component of the callus matures with a concomitant decrease in the number of primitive cells, there is a concomitant decrease in presence of bone morphogenetic protein expressing cells. As osteoblasts start to lay down woven bone on the chondroid matrix, these osteoblastic cells express bone morphogenetic proteins and their receptors. The presence of bone morphogenetic proteins decreases, however, as lamellar bone replaces the primitive woven bone. A similar observation is seen in the areas of the callus undergoing intramembranous ossification. Initially, within several days after the fracture, periosteal cells and osteoblasts show intense expression of bone morphogenetic proteins and their receptors. As the woven bone is replaced with mature lamellar bone, the expression of bone morphogenetic protein decreases. These data and the knowledge of bone morphogenetic proteins' strong osteoinductive capacities suggest that individual bone morphogenetic proteins play important yet different roles during fracture repair.
Fracture healing is a unique repair process in which the events of endochondral and intramembranous bone formation follow a specific time sequence. There are many ways in which these events can be disrupted, leading to unsuccessful fracture healing. This article summarizes the series of cellular and molecular events that take place in the process of endochondral fracture healing, based on observations obtained from an animal model of a femoral fracture.
Fracture healing is a unique biological process regulated by a complex array of signaling molecules and proinflammatory cytokines. Recent evidence for the role of tumor necrosis family members in the coupling of cellular functions during skeletal homeostasis suggests that they also may be involved in the regulation of skeletal repair. The expression of a number of cytokines and receptors that are of functional importance to bone remodeling (osteoprotegerin [OPG], macrophage colony-stimulating factor [M-CSF], and osteoprotegerin ligand [receptor activator of NF-kappaB ligand (RANKL)]), as well as inflammation (tumor necrosis factor alpha [TNF-alpha] and its receptors, and interleukin-1alpha [IL-1alpha] and -beta and their receptors) were analyzed over a 28-day period after the generation of simple transverse fractures in mouse tibias. OPG was expressed constitutively in unfractured bones and elevated levels of expression were detected throughout the repair process. It showed two distinct peaks of expression: the first occurring within 24 h after fracture and the second at the time of peak cartilage formation on day 7. In contrast, the expression of RANKL was nearly undetectable in unfractured bones but strongly induced throughout the period of fracture healing. The peak in expression of RANKL did not correlate with that of OPG, because maximal levels of expression were seen on day 3 and day 14, when OPG levels were decreasing. M-CSF expression followed the temporal profile of RANKL but was expressed at relatively high basal levels in unfractured bones. TNF-alpha, lymphotoxin-beta (LT-beta), IL-1alpha, and IL-1beta showed peaks in expression within the first 24 h after fracture, depressed levels during the period of cartilage formation, and increased levels of expression on day 21 and day 28 when bone remodeling was initiated. Both TNF-alpha receptors (p55 and p75) and the IL-1RII receptor showed identical patterns of expression to their ligands, while the IL-1R1 was expressed only during the initial period of inflammation on day 1 and day 3 postfracture. Both TNF-alpha and IL-1alpha expression were localized primarily in macrophages and inflammatory cells during the early periods of inflammation and seen in mesenchymal and osteoblastic cells later during healing. TNF-alpha expression also was detected at very high levels in hypertrophic chondrocytes. These data imply that the expression profiles for OPG, RANKL, and M-CSF are tightly coupled during fracture healing and involved in the regulation of both endochondral resorption and bone remodeling. TNF-alpha and IL-1 are expressed at both very early and late phases in the repair process, which suggests that these cytokines are important in the initiation of the repair process and play important functional roles in intramembraneous bone formation and trabecular bone remodeling.
Fracture healing is a complex physiological post-natal process, which involves the coordination of several different cell types. Exploring the orchestration of events and the simultaneous activation of osteogenesis and chondrogenesis that recapitulates mammalian embryological skeletal development seems to be not only sophisticated but also challenging. A large number of genes involved in the above process are known, but many more remain to be discovered. The functional characterisation of these genes promises to elucidate the repair process as well as skeletal abnormalities and aging. We here review the current knowledge on early and late gene expression during fracture healing, the genes so far associated with osteoblast and osteoclast differentiation, the BMP antagonists, and the Wnts signalling pathway.
Fracture healing requires the cooperation of multiple molecular signaling pathways. To better understand this cascade of transcriptional events, we compared the gene expression profiles between intact bone and fractured bone at days 1, 2, and 4 using a rat femur model of bone healing. Cluster analysis identified several groups of genes with dynamic temporal expression patterns and stage-specific functions. The immediate-response genes are highlighted by binding activity, transporter activity, and energy derivation. We consider these activities as critical signals for initiation of fracture healing. The continuously increased genes are characterized by those directly involved in bone repair, thus, representing bone specific forefront workers. The constantly upregulated genes tend to regulate general cell growth and are enriched with genes that are involved in tumorigenesis, suggesting common pathways between two processes. The constantly downregulated genes predominantly involve immune response, the significance of which remains for further investigation. Knowledge acquired through this analysis of transcriptional activities at the early stage of bone healing will contribute to our understanding of fracture repair and bone-related pathological conditions.
Fracture repair is the best-characterized situation in which activation of chondrogenesis takes place in an adult organism. To better understand the mechanisms that regulate chondrogenic differentiation of mesenchymal progenitor cells during fracture repair, we have investigated the participation of transcription factors L-Sox5, Sox6, and Sox9 in this process. Marked up-regulation of L-Sox5 and Sox9 messenger RNA (mRNA) and smaller changes in Sox6 mRNA levels were observed in RNAse protection assays during early stages of callus formation, followed by up-regulation of type II collagen production. During cartilage expansion, the colocalization of L-Sox5, Sox6, and Sox9 by immunohistochemistry and type II collagen transcripts by in situ hybridization confirmed a close relationship of these transcription factors with the chondrocyte phenotype and cartilage production. On chondrocyte hypertrophy, production of L-Sox5, Sox9 and type II collagen were down-regulated markedly and that of type X collagen was up-regulated. Finally, using adenovirus mediated bone morphogenetic protein 2 (BMP-2) gene transfer into fracture site we showed accelerated up-regulation of the genes for all three Sox proteins and type II collagen in fractures treated with BMP-2 when compared with control fractures. These data suggest that L-Sox5, Sox6, and Sox9 are involved in the activation and maintenance of chondrogenesis during fracture healing and that enhancement of chondrogenesis by BMP-2 is mediated via an L-Sox5/Sox6/Sox9-dependent pathway.
Fractures of the proximal fifth metatarsal can be divided into two distinct groups based on anatomical location and clinical course. Fractures of the tuberosity often heal well with nonoperative treatment, whereas fractures occurring in the proximal diaphysis (up to 1.5 cm distal to the tuberosity) have significantly increased risk for delayed union or nonunion. It is the purpose of this paper to describe the intraosseous vascular anatomy of the fifth metatarsal, and the clinical implications for basilar fracture healing. Ten fresh-frozen amputation or cadaver specimens were studied following arterial injection with India ink or barium sulfate suspension. The intraosseous blood supply to the fifth metatarsal tuberosity arose from numerous metaphyseal vessels penetrating the nonarticular surfaces of the tuberosity in a random, radiate pattern. The blood supply to the proximal diaphysis was derived primarily from the nutrient artery, which gave rise to longitudinal intramedullary branches. The arterial supply to the tuberosity joined the supply of the proximal diaphysis in the area just distal to the tuberosity, corresponding to the region of poor prognosis for fracture healing. This suggests that a relative lack of blood supply following a proximal diaphyseal fracture may contribute to delayed union and nonunion.
Fracture of the long bones results in a repair process that has the potential to restore the anatomic morphology and mechanical integrity of the bone without scar tissue. The repair process can occur in two patterns. In the first, under conditions of rigid stabilization, direct osteonal remodeling of the fracture line can occur with little or no external callus, a process known as direct bone repair. The second pattern of repair involves bridging of the fragments with external callus and formation of bone in the fracture site by endochondral healing. This type of repair is known as indirect bone healing and occurs under less rigid interfragmentary stabilization. The rate of healing and the extent of callus in this type of repair can be modulated by the mechanical conditions at the fracture site. Applying cyclic interfragmentary micromotion for short periods has been shown to influence the repair process significantly, and characteristics of this stimulus influence the healing response observed. In the current study, a short term interfragmentary cyclic micromovement applied at a high strain rate induced a greater amount of periosteal callus than the same stimulus applied at a low strain rate. This high strain rate stimulus applied later in the healing period significantly inhibited the progress of healing. The beneficial effect of this particular biophysic stimulus early in the healing period may be related to the viscoelastic nature of the differentiating connective tissues in the early endochondral callus. In the early endochondral callus, high rates of movement induce a greater deformation of the fracture fragments because of the stiffening of the callus. Alternatively, the transduction pathway may involve streaming potentials as a result of the high movement rate.
Fractures were created in the femur of dogs by dividing the midshaft with an airdriven saw. Immobilization was achieved with a four-hole compression plate. No methylmethacrylate supplementation was used in the control groups. In the three experimental groups methylmethacrylate was added to the internal fixation by placing it on the endosteal, periosteal, and both surfaces of the bone. Healing of the fractures uniformly failed to occur when methylmethacrylate was apposed to both periosteal and endosteal regions. Histologic, fluorescent, and autoradiographic studies indicated that the bone surface in contact with methylmethacrylate was necrotic and did not incorporate tetracycline or Ca-45. New bone occurred only on the surface which was not in contact with methylmethacrylate.