An architect’s dream: a self-repairing structure




Jean-Marc FÉRON,MD, PhD
Professor of Orthopaedic Surgery
Head of the Orthopaedic Department, Saint Antoine Hospital
Université Pierre et Marie Curie (UPMC)-Sorbonne Universities
Paris, FRANCE

An architect’s dream: a self-repairing structure


by J. M. Féron, France



Fracture healing is one of the most fascinating processes in the body as it does not result in a scar, but in reconstitution of the injured tissue in a structure which cannot differ from its original. “Self-regeneration” of bone—its integrity and biomechanical properties—involves a sequence of extremely complex events governed by a variety of cellular elements and stimulating agents. For simpler description of this dynamic process, it has been arbitrarily divided into a succession of phases that immediately followmechanical insult. Histological features show that fractures heal by a combination of intramembranous and endochondral ossification that is highly dependent on the mechanical environment. The bone repair process looks similar to the normal development of the skeleton during embryogenesis. As knowledge of bone biology has improved over the last decade, we now recognize that many mediators and cellular elements interact at the molecular level in coordination with physiological and mechanical conditions to control bone formation during the fracture healing process. A better understanding of the precise mechanisms of bone formation facilitates the development of new therapeutic strategies to repair damaged bone. Between 5% and 10% of extremity fractures result in delayed union or nonunion with considerable morbidity and economic burden due to the loss of productivity and independence.

Medicographia. 2012;34:185-190 (see French abstract on page 190)



Fractures can be classified according to the characteristics of the force that causes them. During injury, single application of a force may generate tensile, compressive, or shear stresses—or some combination thereof—in the bone, leading to bone breakage. The pattern of bone injury depends on the type of force, the mechanical properties of the bone, and the bone’s energy absorbing capacity. At the moment of impact, the energy absorbed by the bone leads to mechanical and structural failure. High-energy injuries result in more significant structural changes, that is, greater comminution and displacement as well as larger surrounding lesions in soft tissue and periosteum, which may affect healing capacity. In the osteoporotic bone, the decrease in bone mass, the changes in trabecular architecture modification, and the thinning of cortices result in bone fragility, and the risk of low-energy fracture after a simple fall from height is increased.

Fracture healing

Bone differs from other tissues in that it has the capacity to self-repair after fracture, without leaving a scar; bone continuity and mechanical properties are restored and the repaired bone is similar to the original. Fracture healing is a complex physiological process involving biological factors and mechanical principles. For example, fracture stability, depending on the method of fixation chosen by the surgeon, determines the type of bone union.1 Primary fracture healing, also called direct bone union, occurs in fractures under rigid fixation, providing high stability under loading. Secondary fracture healing, also called indirect bone union, is the most common, occurring when there is relative stability at the fracture level, allowing some degree of motion between the fragments. Loading results in formation of an external callus bridging the fracture gap, and the fracture is considered healed when bone continuity is visible by radiography. This indirect bone healing is characteristically seen with nonoperative fracture treatment and with fixation that preserves some elasticity, such as intramedullary nailing, external fixation, or internal plate fixation in complex and comminuted fractures (Figure 1).


Figure 1
Figure 1. X-ray views of secondary healing of a tibia after intramedullary nail fixation.

(A) 1 month post operation. (B) 4 months post operation (hard callus). (C) 1 year post operation (remodeling).



_ Secondary fracture healing
The histology of bone following fracture was first described in 1930 by Ham, and McKibbin later emphasized the cellular mechanism involved in fracture healing.2 In recent decades, better understanding of bone biology has improved our grasp of the molecular control of cellular events.3

The healing process is a combination of intramembranous ossification and endochondral ossification similar to bone formation during osteogenesis.4 Though the healing process has been described as comprising 4 successive phases, in reality it appears that these phases may occur within different timeframes at different sites, and that they sometimes take place simultaneously.5

_ Hematoma and inflammatory phase
The hematoma and inflammatory phase is the immediate reaction to fracture: bleeding occurs from the bone and the surrounding soft tissues; the microvascular disruption leads to hypoxia and causes bone necrosis. The hematoma coagulates around the bone extremities and within the medulla, forming a template for callus formation. The fracture hematoma releases inflammatory mediators (cytokines) and initiates the inflammatory response: increased blood flow, increased vessel permeability, and increased cell migration.6 Osteoclasts are activated to resorb bone debris and vascular proliferation provides stem cells and signaling molecules. This inflammatory response peaks within 24 hours and is complete after 7 days.

_ Proliferation and differentiation phase
The proliferation and differentiation phase is characterized by a proliferation of primitive mesenchymal stem cells (MSCs), which differentiate into cells with osteogenic potential determined by the mechanical environment and biological signals. Tissue formed at the fracture site is called a callus, which becomes stiff as it calcifies. This phase of fracture healing has been classically divided into formation of the soft callus and, through its subsequent calcification, formation of the hard callus.

_ Soft callus formation
Soft callus formation occurs over a 3- to 4-week period. During this process, the clot is invaded by a fibrin-rich granulation tissue. Within this tissue, an endochondral formation develops between the bone extremities, external to the periosteum. This chondroid cartilaginous matrix, rich in proteoglycans and type 2 collagen, is replaced by an osteoid matrix rich in type 1 collagen. The ossified cartilage is replaced progressively by woven bone. Thus, the soft callus enveloping the bone extremities becomes more solid and mechanically rigid (Figure 1).

_ Hard callus formation
Hard callus formation occurs over 3 to 4 months. Overlapping the soft callus formation stage, intramembranous ossification occurs in the subperiosteal area adjacent to the distal and proximal ends of the fracture, forming the peripheral hard callus. The inner layer of the periosteum is rich in osteoblasts which synthesize a matrix rich in type 1 collagen, generating calcified tissue.7 This final central bridging by woven bone provides the fracture with a semi-rigid structure, allowing weight bearing and restoring limb function. At this stage, the woven bone is identical to the secondary spongiosa of the growth plate and the fracture is considered healed (Figure 2).





Figure 2
Figure 2. Bifocal fracture of the tibia, reduction and fixation by intramedullary nailing.

(A) Bifocal fracture of the tibia. (B) Post-operative view. (C) 6 months post operation; complete healing.



Figure 3
Figure 3. Periprosthetic fracture in a 72-year-old osteoporotic woman treated by plate fixation.

(A) Periprosthetic fracture. (B) Plate fixation. (C) Healing at 3 months. (D) View of remodeling, 15 months after plate removal.



_ Remodeling phase
Once the fracture has been bridged by the callus, the process of fracture repair continues with remodeling slowly replacing the new woven bone with lamellar bone. This remodeling process, resulting in a balanced resorption of hard callus by osteoclasts and lamellar bone deposition by osteoblasts, is initiated as early as the first month and takes years to achieve a fully regenerated bone structure (Figure 3).

_ Primary fracture healing
Direct bone union is not common in the natural process of fracture healing, because it requires an anatomical reduction of the fracture, without any gap, and a very rigid fixation. Bone on one side of the cortex can unite with the other side only when the cells within the fracture are subject to zero strain. Primary bone healing can occur by direct remodeling of lamellar bone without formation of a periosteal callus.5

Disorders of bone union

The bone healing process fails in 5% to 20% of fractures and the management of nonunion is challenging for an orthopedic trauma surgeon. The diagnosis itself is difficult because of a lack of consensus about the definitions of delayed union and nonunion.8 This paper discusses aseptic nonunion only, excluding the problem of local infection which is itself a major cause of nonunion.

_ Delayed union
Delayed union is a situation where there are distinct clinical and radiological signs of prolonged fracture healing time. It describes a fracture which has not healed within the expected timeframe and for which the outcome remains uncertain.

_ Nonunion
Nonunion is generally defined as a fracture that has failed to unite within 9 months and that has no radiographic sign of healing for 3 consecutive months. Sometimes, the distinction between delayed union and nonunion is difficult to make and may just reflect the surgeon’s hope for healing without further intervention. The diagnosis is based on clinical symptoms such as pain, inability to bear weight, persistence of motion at the fracture site, and absence of bridging callus on x-ray.

X-ray patterns for nonunion have been described according to callus formation.9 Hypertrophic nonunion is linked with inadequate immobilization and appears to have a normal blood supply and healing response; x-rays show poor callus forma-tion and an elephant foot configuration. Atrophic nonunion is linked to a poorly vascularized nonunion with very poor healing potential; x-rays show little callus formation, a persistent gap usually filled with fibrous tissue, and resorption of bone cortex.

Understanding the underlining causes of nonunion is key to deciding on the best therapeutic strategy. Giannoudis et al previously described the “diamond concept” of requirements for successful bone healing.10 The mandatory factors for optimization of fracture repair are not only the fundamental constituents of bone repair—potent osteogenic cell populations, osteoinductive stimulants, and an osteoconductive scaffold— but also mechanical stability. More recently, the same authors emphasized the contribution of other factors, such as vascularization and existing biological variation of the host.11 Therefore, the progression of fracture healing can be compromised by many physiologic, pathologic, or environmental factors. Surgical treatment has been effective for years, acting only on mechanical and local biological conditions.12 In hypertrophic nonunion, therapeutic intervention aims to correct the insufficiency of fracture stability with stable fixation, without impairing the blood supply. In atrophic nonunion, the objective of the intervention is to provide, of course, stability, but moreover to improve the poor biological environment. This includes removal of necrotic bone and fibrous scar tissues, and autologous bone grafting to fill in the bone defect and to provide a sufficient amount ofmesenchymal cells, growth and differentiation factors, and a scaffold to enhance bone formation. Noninvasive adjuvant physical therapies like low-intensity pulsed ultrasound, extracorporeal shockwave therapy, and electrical stimulation have had some success, but the amount of evidence is small due to the heterogeneity of results and lack of a sufficient number of randomized control trials.13-15

Emerging bone healing therapies

Elucidation of the molecular and cellular basis of bone repair has great potential to improve the treatment of bone union disorders; novel therapies are emerging.16

_ Molecular therapy
A number of key molecules that regulate the fracture healing process, such as growth factors, have been identified and are used in clinical practice or are under investigation.17 Bone morphogenetic proteins (BMPs) are members of the transforming growth factor superfamily (TGF); they play an important role at the beginning of the process, acting on the MSCs to promote osteoblastic differentiation. Using recombinant DNA technology, BMP-2 and BMP-7 have been produced and licensed for clinical use to improve bone healing in restricted indications: open fractures, recalcitrant nonunion (Figure 4), or spine fusion. Their use is increasing, more often in association with bone graft in off-label indications, despite some concerns: they have a possible side effect (ectopic bone formation), they are expensive to manufacture, and difficult to handle. Many studies are underway to optimize the delivery process, mini-invasively, and assess the cost effectiveness of the product. Platelet- derived growth factors (PDGFs) can be delivered to the fracture site as platelet-rich plasma: a volume of the plasma fraction of autologous blood with a concentration of platelets is delivered in situ, often mixed with thrombin to create a gel; however, the clinical efficacy of this procedure is unclear.


Figure 4
Figure 4. Evolution of healing in atrophic nonunion treated with revision surgery.

(A) Atrophic nonunion of a distal humerus 2 years after fracture, despite several bone grafting procedures.
(B) Evolution of the bone healing process following revision surgery (reduction, stable fixation, and in situ administration
of bone morphogenetic protein). (Courtesy of Prof L. Obert).
Abbreviation: m, month.



_ Bone marrow cells (BMCs)
Bone marrow aspirate, injected into the fracture, has been demonstrated to enhance bone healing.18 Centrifugation of the aspirate optimizes the procedure by concentrating the marrow, which has osteogenic effect, and discarding fat and cellular aggregate. Treatment of nonunion appears more effective when a minimum of 2600 progenitor cells/mm3 is used.19

_ Systemic drug delivery
A major concern in clinical practice, the impact of osteoporosis drugs on fracture healing has been widely evaluated in preclinical studies. While the main goal of osteoporosis treatment is fracture prevention, it should ideally have a positive, or at least a neutral, effect on fracture repair. There is no evidence at this time that osteoporosis treatment impairs the fracture healing process.20-21 The most used, the bisphosphonates, were expected to delay callus formation due to their mode of action. However, experimental data have suggested that callus size and strength were increased in treated animals compared with controls. Late remodeling is delayed, but that doesn’t affect long bone fracture healing in the long term. So, there is no evidence-based reason to withhold antiresorptive therapy while a fracture heals, regardless of whether the patient was taking such therapy when the fracture occurred.

Agents with bone-forming properties are expected to improve fracture healing and have been widely studied, showing preclinical evidence of their role in bone repair. Here, two such agents are discussed: parathormone (PTH) and strontium ranelate (SR).

Recent studies in animals and humans have shown compelling evidence of a positive action of PTH on bone fracture healing.22 Two controlled trials in postmenopausal women have demonstrated that PTH administration accelerates fracture healing time in conservatively treated distal radius fractures23 and in pubic bone fractures.24 Positive effects of PTH in fracture healing have been noted in case reports for hip fractures25 and nonunions.26

SR has a dual mechanism with a net bone-forming effect. Preclinical studies have suggested that fractures heal better and faster with SR treatment, showing an increase in the volume and resistance of the callus.27-29 Case reports also support the beneficial impact of SR on fracture healing and fracture nonunion.30-31 Recently, there have been reports of SR or PTH treatment of nonunion of atypical femoral fracture resulting in a similar reversal action on bone-formation markers32 An ongoing clinical study in male and female osteoporotic patients with distal radius fracture aims to confirm the efficacy of SR on fracture healing. The primary objective of this study is to evaluate whether radiological healing is accelerated under SR treatment compared with placebo.

Conclusions

The role of the orthopedic surgeon in fracture treatment is to reconstruct the normal anatomy of the injured bone to restore normal function. Providing stable fixation of the fracture and preserving its biological environment are essential requirements for satisfactory performance of the physiological and extremely complex healing process. Despite a tremendous improvement in surgical techniques, it is the better knowledge of bone biology that has led to development of new physical therapies and local biological treatment to enhance fracture healing. Future use of systemic drugs that lower the rate of healing disorders and accelerate bone union time is very promising, and would be a major advance in the management of fractures, hopefully minimizing the economic burden of skeletal injury.


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Keywords: bone biology; bone nonunion; bone repair; fracture callus; fracture healing