Accelerated Fracture Healing - Mechanisms and Interventions

Introduction:

The human skeletal bones are one of the hardest structures in the body, however, any high impact forces over the bone may result in broken bones (fracture). It can either occur as a partial or complete fracture in various ways. The recovery period for a broken bone is dependent on:

1. The type of fracture,

2. Its location.

3. Severity.

4. The patient’s age.

5. Health condition.

Healing of the fractured bone also depends on the treatment option and prognosis of the patient. Speeding up the healing process can benefit in various ways by decreasing the time taken to return back to normal functions and enhancing the quality of life in these patients. This article discusses the mechanism of fracture healing and various interventions that can help speed up the process.

What Are the Stages of Fracture Healing?

Healing of a fractured bone is achieved through the formation of a callus (a type of soft bone). This process occurs in three consecutive phases: Inflammatory phase, reparative phase, and remodeling phase.

• The inflammatory phase occurs in the first few hours to days. There is a disruption of vascular flow in the fracture site which results in the formation of a hematoma (blood clot). This results in the release of cytokines, prostaglandins, and growth factors that are essential for healing. The fracture hematoma is infiltered by the fibrovascular tissue which forms the base for the primary callus formation.

• The reparative phase occurs in the next few days to weeks. This phase involves chondrogenesis and endochondral ossification. During this phase, the callus forms around the ends of the bone, replacing the hematoma, and stabilization of the fracture site is achieved. The soft callus takes several weeks to remodel and becomes a hard callus.

• The remodeling phase takes several months to years. During this phase, there is replacement of the cartilaginous callus with a bony callus by skeleton remodeling. The callus formation acts as a stabilizer and stress shield until complete bone formation and reunion of fractured bone fragments occurs. This phase is characterized by neovascularization which involves the differentiation of mesenchymal cells into bone-forming cells.

What Are the Various Interventions to Accelerate Fracture Repair?

The four critical elements necessary for healing of the fracture involve osteoconductive growth material, intact vascular supply, stem cells, and osteoinductive growth factors.

• Osteoconductive Material or Matrix: One of the primary steps in fracture healing involves conversion of undifferentiated mesenchymal stem cells into mature cells. The matrix acts as the medium for the stem cells to grow and differentiate into mature cells. When a larger part of the bone is lost during a fracture, it may result in large gaps between the bones. This disrupts the work of stem cells in promoting healing. In these conditions, larger gaps are filled with an osteoconductive material to facilitate the stem cells in fracture healing. The most preferred osteoconductive material to speed up fracture repair is bone grafts. The types of bone grafts are autograft, allograft, and synthetic variants of bone graft.

  1. An autologous bone graft is derived from the same individual and transplanted in another anatomic site.

  2. Allograft is used as an alternative to autograft and they are derived from the cadaver bone.

  3. Synthetic variants of bone grafts are man-made materials stimulating the properties of a bone graft. These include calcium phosphate, calcium sulfate, and tricalcium phosphate.

• Growth Factors: Growth factors are found in the body in lower concentrations and have the capability for angiogenesis (new blood vessel formation), cell growth, proliferation, and tissue repair.

  1. The role of growth factors is widely recognized in fracture repair, especially the bone morphogenic proteins (BMP), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1) and transforming growth factor-β1 (TGF-β1).

  2. Recombinant growth factors are produced in higher concentrations in tissue engineering to help enhance and speed up bone healing. However, only BMP-2 and BMP-7 have achieved commercial success.

  3. These growth factor proteins play a critical role in attracting the stem cells to the injured site where they are differentiated into pre-osteoblasts (bone-forming cells). This process is called chemoattraction.

• Stem Cells: Stem cells are biological immature cells that have the ability to proliferate, self-heal, regenerate tissues, and differentiate into other cells based on the influence of the surroundings.

  1. When they are introduced to an injured site they can differentiate into the type of cell needed to promote healing.

  2. They are easily derived and isolated from their source. They are mainly obtained from the bone marrow, adipose tissue, and muscles.

  3. The highest concentrations of stem cells are located in the pelvic bone and they are common source for obtaining stem cells.

  4. During the surgical procedure of fracture management, the orthopedic surgeon injects and releases higher concentrations of stem cells into the injured site to speed up the healing process.

  5. In tissue engineering, they are combined with scaffolds or suitable carriers to be delivered to the affected site to promote healing.

• Parathyroid Hormone: It is a naturally occurring polypeptide hormone produced by the parathyroid glands located in front of the neck. They are responsible for the regulation of calcium homeostasis in the body.

1. Intermittent administration of parathyroid hormone has been shown to increase bone strength and improve bone repair. However, the underlying mechanism is not well understood and further research is needed.

2. Teriparatide, a synthetic variant of the human parathyroid hormone consists of 1-34 terminal amino acid sequences.

3. Recent studies conducted in the animal model with fractures are given with intermittent administration of teriparatide in the dose range of 5 to 200 micrograms per kilogram. And they have been shown to enhance the process of early chondrogenesis and endochondral ossification which results in callus formation with superior biomechanical strength.

4. However, it has a few limitations and contraindications in humans. Various studies and literature have shown the effectiveness of parathyroid hormone in treating fractures.

Conclusion

Every year 6.3 billion people in the Unites States have fractures. The average recovery time taken for the healing of fractured bones is six months to one year. Multiple interventions have been studied to accelerate the healing time. A proper understanding of the mechanism of fracture is necessary to determine the appropriate intervention technique to accelerate fracture healing. Currently, various research and studies are being conducted to explore options that can help speed up the process of bone healing.