Researching of Fracture Healing

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Introduction

Small bone fractures are a global health issue, given the degree of disability associated with the condition. It is estimated that in 2019, there were approximately 178 million new fractures globally, which marked a 33.4% increase since 1990 (Wu et al., 2021). Over the last five years, the incidence of fractures in Canada has been 150 fractures per 100,000 individuals annually (Osteoporosis Canada, 2022). The higher frequency of fractures in males is attributed to occupational hazards and engagement in sporting activities (Wu et al., 2021). Increased screening for osteoporosis could potentially reduce the incidence of fractures. Fracture prevention initiatives are important, given their potential to reduce the overall disability burden in any given population.

Primary and Secondary Healing

The key processes involved in small fracture healing are direct or primary healing and secondary or indirect healing. The primary healing process occurs when there is a direct transition of mesenchymal cells to osteoblasts (Bahney et al., 2019). Secondary healing involves a cartilage intermediate before bone formation (Bahney et al., 2019). It is vital to note that most skeletal bones are repaired through the aforementioned process. Numerous cellular components, such as inflammatory cells, mesenchymal cells, chondrocytes, osteoblasts, and osteoclasts, are involved in the healing process (Bahney et al., 2019).

Acute Inflammation

A fracture causes the disruption of bone structure and the architecture of vascular supply in the affected tissues. The resultant decline in tissue oxygenation leads to the release of bioactive factors (Bahney et al., 2019). A few minutes after injury, fibrin-rich blood clots form to facilitate hemostasis. The release of cytokines facilitates the activation of inflammatory cells such as macrophages, lymphocytes, neutrophils, and eosinophils (Dincel et al., 2018). Inflammatory cells also produce growth factors such as Fibroblast Growth Factor, Platelet Derived Growth Factor, and Transforming Growth Factor beta, which are responsible for the proliferation and differentiation of stem cells (Bahney et al., 2019). The macrophages and other cells actively debride the injury site.

Chronic Inflammation

The healing process is actively impeded in the context of chronic inflammation for small fractures. Conditions such as diabetes and old age are linked to impaired healing. An increase in the production of CD8+ cells is often seen in chronic inflammatory states (Bahney et al., 2019). The cells produce high levels of TNF-alpha and interferon-gamma, as well as CXCL8 and CXCL9 cytokines, which cause delays in callus formation and promote a decline in bone density (Bahney et al., 2019).

Fibrovascular Phase: Revascularization

There is a significant disruption of the medullary, cortical and periosteal blood supply after an injury, resulting in cellular acidosis and necrosis. The result is a decline in oxygen tension from 5% to 0.1-2% in affected tissues (Bahney et al., 2019). Revascularization is necessary to restore the supply of oxygen and nutrients. Vascular Endothelial Growth factor, which is produced by cells in the injured callus, facilitates vasculogenesis and angiogenesis, which are visible histologically. (Bahney et al., 2019). The extracellular matrix may negatively impact cellular angiogenesis through thrombospondins, which actively inhibit the formation of new vessels (Bahney et al., 2019).

Fibrovascular Phase: Mesenchymal Progenitor Cells

Mesenchymal Progenitor Cells are multipotent in nature and give rise to chondrocytes, osteoblasts, myocytes, fibroblasts, adipocytes, and myocytes (Wang et al., 2018). The cells are derived from the local periosteum and bone marrow. The molecular regulation of Mesenchymal Progenitor Cells is controlled by cytokines such as CXCL12, which is released by inflammatory cells at the fracture site (Bahney et al., 2019). Factors such as oxygen tension and mechanical factors influence the transition of progenitor cells, which take the chondrogenic or osteogenic pathway (Bahney et al., 2019). It is vital to note that increased motion has been associated with enhanced chondrocyte formation, which triggers endochondral ossification.

Bone Formation: Osteoblasts

The process of differentiation from mesenchymal cells to osteoblasts occurs almost exclusively in small and stabilized defects through the process of intramembranous ossification. The process also occurs on endosteal and periosteal surfaces in unstable defects (Bahney et al., 2019). The osteogenic differentiation of periosteal progenitor cells gives rise to the intramembranous bone on the bone surfaces around the fracture site. The same cells migrate into the fracture site, where they undergo chondrogenesis (Bahney et al., 2019). Unlike periosteal progenitor cells, endosteal progenitor cells are strictly uni-potent and are responsible for bridging the gap at the fracture by closing the marrow cavity.

Bone Formation: Chondrocytes

The process of chondrogenesis mainly occurs in the fracture gap, where the periosteal stem cells are the primary source of the chondrocytes. The conversion of cartilage to callus occurs as a result of a highly regulated process that facilitates the maturation of chondrocytes from a proliferative to a hypertrophic state. The hypertrophic maturation stage is morphologically distinct by virtue of the fact that it causes an increase in cell volume (Umiatin et al., 2021). The chondrocytes on the growth plate experience a twenty-fold increase in size (Bahney et al., 2019). The large cells encourage further vasculogenesis and begin expressing canonical markers of bone, such as alkaline phosphatase and osteocalcin (Bahney et al., 2019). The cartilage matrix undergoes increased calcification, resulting in the formation of bone.

Callus Remodeling

The callus remodeling process is principally the final stage of fracture repair. It is an essential step because it facilitates the removal of provisional bone, also referred to as woven bone, to facilitate the formation of mature lamellar bone (Bahney et al., 2019). Osteoclasts are formed from hematopoietic macrophage/monocyte lineage precursor cells. The proliferation of the cells is stimulated by the interaction of the aforementioned progenitor cells and colony-stimulating factors (Bahney et al., 2019). Bone degradation by osteoclasts is a typical feature of the remodeling process. The cells use membrane-bound lysosomal proteins to break down the bone (Bahney et al., 2019). The result is a well-healed fracture site that resembles the initial anatomic contours.

Conclusion

The phases of healing often overlap despite the fact that this discussion highlights district stages. The key processes involved in bone healing are direct or primary healing and secondary or indirect healing. While acute inflammation often promotes fracture repair, chronic inflammatory states occasioned by diabetes or old age may impede the healing process. The fibrovascular phase involves the process of revascularization, which is necessary to restore the supply of oxygen, nutrients, and pro-inflammatory cells to the callus. In addition, it includes the recruitment of Mesenchymal Progenitor Cells, which are multipotent in nature and give rise to chondrocytes. Bone formation occurs with the aid of osteoblasts and chondrocytes. The final stage is callus remodeling, which restores the fractured bone to its original shape.

References

Bahney, C. S., Zondervan, R. L., Allison, P., Theologis, A., Ashley, J. W., Ahn, J., Miclau, T., Marcucio, R. S., & Hankenson, K. D. (2019). Cellular biology of fracture healing. Journal of Orthopaedic Research, 37(1), 35–50. Web.

Dincel, Y. M., Alagoz, E., Arikan, Y., Caglar, A. K., Dogru, S. C., Ortes, F., & Arslan, Y. Z. (2018). Biomechanical, histological, and radiological effects of different phosphodiesterase inhibitors on femoral fracture healing in rats. Journal of Orthopaedic Surgery, 26(2), 1–9. Web.

Osteoporosis Canada. (2022). Facts and stats. Web.

Umiatin, U., Hadisoebroto D. I., Sari, P., & Kusuma W. S. (2021). Histological analysis of bone callus in delayed union model fracture healing stimulated with pulsed electromagnetic fields (PEMF). Scientifica, 2021, 1–6. Web.

Wang, X., Wang, C., Gou, W., Xu, X., Wang, Y., Wang, A., Xu, W., Guo, Q., Liu, S., Lu, Q., Meng, H., Yuan, M., Peng, J., & Lu, S. (2018). The optimal time to inject bone mesenchymal stem cells for fracture healing in a murine model. Stem Cell Research and Therapy, 9(1), 1–10. Web.

Wu, A. M., Bisignano, C., James, S. L., Abady, G. G., Abedi, A., Abu-Gharbieh, E., Alhassan, R. K., Alipour, V., Arabloo, J., Asaad, M., Asmare, W. N., Awedew, A. F., Banach, M., Banerjee, S. K., Bijani, A., Birhanu, T. T. M., Bolla, S. R., Cámera, L. A., Chang, J. C., … Vos, T. (2021). Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: A systematic analysis from the Global Burden of Disease Study 2019. The Lancet Healthy Longevity, 2(9), 580–592. Web.

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