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What is Bone Repair and how does it occur?
What is Bone Repair and how does it occur?
Bones can fracture when enough force is applied. However, there are also other scenarios such as disease/defects that mitigate bone regeneration (Marsell & Einhorn, 2011). The process of how bone repair occurs is not as commonly understood, and there is further research being done to remedy abnormal bone conditions.
To explain the repair process, there are four stages of bone repair that will be discussed. The first stage is the hematoma formation. Immediately after the fracture, blood vessels and periosteum are ruptured and this results in a clotting to be formed, or a hematoma, at the site of injury (Sheen & Garla, 2021). The hematoma clots and provides a site for the bone to secrete pro-inflammatory cytokines like TNF-a, bone morphogenic proteins (BMPs) and interleukins. These are responsible for the recruitment of macrophages, monocytes, and lymphocytes which are necessary to stimulate the healing process of the bone (Sheen & Garla, 2021). These also secrete vascular endothelial growth factors (VEGFs) at the site of injury. The second stage is the fibrocartilaginous callus formation. VEGFs result in angiogenesis, the formation of new blood vessels, and in this stage a weak callus is formed. Mesenchymal stem cells are also recruited to the area which differentiate into fibroblasts, which form the connecting fibers of the bone, into chondroblasts forming the cartilage (Sheen & Garla, 2021), and osteoblasts, which begin the bone-tissue formation (Dimitriou et al., 2011). The third stage is the bony callus formation. It is like the second stage in that it further results in mesenchymal stem cell differentiation, but it results in a sturdier immature bone (Sheen & Garla, 2021). The fourth stage and longest stage is the remodeling stage. In this stage, osteoclasts which are responsible for bone resorption, along with the osteoblasts work together to form the new bone and ultimately heal the fracture.
Current Research of Stem Cells for Bone Defect Treatment
Despite the copious amounts of research and experiments performed to remedy the issues of bone defects, there is still a lot to be done to ensure efficient and lasting solutions to them. Stem cells and delivery methods of them are being studied to find a new solution to this issue. Stem cells are a strong candidate to these as they possess the ability to regenerate functional tissues when delivered to the site of musculoskeletal defects in animals (Bruder et al., 1998). Mesenchymal stem cells derived from the adult bone marrow can perform bone repair and it has been seen to work on rats, dogs, and in human clinical trials. (Bruder et al., 1998).
Figure 1. Cellular delivery containing stem cells in comparison to acellular delivery. Stem cells delivered presented a clear increase in regenerative capability after 12 weeks (Dupont et al., 2010).
Although it is known that stem cells do contribute to bone repair, it is not certain of the optimal delivery methods and the exact process of how stem cells promote enhanced repair (Dupont et al., 2010). A study performed by Dupont and colleagues (2010) used the delivery of stem cells on a porous polymer scaffold as a means of testing the enhanced healing of stem cells on bone defects. They compared the effects of this treatment to one with acellular scaffolding being delivered in addition to comparing fetal and adult stem cell sources. Stem cell delivery demonstrated enhanced bone repair, but between fetal and adult sources, there were no notable differences. Despite bone repair being evident, bone bridging was absent resulting in a limitation in the procedure. Fluorescent quantum dots were used as a means of non-invasive tracking for the delivery of the stem cells to identify the issue, but it eliminated the transplant’s therapeutic effects (Dupont et al., 2010). Still, the issue of identifying the healing method in bones through stem cells are not well known. The work of Dupont and colleagues is a demonstration of the struggle of understanding this novel form of therapy.
Issues with Current Usage of Stem Cells in Bone Repair
Unfortunately, even though mesenchymal stem cells demonstrate enhanced bone repair, it is not without its flaws. Osteoblasts are responsible for bone formation and are produced by MSCs. The issue that many face due to aging is the deficiency of these mesenchymal stem cells that produce osteoblasts (Gao et al., 2012). A transplantation of mesenchymal stem cells is a method to potentially counteract this, but there is high variability in donors which cause different differentiation capability and MSC numbers. This results in poorer efficacies of this treatment method (Santiago et al., 2009). The traditional extraction method of MSCs from the bone are also painful and invasive (Hjortholm et al., 2012). In addition, it is still relatively unknown of the exact process of how stem cells can enhance bone regeneration. It is understood that MSCs can result in greater formation of osteoblasts, but the optimal delivery method and the ideal combination of stem cells to demonstrate greatest efficacy is still yet to be discovered (Dupont et al., 2010).
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