Cellular and Molecular Repair of Fracture Non-Union

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Background

Recently, the rate of fracture non-union has remained largely unchanged for many years, despite the enhancement in scientific understanding and treatment methods. However, delayed bone healing and fracture non-union are of great challenge for surgeons. In addition, many endocrine, nutritional or pharmaceutical side effects and other factors may contribute to delayed bone healing. For example, there is a higher incidence of bone delayed union and non-union in diabetic patients compared to non-diabetic ones. Fracture non-union remains a clinical problem in different anatomical sites, such as the tibia, humerus, or scaphoid. It can be divided into two types: the atrophic one is usually due to an underlying biological mechanism-resulted impaired bone healing, and the hypertrophic one is due to inadequate fracture fixation.

In studies, bone morphogenetic protein (BMP) was found to be low in bone ends and absent in the extracellular matrix at the non-union site. And Dickkopf-1 was higher in atrophic non-union. Studies of genetic polymorphisms have shown that the BMP and matrix metalloprotein (MMP) pathways play an important role in fracture non-union. Additionally, some micro RNAs (miRNAs) significantly upregulated in atrophic non-union, including hsa-miR-149, hsa-miR-221, has-miR-628-3p, hsa-miR-654-5p, et al. The vascularization in the site of bone fracture is also the focus of bone non-union.

Local delivery of growth factors to promote bone formation, including recombinant parathyroid hormone, vascular endothelial growth factor, and transforming growth factor-β, is used to treat non-union and delayed union of fractures. In clinical trials, several studies have been registered on stem cell therapy for bone non-union. And some small molecules, including strontium, stimulate the bone non-union in animal models. Although there are many treatments for fracture non-union, the mechanisms involved are not clear.

The gold standard strategy for bone non-union is bone implantation based on stable internal fixation. The clinical bone graft materials include autologous bone grafts, allografts and artificial bone. Autologous bone grafts are optimal for osteoconduction and osteogenesis, but their use is restricted by their limited source and by chronic pain and other adverse events at the donor site. Allogeneic bone grafts are less commonly used in clinical practice due to their immunogenicity. Whereas artificial bone is the most promising area of research. Many studies have found that the combination of biological factors, stem cells or genetically regulated stem cells in artificial bone significantly increases the osteogenic effect and has been shown in animal studies to be effective in repairing bone nonunion. With the development of 3D printing technology, artificial bone more closely simulates the structure and mechanical function of human bone. Hydroxylapatite (HA) has been approved by the FDA for the repair of bone defects, but HA with compound cell enrichment and exosomes is under clinical investigation. Composite biological factors, stem cells can functionalize biomaterials, and such artificial bone with specific functions will be one of the future treatments for bone non-union.

This Research Topic aims to identify potential biological mechanisms for fracture non-union. We also encourage the translation of basic research into new therapeutical approaches for fracture non-union.

We welcome submissions of Original Research, Reviews, Mini-reviews, Perspectives, and Opinion articles regarding the following sub-themes in endocrinology, orthopedics, and related fields, including but not limited to:
• The relationship between immune cells, including macrophages and granulocytes, and bone healing and the underlying molecular mechanism
• Stem cells and exosomes, mechanism of action in fracture non-union
• Exploration of molecular mechanisms at different stages of the healing process of fracture non-union
• Research on biomaterials, including biomaterials modification, 3D printing biomaterials, composite biofactors, and cells for the treatment of bone non-union

Keywords: Fracture, Bone healing, Bone metabolism, Non-union, Metabolomics

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