Abstract
Single trauma injuries or isolated fractures are often manageable and generally heal without complications. In contrast, high-energy trauma results in multi/poly-trauma injury patterns presenting imbalanced pro- and anti- inflammatory responses often leading to immune dysfunction. These injuries often exhibit delayed healing, leading to fibrosis of injury sites and delayed healing of fractures depending on the intensity of the compounding traumas. Immune dysfunction is accompanied by a temporal shift in the innate and adaptive immune cells distribution, triggered by the overwhelming release of an arsenal of inflammatory mediators such as complements, cytokines and damage associated molecular patterns (DAMPs) from necrotic cells. Recent studies have implicated this dysregulated inflammation in the poor prognosis of polytraumatic injuries, however, interventions focusing on immunomodulating inflammatory cellular composition and activation, if administered incorrectly, can result in immune suppression and unintended outcomes. Immunomodulation therapy is promising but should be conducted with consideration for the spatial and temporal distribution of the immune cells during impaired healing. This review describes the current state of knowledge in the spatiotemporal distribution patterns of immune cells at various stages during musculoskeletal wound healing, with a focus on recent advances in the field of Osteoimmunology, a study of the interface between the immune and skeletal systems, in long bone fractures. The goals of this review are to (1) discuss wound and fracture healing processes of normal and delayed healing in skeletal muscles and long bones; (2) provide a balanced perspective on temporal distributions of immune cells and skeletal cells during healing; and (3) highlight recent therapeutic interventions used to improve fracture healing. This review is intended to promote an understanding of the importance of inflammation during normal and delayed wound and fracture healing. Knowledge gained will be instrumental in developing novel immunomodulatory approaches for impaired healing.
Highlights
Inflammation is the first response in the process of wound and fracture healing, and appropriate activation of the immune system is integral for maintaining tissue integrity and facilitating a return to homeostasis
Much of the research focus has been placed on the regulation of the events in fracture healing by paracrine signaling, rather than direct cellular activities, mainly due to lack of information on the temporal distribution of innate and adaptive immune cells during fracture, and this review aims to address the issue in both normal and delayed fracture healing
Early circulating IgM+CD27+ B cells from normal healing patients demonstrated robust suppressive function, while the later circulating IgM+CD27+ B cells did not present regulatory functions in both normal and delayed healing patients [79]. These findings indicate that dysfunctional Breg have a role in instigating delayed fracture healing and this dysfunction is accompanied by increased pro-inflammation and dysregulated lymphocyte responses
Summary
Inflammation is the first response in the process of wound and fracture healing, and appropriate activation of the immune system is integral for maintaining tissue integrity and facilitating a return to homeostasis. Fracture healing is initiated by a local acute inflammatory response that includes the formation of a fracture hematoma and clearing of necrotic cell debris and DAMPs from the fracture site This activity promotes the recruitment of MSCs and additional immune cells to the fracture site to initiate the repair phases, including the initial formation of a cartilaginous soft callus which is soon converted into a hard-bony trabecular callus or woven bone. These observations imply that T and B cells are detected as early as the soft callus formation begins (i.e., 5–7 dpf), where they secrete OPG in an incremental fashion as the callus formation progresses from 14 to 21 dpf and until the remodeling phase This suggests that the T and B cells contribute to bone formation by regulating osteoclastogenesis during the later stage of healing. Treatment with FK506 reduced macrophages and T cells infiltration within the TABLE 1 | Immunomodulatory therapies for fracture healing
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