The early fracture hematoma and its potential role in fracture healing.

Research regarding the potency and potential of the fracture hematoma has begun to receive increasing attention. However, currently there is a paucity of relevant literature on the capability and composition of the fracture hematoma. This review briefly summarizes the regenerative fracture healing process and the close interplay between the skeletal and immune systems. The role of immune cells in wound healing is also discussed to clarify their involvement in immunological processes during regeneration. We attempt to describe the current state of knowledge regarding the fracture hematoma as the initial stage of the regenerative process of fracture healing. The review discusses how a better understanding of immune reactions in the hematoma may have implications for bone tissue engineering strategies. We conclude the review by emphasizing how additional investigations of the initial phase of healing will allow us to better differentiate between deleterious and beneficial aspects of inflammation, thereby facilitating improved fracture treatment strategies.

[1]  T. Koh,et al.  Selective and specific macrophage ablation is detrimental to wound healing in mice. , 2009, The American journal of pathology.

[2]  Georg N Duda,et al.  Differential regulation of blood vessel formation between standard and delayed bone healing , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[3]  G. Duda,et al.  Cellular composition of the initial fracture hematoma compared to a muscle hematoma: A study in sheep , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[4]  Hicham Drissi,et al.  Reduced COX-2 Expression in Aged Mice Is Associated With Impaired Fracture Healing , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[5]  Aaron Schindeler,et al.  Bone remodeling during fracture repair: The cellular picture. , 2008, Seminars in cell & developmental biology.

[6]  R. Guldberg,et al.  A Perspective: Engineering Periosteum for Structural Bone Graft Healing , 2008, Clinical orthopaedics and related research.

[7]  R. M. Smith.  Immunity, trauma and the elderly. , 2007, Injury.

[8]  A. Cope,et al.  Treg cells suppress osteoclast formation: a new link between the immune system and bone. , 2007, Arthritis and rheumatism.

[9]  Maurilio Marcacci,et al.  Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. , 2007, Tissue engineering.

[10]  H. Takayanagi.  Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems , 2007, Nature Reviews Immunology.

[11]  P. Moss,et al.  Ageing is associated with a decline in peripheral blood CD56bright NK cells , 2006, Immunity & Ageing.

[12]  M. Ishikawa,et al.  Postoperative host responses in elderly patients after gastrointestinal surgery. , 2006, Hepato-gastroenterology.

[13]  M. Blackman,et al.  Immunity and age: living in the past? , 2006, Trends in Immunology.

[14]  N. Haas,et al.  Osteoclastic activity begins early and increases over the course of bone healing. , 2006, Bone.

[15]  Y. Kadono,et al.  Osteoimmunology: interplay between the immune system and bone metabolism. , 2006, Annual review of immunology.

[16]  Hanna Schell,et al.  CYR61 (CCN1) Protein Expression during Fracture Healing in an Ovine Tibial Model and Its Relation to the Mechanical Fixation Stability , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[17]  B. Riggs,et al.  The role of the immune system in the pathophysiology of osteoporosis , 2005, Immunological reviews.

[18]  S. Kazi,et al.  Effects of Perioperative Antiinflammatory and Immunomodulating Therapy on Surgical Wound Healing , 2005, Pharmacotherapy.

[19]  A. M. Phillips.  Overview of the fracture healing cascade. , 2005, Injury.

[20]  D. Möbest,et al.  Differentiation of osteoblasts in three-dimensional culture in processed cancellous bone matrix: quantitative analysis of gene expression based on real-time reverse transcription-polymerase chain reaction. , 2005, Tissue engineering.

[21]  F Beaujean,et al.  Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. , 2005, The Journal of bone and joint surgery. American volume.

[22]  Georg N Duda,et al.  Initial vascularization and tissue differentiation are influenced by fixation stability , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[23]  Hiroshi Takayanagi,et al.  Mechanistic insight into osteoclast differentiation in osteoimmunology , 2005, Journal of Molecular Medicine.

[24]  S. Théoleyre,et al.  The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. , 2004, Cytokine & growth factor reviews.

[25]  I. Chaudry,et al.  Are the immune responses different in middle-aged and young mice following bone fracture, tissue trauma and hemorrhage? , 2004, Cytokine.

[26]  A. Barbul,et al.  Understanding the role of immune regulation in wound healing. , 2004, American journal of surgery.

[27]  K. Seibert,et al.  Differential inhibition of fracture healing by non‐selective and cyclooxygenase‐2 selective non‐steroidal anti‐inflammatory drugs , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[28]  D. E. Faunce,et al.  Aging enhances lymphocyte cytokine defects after injury , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  J. Street,et al.  Fracture hematoma is a potent proinflammatory mediator of neutrophil function. , 2003, The Journal of trauma.

[30]  M. Silva,et al.  Effect of repeated irrigation and debridement on fracture healing in an animal model , 2002, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[31]  Sundeep Khosla,et al.  Sex steroids and the construction and conservation of the adult skeleton. , 2002, Endocrine reviews.

[32]  E. Schwarz,et al.  Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. , 2002, The Journal of clinical investigation.

[33]  L. Bonassar,et al.  Replacement of an avulsed phalanx with tissue-engineered bone. , 2001, The New England journal of medicine.

[34]  N. Esen,et al.  The Relationship between Neutrophils and Incisional Wound Healing , 2001, Skin Pharmacology and Physiology.

[35]  R Cancedda,et al.  Repair of large bone defects with the use of autologous bone marrow stromal cells. , 2001, The New England journal of medicine.

[36]  Yongwon Choi,et al.  Osteoimmunology: Bone versus immune system , 2000, Nature.

[37]  Hiroshi Takayanagi,et al.  T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ , 2000, Nature.

[38]  S. Opal.  Phylogenetic and functional relationships between coagulation and the innate immune response. , 2000, Critical care medicine.

[39]  H. Redmond,et al.  Is human fracture hematoma inherently angiogenic , 2000 .

[40]  A. Remedios,et al.  Bone and bone healing. , 1999, The Veterinary clinics of North America. Small animal practice.

[41]  E. Bogoch,et al.  Bone abnormalities in the surgical treatment of patients with rheumatoid arthritis. , 1999, Clinical orthopaedics and related research.

[42]  M. Munder,et al.  Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. , 1998, Journal of immunology.

[43]  A. Barbul,et al.  Lymphocyte function in wound healing and following injury , 1998, The British journal of surgery.

[44]  M. Devidas,et al.  The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. , 1997, The Journal of trauma.

[45]  M. Devidas,et al.  Production of interleukin-10 in human fracture soft-tissue hematomas. , 1996, Shock.

[46]  A. Meyer,et al.  THE IMPACT OF FEMUR FRACTURE WITH ASSOCIATED SOFT TISSUE INJURY ON IMMUNE FUNCTION AND INTESTINAL PERMEABILITY , 1996, Shock.

[47]  I. Chaudry,et al.  Trauma-induced suppression of antigen presentation and expression of major histocompatibility class II antigen complex in leukocytes. , 1996, Shock.

[48]  O. Reikerås,et al.  The importance of the hematoma for fracture healing in rats. , 1993, Acta orthopaedica Scandinavica.

[49]  M. Tsunoda,et al.  The osteogenic potential of fracture hematoma and its mechanism on bone formation--through fracture hematoma culture and transplantation of freeze-dried hematoma. , 1993, The Kobe journal of medical sciences.

[50]  K. Mizuno,et al.  Enhancement of new bone formation by hematoma at fracture site. , 1991, Nihon Seikeigeka Gakkai zasshi.

[51]  K. Mizuno,et al.  The osteogenetic potential of fracture haematoma. Subperiosteal and intramuscular transplantation of the haematoma. , 1990, The Journal of bone and joint surgery. British volume.

[52]  J. Efron,et al.  Wound healing and T-lymphocytes. , 1990, The Journal of surgical research.

[53]  A. Barbul,et al.  The wound is a possible source of posttraumatic immunosuppression. , 1989, Archives of surgery.

[54]  A. Barbul,et al.  The Effect of In Vivo T Helper and T Suppressor Lymphocyte Depletion on Wound Healing , 1989, Annals of surgery.

[55]  E. Canalis,et al.  Tumor necrosis factor-alpha inhibits collagen synthesis and alkaline phosphatase activity independently of its effect on deoxyribonucleic acid synthesis in osteoblast-enriched bone cell cultures. , 1988, Endocrinology.

[56]  A. Barbul,et al.  Inhibition of host immunity by fluid and mononuclear cells from healing wounds. , 1984, Surgery.

[57]  B. Mckibbin,et al.  The biology of fracture healing in long bones. , 1978, The Journal of bone and joint surgery. British volume.

[58]  S. Mergenhagen,et al.  Bone Resorbing Activity in Supernatant Fluid from Cultured Human Peripheral Blood Leukocytes , 1972, Science.

[59]  Brighton Ct,et al.  Oxygen tension of nonunion of fractured femurs in the rabbit. , 1972, Surgery, gynecology & obstetrics.

[60]  R. Ross,et al.  The neutrophilic leukocyte in wound repair a study with antineutrophil serum. , 1972, The Journal of clinical investigation.

[61]  C. Brighton,et al.  Oxygen tension of healing fractures in the rabbit. , 1972, The Journal of bone and joint surgery. American volume.

[62]  Wray Jb.  The biochemical characteristics of the fracture hematoma in man. , 1970 .

[63]  A. Ham.  A HISTOLOGICAL STUDY OF THE EARLY PHASES OF BONE REPAIR , 1930 .

[64]  M. Kurosaka,et al.  An in vitro study demonstrating that haematomas found at the site of human fractures contain progenitor cells with multilineage capacity. , 2007, The Journal of bone and joint surgery. British volume.

[65]  A. Rüter,et al.  [Fracture healing. Morphologic and physiologic aspects]. , 1996, Der Unfallchirurg.

[66]  H. Yssel,et al.  IL-4 and IL-13, but not IL-10, are chemotactic factors for human osteoblasts. , 1995, Cytokine.

[67]  E. Peacock,et al.  Induction of collagen synthesis in rats by transplantation of allogenic macrophages. , 1976, Surgical forum.

[68]  M. Müller,et al.  Manual der OSTEOSYNTHESE , 1969 .