Synopsis of Orthopaedic Trauma Management. Brian H. Mullis

Nonunions and malunions are challenging problems as they are associated with high complication rates and high cost to the health care system and society.

      B. Understanding the causative factor is critical to developing a successful treatment plan for nonunions. Correction of medical or other associated comorbidities (if present) is of paramount importance for a surgical procedure to be successful.

      C. Understanding a patient’s functional limitations due to malunion and understanding the different options available to correct them is important in developing deformity correction treatment plans.

      D. Whether addressing malunion or nonunion, the decision when and on whom to intervene is of the utmost importance; nonoperative treatment is always possible.

      E. A successful result is physician- and patient-dependent.

      F. Understanding your own limitations will help maintain safety and minimize complications.

      Suggested Readings

      Brinker MR, O’Connor DP, Monla YT, Earthman TP. Metabolic and endocrine abnormalities in patients with nonunions. J Orthop Trauma 2007;21(8):557–570

      Bishop JA, Palanca AA, Bellino MJ, Lowenberg DW. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012;20(5):273–282

      Calori GM, Colombo M, Mazza EL, et al. Validation of the non-union scoring system in 300 long bone non-unions. Injury 2014; 45(Suppl 6):S93–S97

      Cierny G III, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Contemp Orthop 1985(10):17–37

      Weber BG, Brunner C. The treatment of nonunions without electrical stimulation. Clin Orthop Relat Res 1981(161):24–32Nauth A, Lane J, Watson JT, Giannoudis P. Bone graft substitution and augmentation. J Orthop Trauma 2015;29(Suppl 12):S34–S38

      8 Biologics

       J. Tracy Watson

      Introduction

      This chapter reviews stages of fracture healing and the therapeutics that inhibits or augments fracture healing. Multiple adjuvants are clinically available for use. The biology of graft substitutes and mechanisms of action are discussed with each major category of adjuvant reviewed.

      I. The Biology of Bone Grafts

      The biology of bone grafts and their substitutes is appreciated from an understanding of the bone formation processes of osteogenesis, osteoinduction, and osteoconduction.

      A. Osteogenesis: The ability of cellular elements within a donor graft, which survive transplantation, to synthesize new bone at the recipient site. Transplantation of marrow elements alone have demonstrated the ability to survive and form bone.

      B. Osteoconduction: Substrate site for cellular attachment with the appropriate three-dimensional architecture to allow for these cells to proliferate. Material acts as a scaffolding through which to build bone. This three-dimensional process involves vascular proliferation and ingrowth of capillaries along the open spaces in the substrate. Therefore, the porosity of these materials is critical.

      C. Osteoinduction: A process that supports the mitogenesis of undifferentiated mesenchymal cells leading to the formation of osteoprogenitor cells which have the capacity to form new bone. Thus, any material that induces this process could be considered to be osteoinductive material.

      1. All skeletal tissues evolve from undifferentiated mesenchymal stem cells and make a genetic commitment to a particular cellular lineage early in the developmental or repair process. The stimulus that causes these undifferentiated mesenchymal cells to differentiate along a chondro-osteogenic pathway is known as an inductive factor.

      2. These cells are influenced by multiple factors which cause them to migrate, attach, and multiply at the locale that provides a competent osteoconductive substrate as a site of cellular attachment.

      3. Osteoinductive new bone formation is realized through the active recruitment of host mesenchymal stem cells from the surrounding tissue which differentiate into bone-forming osteoblasts. This process is facilitated by the presence of “inductive” growth factors within the graft.

      II. Influence of Growth Factors and Antagonists on the Phases of Fracture Healing

      A. Inflammatory phase—most important for fracture healing to progress. It starts with injury and is complete within 2 to 3 weeks or earlier (▶Fig. 8.1).

      1. Hematoma invasion by macrophages, leukocytes, and lymphocytic cells.

      a. Platelets degranulate releasing signaling molecules.

      i. Transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF).

      ii. Promote chemotaxis, angiogenesis, and proliferation and differentiation of the cells that have migrated to the fracture.

      b. Characterized by neovascularization and ingrowth of proliferative blood vessels.

      c. Cellular attachment to extracellular matrix (ECM) and conductive substrate occurs. Integrins are membrane receptors that facilitate cell adhesion and attachment.

      Fig. 8.1 Time table for the stages of fracture healing. This is a continuum, with all phases occurring in a sequential fashion with each phase overlapping.

      Fig. 8.2 Wnt signaling pathway, its antagonists and actions of parathyroid hormone (PTH).

      2. Factors influencing the inflammatory phase—arachidonic acid metabolism.

      a. Enzymes cyclooxygenase (COX)-1 and -2 metabolize arachidonic acid to prostaglandin.

      i. COX inhibitors prevent the production of prostaglandin products. It inhibits all phases of the inflammatory process.

      ii. Important to refrain from these medications for the first 2 to 3 weeks post injury until inflammatory phase is complete.

      b. COX inhibitors are nonsteroidal anti-inflammatory drugs (NSAIDs). Largest effect on basic science models is either right before fracture or within the first few days following fracture.

      c. COX-2 inhibitors target COX-2 which is responsible for inflammation and pain.

      d. Targeting selectivity for COX-2 reduces peptic ulceration, but still has fracture healing side effects of NSAIDs and risk for fracture healing.

      3. Wnt pathway (▶Fig. 8.2).

      a. Wnt are signal transduction pathways made of proteins that pass signals from outside a cell through cell surface receptors to the inside of the cell.

      b. Wnt regulates gene transcription conversion of undifferentiated mesenchymal stem cells into an osteoblastic lineage.

      c. Induction of the Wnt promotes bone formation; inactivation leads to osteopenia.

      i. Sclerostin produced by osteocytes inhibits the Wnt signaling pathway.

      ii. Wnt pathway inhibition leads to decreased bone formation.

      4. Anti-sclerostin antibody (Romosozumab)—antibodies against sclerostin promote bone formation and increased callous size.

      B. Callous phase of healing involves