Non-union of bone following fracture is an orthopaedic condition with a high morbidity and clinical burden. Despite its estimated global prevalence of nine million annually, the limit of bone regeneration therapy still results in patients living with pain, a reduced quality of life and associated psychological, social and financial repercussions. This review provides an overview of the current epidemiological and aetiological data, and highlights where the clinical challenges in treating non-union lie. Current treatment strategies are discussed as well as promising future research foci. Development in biotechnologies to treat non-union provides exciting scope for more effective treatment for this debilitating condition.

/pdf/fracture-non-union-a-review-of-clinical-challenges-and-2c9yedx2ea.pdf

Fracture Non-Union: A Review of Clinical Challenges and Future Research Needs.

Nonunion is a highly morbid complication that exacerbates the pain, disability and financial burden of distal and diaphyseal femur fractures. This study examined the modern rates of healing, nonunion, and other complications requiring reoperation of different fixation methods for distal and diaphyseal femur fractures. A systematic review and meta-analysis of all records from PubMed, Embase and the Cochrane Review system was performed. Included studies had >20 acute, non-pathologic distal or diaphyseal femur fractures treated with primary internal fixation. Excluded were studies on abnormal patient/fracture populations, external fixation, or cement/bone graft use. Thirty-eight studies with 2,829 femoral shaft fractures and 11 studies with 505 distal femur fractures were included. Distal fractures had a lower healing rate (86.6% vs. 93.7%) and a higher re-operation rate (13.4% vs 6.1%) than shaft fractures (p < 0.00001), primarily due to higher rates of mechanical failure (p < 0.00001). Nonunion was the most frequent complication, occurring in 4.7% of distal fractures and 2.8% of shaft fractures. There was no difference between plate and nail fixation of distal fractures in healing, nonunion, or other causes of re-operation. Shaft fractures developed nonunion in 6.6% of unreamed nails and 2.1% of reamed nails (p = 0.002). Nonunion occurred in 2.3% of antegrade nailed fractures and 1.5% of retrograde nailed fractures (p = 0.66). Approximately one out of every eight distal fractures and one of every 16 shaft fractures requires re-operation. The most common cause of fixation failure is nonunion. Further research is needed to improve outcomes, particularly in distal femur fractures.

Healing, nonunion, and re-operation after internal fixation of diaphyseal and distal femoral fractures: a systematic review and meta-analysis

Pluripotent stem cells (PSCs) are attractive regenerative therapy tools for skeletal tissues. However, a deep understanding of skeletal development is required in order to model this development with PSCs, and for the application of PSCs in clinical settings. Skeletal tissues originate from three types of cell populations: the paraxial mesoderm, lateral plate mesoderm, and neural crest. The paraxial mesoderm gives rise to the sclerotome mainly through somitogenesis. In this process, key developmental processes, including initiation of the segmentation clock, formation of the determination front, and the mesenchymal–epithelial transition, are sequentially coordinated. The sclerotome further forms vertebral columns and contributes to various other tissues, such as tendons, vessels (including the dorsal aorta), and even meninges. To understand the molecular mechanisms underlying these developmental processes, extensive studies have been conducted. These studies have demonstrated that a gradient of activities involving multiple signaling pathways specify the embryonic axis and induce cell-type-specific master transcription factors in a spatiotemporal manner. Moreover, applying the knowledge of mesoderm development, researchers have attempted to recapitulate the in vivo development processes in in vitro settings, using mouse and human PSCs. In this review, we summarize the state-of-the-art understanding of mesoderm development and in vitro modeling of mesoderm development using PSCs. We also discuss future perspectives on the use of PSCs to generate skeletal tissues for basic research and clinical applications. A deeper understanding of skeletal tissue development and improvements in tissue engineering will help pluripotent stem cell (PSC) therapies to reach their full potential for skeletal repair. The paraxial mesoderm, an embryonic germ layer, is crucial to the formation of healthy axial skeleton. Shoichiro Tani at the University of Tokyo, Japan, and co-workers reviewed current understanding of paraxial mesoderm development and studies involving in vitro PSC skeletal modeling. The formation of the paraxial mesoderm and associated connective tissues comprises multiple stages, and studies in vertebrate embryos have uncovered critical signaling pathways and cellular components important to PSC modeling. Although many individual cellular components can now be modeled, it remains challenging to recreate three-dimensional skeletal tissues. Such an achievement would facilitate a functioning model of bone metabolism, the next step in achieving skeletal regeneration.

/pdf/understanding-paraxial-mesoderm-development-and-sclerotome-25vvq2xa9r.pdf

Understanding paraxial mesoderm development and sclerotome specification for skeletal repair.

Fracture fixation aims to provide stability and promote healing, but remains challenging in unstable and osteoporotic fractures with increased risk of construct failure and nonunion. The first part of this article reviews the clinical motivation behind finite element analysis of fracture fixation, its strengths and weaknesses, how models are developed and validated, and how outputs are typically interpreted. The second part reviews recent modeling studies of the femur and proximal humerus, areas with particular relevance to fragility fractures. There is some consensus in the literature around how certain modeling aspects are pragmatically formulated, including bone and implant geometries, meshing, material properties, interactions, and loads and boundary conditions. Studies most often focus on predicted implant stress, bone strain surrounding screws, or interfragmentary displacements. However, most models are not rigorously validated. With refined modeling methods, improved validation efforts, and large-scale systematic analyses, finite element analysis is poised to advance the understanding of fracture fixation failure, enable optimization of implant designs, and improve surgical guidance.

Finite Element Analysis of Fracture Fixation

OBJECTIVES To investigate the biomechanical properties of a lateral locked plate alone or in combination with a supplemental medial plate or an intramedullary nail (IMN). METHODS Intra-articular distal femur fractures with metaphyseal comminution (OTA/AO 33-C) were simulated with a standardized model in 28 synthetic femora and divided into 4 groups. Group I was instrumented with a 4.5-mm lateral locked distal femoral plate alone, group II with a lateral locked plate plus a low-profile precontoured 3.5-mm medial distal tibial plate, group III with a lateral locked plate plus a medial 3.5-mm reconstruction plate, and group IV with a lateral locked plate plus a retrograde IMN. Specimens were then axially loaded and cycled to failure or runout. Outcomes of interest were baseline stiffness, survivability, and cycles to failure. RESULTS Groups III and IV have a significantly higher baseline stiffness (P < 0.001) when compared with groups I and II. Furthermore, groups III and IV had a higher max load to failure (P < 0.01) when compared with groups I and II. The survivability in groups III and IV was 71% and 100%, respectively, while no specimens in group I or II survived maximum loading. There was no significant difference between group III and IV regarding stiffness, survivability, and cycles to failure. CONCLUSION When considering fixation for intra-articular distal femur fractures with metaphyseal comminution (OTA/AO 33-C), we found that supplementation of a lateral locked plate with a medial plate or an IMN to be biomechanically superior to lateral locked plating alone regarding stiffness, survivability, and cycles to failure. A low-profile precontoured plate did not add significantly to the construct stiffness in this study.

Supplementation of Lateral Locked Plating for Distal Femur Fractures: A Biomechanical Study.

Management of Aseptic Tibial and Femoral Diaphyseal Nonunions Without Bony Defects

Below-knee amputation (BKA) requires 40 % less energy expenditure when compared with aboveknee amputation (AKA) (Waters RL, Perry J, Antonelli D, Hislop H, J Bone Jt Surg 58(1):42–46, 1976), and compliance with prosthesis use is twice as likely with a BKA when compared with an AKA (Hagberg E, Berlin OK, Renström P, Prosthet Orthot Int 16(3):168–173, 1992). However, despite the advantages, when a residual BKA stump is foreshortened, patients exhibit inefficient gait and significant functional loss, and prosthesis fit becomes difficult (Bowen RE, Struble SG, Setoguchi Y, Watts HG, J Pediatr Orthop 25(4):543–547, 2005). BKA stump lengthening with an Ilizarov is an option in patients with short residual BKA stumps, who have a healthy, well-perfused soft tissue envelope and who understand the risks and benefits of Ilizarov application. 1 Brief Clinical History A 27-year-old male sustained a traumatic crush injury to his left lower extremity in an offshore pipe elevator. As a result of the profound nature of his tibia and fibula fractures, in combination with a grossly contaminated wound and prolonged ischemic time, the patient underwent a below-knee amputation, followed by two additional irrigation and debridements prior to presenting to our institution for definitive management. The patient presented with some erythema surrounding the stump, so repeat irrigation and debridement and further shortening of the stump were performed to allow firsthand assessment of the bony integrity and to decrease the risk of infection prior to proceeding with definitive lengthening. The patient was assessed by a plastic surgeon with experience in traumatic wounds who performed several repeat irrigation and debridements, followed by a latissimus dorsi free flap prior to proceeding with stump lengthening. The time between flap coverage and lengthening was 2 months, in order to allow sufficient time for soft tissue healing. The patient and his wife attended numerous preoperative clinic consultations to ensure their understanding of the treatment plan. 2 Preoperative Clinical Photos and Radiographs

Below-Knee Amputation Stump Lengthening

Case 14: Double Level Bone Transport for Severe Bone Loss

A 36 year old male sustained a high-energy Gustilo-Anderson Type IIIB open, comminuted tibia fracture and underwent serial irrigation and debridements resulting in an 18 cm tibial bone defect and significant soft tissue loss. The patient underwent soft tissue reconstruction with a gastrocnemius rotational flap and split-thickness skin grafting. The patient was then treated with a doublelevel tibial bone transport over the course of 18 months. The importance of determining the rate of regenerate consolidation, close follow-up, multidisciplinary collaboration, and patient compliance is discussed. Technical tricks for optimizing healthy regenerate growth and achieving docking site union are presented. The patient is full weightbearing and happy with his clinical outcome. 1 Brief Clinical History A 36 year old healthy male was involved in a motorcycle collision and sustained a left GustiloAnderson Type IIIB open, comminuted distal tibia fracture with an associated segmental fibula fracture (Fig. 1). The patient underwent irrigation and debridement, placement of a spanning external fixator, and wound vacuum-assisted closure dressing (Fig. 2). Serial irrigation and debridements, revision of the external fixator, and open reduction and internal fixation of the segmental fibula fracture, both proximally and distally, were performed (Fig. 3). Serial antibiotic-impregnated beads were placed and exchanged in the defect. The patient underwent soft tissue reconstruction with a gastrocnemius rotational flap and split-thickness skin grafting. The patient presented to our hospital 3 weeks post-injury with an 18 cm left tibial bone defect. 2 Preoperative Clinical Photos and Radiographs (See Figs. 1, 2, and 3). 3 Preoperative Problem List 1. 18 cm tibial bone defect 2. Extensive soft tissue reconstruction 3. Segmental fibula fracture with previous open reduction and internal fixation (ORIF) 4. Syndesmosis injury with previous ORIF 5. Prior grossly contaminated open wound *Email: prism.schneider@gmail.com Limb Lengthening and Reconstruction Surgery Case Atlas DOI 10.1007/978-3-319-02767-8_184-1 # Springer International Publishing Switzerland (outside the USA) 2014

http://link.springer.com/content/pdf/10.1007%2F978-3-319-02767-8_184-1.pdf

Double-Level Bone Transport for Severe Bone Loss

Case 12: Open IIIB Tibia Fracture, Severely Contaminated, Treated with Ilizarov

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