A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair.

While formation and regeneration of the skeleton have been studied for a long period of time, significant scientific advances in this field continue to emerge based on an unmet clinical need to improve options to promote bone repair. In this review, we discuss the relationship between mechanisms of bone formation and bone regeneration. Data clearly show that regeneration is not simply a reinduction of the molecular and cellular programs that were used for development. Instead, the mechanical environment exerts a strong influence on the mode of repair, while during development, cell-intrinsic processes drive the mode of skeletal formation. A major advance in the field has shown that cell fate is flexible, rather than terminal, and that chondrocytes are able to differentiate into osteoblasts and other cell types during development and regeneration. This is discussed in a larger context of regeneration in vertebrates as well as the clinical implication that this shift in understanding presents.

The Contribution of Macrophages in Old Mice to Periodontal Disease.

The prevalence of periodontal disease increases with age. Systemic inflammatory dysregulation also increases with age and has been reported to contribute to the myriad of diseases and conditions that become more prevalent with advanced age. As periodontal disease involves a dysregulated host inflammatory response, the age-related inflammatory dysregulation may contribute to the pathogenesis of periodontal disease in aging populations. However, our understanding of what drives the age-related inflammatory dysregulation is limited. Here, we investigate the macrophage and its contribution to periodontal disease in old and young mice using a ligature-induced periodontal disease model. We demonstrate that control old mice present with an aged periodontal phenotype, characterized by increased alveolar bone loss and increased local inflammatory cytokine expression compared to young mice. Macrophages were demonstrated to be present in the periodontium of old and young mice in equal numbers in controls, during disease induction, and during disease recovery. However, it appears age may have a detrimental effect on macrophage activity during disease recovery. Depletion of macrophages during disease recovery in old mice resulted in decreased inflammatory cytokines within the gingiva and decreased bone loss as measured by micro-computed tomography. In young mice, macrophage depletion during disease recovery had no beneficial or detrimental effect. Macrophage depletion during disease induction resulted in decreased disease severity similarly in young and old mice. Findings from this work support the diverse roles of macrophages in disease induction as well as the active roles of disease recovery, including the resolution of inflammation. Here, we conclude that age-related changes to the macrophage appear to be detrimental to the recovery from disease and may explain, in part, the age-related increase in prevalence of periodontal disease. Future studies examining the specific intrinsic age-related changes to the macrophage will help identify therapeutic targets.

The Burden of High-Energy Musculoskeletal Trauma in High-Income Countries.

INTRODUCTION TO THE PROBLEM: Though declining in the recent decades, high-energy musculoskeletal trauma remains a major contributor to the burden of disease in high-income countries (HICs). However, due to limitations in the available body of the literature, evaluation of this burden is challenging. The purpose of this review is to assess: (1) the current epidemiologic data on the surgical burden of high-energy musculoskeletal trauma in HICs; (2) the current data on the economic impact of high-energy musculoskeletal trauma; and (3) potential strategies for addressing gaps in musculoskeletal trauma care for the future. REVIEW OF LITERATURE: In 2016, mortality from road traffic injuries (RTIs) between the ages of 15-49 was reported to be 9.5% (9.0-9.9) in high-income countries, accounting for approximately 255 million DALYs. While RTIs do not fully capture the extent of high-energy musculoskeletal trauma, as the most common mechanism, they serve as a useful indicator of the impact on the surgical and economic burden. In 2009, the global losses related to RTIs were estimated to be 518 billion USD, costing governments between 1 and 3% of their gross domestic product (GDP). In the last decade, both the total direct per-person healthcare cost and the incremental direct per-person costs for those with a musculoskeletal injury in the USA rose 75 and 58%, respectively. FUTURE DIRECTIONS: ADDRESSING THE GAPS: While its impact is large, research on musculoskeletal conditions, including high-energy trauma, is underfunded compared to other fields of medicine. An increased awareness among policy makers and healthcare professionals of the importance of care for the high-energy musculoskeletal trauma patient is critical. Full implementation of trauma systems is imperative, and metrics such as the ICD-DALY have the potential to allow for real-time evaluation of prevention and treatment programs aimed to reduce injury-related morbidity and mortality. The dearth in knowledge in optimal and cost-effective post-acute care for high-energy musculoskeletal trauma is a reason for concern, especially since almost half of the costs are attributed to this phase of care. Multidisciplinary rehabilitation teams as part of a musculoskeletal trauma system may be of interest to decrease further the long-term negative effects and the economic burden of high-energy musculoskeletal trauma.

Fracture repair in the elderly: Clinical and experimental considerations.

Fractures in the elderly represent a significant and rising socioeconomic problem. Although aging has been associated with delays in healing, there is little direct clinical data isolating the effects of aging on bone healing from the associated comorbidities that are frequently present in elderly populations. Basic research has demonstrated that all of the components of fracture repair-cells, extracellular matrix, blood supply, and molecules and their receptors-are negatively impacted by the aging process, which likely explains poorer clinical outcomes. Improved understanding of age-related fracture healing should aid in the development of novel treatment strategies, technologies, and therapies to improve bone repair in elderly patients.

Tissue engineering and regenerative approaches to improving the healing of large bone defects.

Despite the high innate regenerative capacity of bone, large osseous defects fail to heal and remain a clinical challenge. Healing such defects requires the formation of large amounts of bone in an environment often rendered hostile to osteogenesis by damage to the surrounding soft tissues and vasculature. In recent years, there have been intensive research efforts directed towards tissue engineering and regenerative approaches designed to overcome this multifaceted challenge. In this paper, we describe and critically evaluate the state-of-the-art approaches to address the various components of this intricate problem. The discussion includes (i) the properties of synthetic and natural scaffolds, their use in conjunction with cell and growth factor delivery, (ii) their vascularisation, (iii) the potential of gene therapies and (iv) the role of the mechanical environment. In particular, we present a critical analysis of where the field stands, and how it can move forward in a coordinated fashion.

Cell therapy for bone repair: narrowing the gap between vision and practice.

This position paper summarises a vision of how cell-based therapies can be applied clinically to regenerate bone, as well as the steps needed to narrow the gap between that vision and clinical reality. It is a result of the presentations and discussion of the "Cell Therapy for Bone Repair" breakout session at the AO Foundation Symposium "Where Science Meets Clinics" in Davos, Switzerland from September 5-7, 2013. Participants included leaders from science, medicine, and industry from around the world. The session included clinical and scientific presentations, as well as an extended discussion among participants. Bone tissue has an innate regenerative capacity that in most cases allows functional healing at damage sites. However, there are a number of serious conditions in which bone does not fully heal and the result is significant morbidity. The clinical need for new therapies is clear, and the breakout session participants were enthusiastic about the potential impact on cell-based therapies for bone repair in the clinic. However, they also recognised the significant challenges that face the development of commercially viable cell therapy products. This paper outlines a vision in which patient selection is based on expected therapeutic outcome to create a consistently successful, cost-effective, cell-based therapy for bone repair. The need for a more complete understanding of bone repair, a better infrastructure for preclinical studies, and the need for collaboration among stakeholders is discussed.

Barriers and strategies for the clinical translation of advanced orthopaedic tissue engineering protocols.

Research in orthopaedic tissue engineering has intensified over the last decade and new protocols continue to emerge. The clinical translation of these new applications, however, remains associated with a number of obstacles. This report highlights the major issues that impede the clinical translation of advanced tissue engineering concepts, discusses strategies to overcome these barriers, and examines the need to increase incentives for translational strategies. The statements are based on presentations and discussions held at the AO Foundation-sponsored symposium "Where Science meets Clinics 2013" held at the Congress Center in Davos, Switzerland, in September, 2013. The event organisers convened a diverse group of over one hundred stakeholders involved in clinical translation of orthopaedic tissue engineering, including scientists, clinicians, healthcare industry professionals and regulatory agency representatives. A major point that emerged from the discussions was that there continues to be a critical need for early trans-disciplinary communication and collaboration in the development and execution of research approaches. Equally importantly was the need to address the shortage of sustained funding programs for multidisciplinary teams conducting translational research. Such detailed discussions between experts contribute towards the development of a roadmap to more successfully advance the clinical translation of novel tissue engineering concepts and ultimately improve patient care in orthopaedic and trauma surgery.

Patient-important outcome for the assessment of fracture repair.

Current evidence indicates that fracture healing assessment is limited to the use of one or two domains (such as pain, range of motion or mobility) in any single study. Functional outcome measures, which include physician-rated or observer-based impairment ratings and patient self-reported or observer-based activity limitation measures, better position the effectiveness of a given intervention towards patient-important outcomes. Health status measures, for example, cover a wide-range of physical, emotional, and social health dimensions. In this paper, we will examine the utility of metrics to assess fracture healing that are important to both the patient and provider, with selected examples from the recent literature. We recommend outcome measures with established and verified reliability and validity. Policy-makers and other stakeholders need to have an accurate assessment of treatment outcome that includes changes in function over time-adequate measures, should be re-applied at periodic intervals.

Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions?

Nonunion is a common complication following long-bone fracture, with a prevalence that ranges from 2.5-46%, depending on the location and severity of the injury to the bone, soft tissue, and vascular structures. The treatment of nonunions involves addressing the biology of fracture repair and the mechanical stability of fracture fixation, which are interrelated. Nonunion treatment has traditionally included the addition of autograft from the iliac crest to enhance healing. However, there an associated morbidity with the harvesting of the graft, and alternatives such as bone marrow aspirate, platelet-rich plasma, allograft, and ceramics have also been studied. In addition, new advances in the understanding of the cellular and molecular mechanisms of fracture repair have led to the use of growth factors, such as bone morphogenetic proteins, to accelerate bone healing. This article reviews the benefits of iliac crest bone graft relative to those of other modalities in the treatment of nonunions.

Cellular and molecular characterization of a murine non-union model.

PURPOSE: We have developed a method to study the molecular and cellular events underlying delayed skeletal repair in a model that utilizes distraction osteogenesis. METHODS: The clinical states of delayed union and non-union were reproduced in this murine model by altering distraction parameters such as the inclusion and exclusion of a latency phase and variations in the rate and rhythm of distraction. Radiographic, cellular, and molecular analyses were performed on the distraction tissues. RESULTS: Eliminating the latency period delayed bony union, but did not appreciably alter the extent of platelet endothelial cell adhesion marker (PECAM) immunostaining. Following elimination of a latency phase and a threefold increase in the rate of distraction, there was a further delay in bone regeneration and a higher rate of non-union (60%). Instead of bone, the distraction gap was comprised of adipose or fibrous tissue. Once again, despite the rigorous distraction protocol, we detected equivalent PECAM staining within the distraction gap. In a minority of cases, cartilage and osseous tissues occupied the distraction gap likely by a prolonged process of endochondral ossification. CONCLUSIONS: Here, we have altered the mechanical environment in such a way to reproducibly create delays in skeletal regeneration. These delays in skeletal tissue regeneration appear to develop even in the presence of endothelial cells, which suggests that mechanisms other than a disruption to the vascular network can account for some cases of non-union.

[Treatment approaches in gunshot injuries of the extremities]. / Behandlung von Schussverletzungen des Bewegungsapparates.

In the view of efficiency and cost effectiveness the increasing incidence of gunshot wounds in Europe demands a modification of treatment protocols. The general basis are debridement of soft tissue injuries, antibiotics and fracture stabilization. The pathology of gunshot wounds and established treatment algorhithms, however have to be adjusted to the ongoing development of gun technology and the thereby caused specific lesions. The treatment of injuries caused by high velocity projectiles necessitates a proactive surgical strategy. Small caliber gunshot wounds can be treated more conservatively. The following review presents an overview on the ballistic and surgical basis for the treatment of gunshot wounds of the musculoskeletal system.

A minimally invasive medial approach for proximal tibial fractures.

Numerous techniques have been described for MIPPO (minimally invasive percutaneous plate osteosynthesis) for metaphyseal or combined metaphyseal-articular fractures of the proximal tibia. Surgical management is often complicated by the initial soft tissue damage, malalignment, remaining instability, or infection. In this prospective cohort study, we describe the diagnostic procedures vital for preoperative planning. These include plain radiographs and CT scans in case of articular fracture components. The techniques for temporary stabilization and definitive fracture care using 4.5 mm DCP, LC-DCP, and LISS (Less Invasive Stabilization System) by limited medial incisions are described in a stepwise protocol. From 1996 to 1998, six fractures in six patients were studied. According to the AO classification, there were four type 41 fractures and two type 42 fractures. One patient died of ARDS. All patients had an intact medial soft tissue coverage allowing a medial approach. One patient developed a compartment syndrome, which was addressed by lateral dermato-fasciotomy prior to osteosynthesis. A LISS was used in three patients. The only complication related to surgery was in a patient with a four-part fracture with lateral comminution and a dislocated postero-medial fragment, which was reduced and buttressed with a short posteromedial 3.5 mm small fragment plate. This patient developed a deep, intraarticular infection, which was successfully treated with revision surgery; the implants were left in situ. At her latest follow-up at 18 months, she had a range of motion of 0/10/110, was back at work, and able to participate in recreational sports. The average time to healing was between 12 and 20 weeks postoperatively. There was no delayed healing, pseudarthrosis, recurrent fracture or late infection. None of the cases needed bone grafting. At the most recent follow-up, all patients were bearing full weight without walking aids. All cases achieved a neutral alignment and satisfactory range of movement. Though further data are needed we have sound reason to propagate a single medial approach and minimally invasive osteosynthesis as a sufficient and subtle technique for stabilization of these complicated fractures.

Computed tomography assessment of sacroiliac screw placement relative to the first sacral neuroforamen.

The radiographic interpretation of sacroiliac screws relative to the S1 neuroforamen is difficult for orthopedic surgeons and radiologists. Computed tomography (CT) with axial images alone or combined with multiplanar reconstructions are often used to assess screw position. The reliability, reproducibility, and accuracy of orthopedist and radiologist interpretations of axial CT images with and without multiplanar reconstructions was determined using 24 cadaveric hemipelves with known sacroiliac screw position. Interobserver reliability of determining screw position was fair for orthopedists and slight for radiologists regardless of imaging modality or screw composition. Intraobserver reproducibility was moderate for orthopedists regardless of imaging modality or screw type. Reproducibility among radiologists was moderate using axial images of titanium screws and substantial with addition of multiplanar reconstructions. Overall accuracy was similar for orthopedists and radiologists. CT images with multiplanar reconstructions improve accuracy in determining sacroiliac screw position, but not significantly. Current imaging modalities are limited by large inaccuracies and by interobserver and intraobserver variation.

Molecular aspects of healing in stabilized and non-stabilized fractures.

Bone formation is a continuous process that is initiated during fetal development and persists in adults in the form of bone regeneration and remodeling. These latter two aspects of bone formation are clearly influenced by the mechanical environment. In this study we tested the hypothesis that alterations in the mechanical environment regulate the program of mesenchymal cell differentiation, and thus the formation of a cartilage or bony callus, at the site of injury. As a first step in testing this hypothesis we produced stabilized and non-stabilized tibial fractures in a mouse model, then used molecular and cellular methods to examine the stage of healing. Using the "molecular map" of the fracture callus, we divided our analyzes into three phases of fracture healing: the inflammatory or initial phase of healing, the soft callus or intermediate stage, and the hard callus stage. Our results show that indian hedgehog(ihh), which regulates aspects of chondrocyte maturation during fetal and early postnatal skeletogenesis, was expressed earlier in an non-stabilized fracture callus as compared to a stabilized callus. ihh persisted in the non-stabilized fracture whereas its expression was down-regulated in the stabilized bone. IHH exerts its effects on chondrocyte maturation through a feedback loop that may involve bone morphogenetic protein 6 [bmp6; (S. Pathi, J.B. Rutenberg, R.L. Johnson, A. Vortkamp, Developmental Biology 209 (1999) 239-253)] and the transcription factor gli3. bmp6 and gli3 were re-induced in domain adjacent to the ihh-positive cells during the soft and hard callus stages of healing. Thus, stabilizing the fracture, which circumvents or decreases the cartilaginous phase of bone repair, correlates with a decrease in ihh signaling in the fracture callus. Collectively, our results illustrate that the ihh signaling pathway participates in fracture repair, and that the mechanical environment affects the temporal induction of ihh, bmp6 and gli3. These data support the hypothesis that mechanical influences affect mesenchymal cell differentiation to bone.

Evolution of minimally invasive plate osteosynthesis (MIPO) in the femur.

Problems with conventional open reduction and internal plate fixation of distal femoral fractures are well established. These problems have been associated with extensile exposures of the fracture site. "Biological plating", like intramedullary nail fixation, of distal femoral fractures preserves the soft tissues about the fracture, and is associated with early fracture consolidation and low rates of infection. Anatomical restoration of the articular surface continues to be the main goal in the treatment of these fractures regardless of the stabilization technique. Submuscular plating techniques, which provide for closed reduction of the diaphyseal/metaphyseal component of the fracture, have improved significantly.

Necrotizing soft-tissue infections.

Necrotizing fasciitis is a rare and often fatal soft-tissue infection involving the superficial fascial layers of the extremities, abdomen, or perineum. Necrotizing fasciitis typically begins with trauma; however, the inciting event may be as seemingly innocuous as a simple contusion, minor burn, or insect bite. Differentiating necrotizing infections from common soft-tissue infections, such as cellulitis and impetigo, is both challenging and critically important. A high degree of suspicion may be the most important aid in early diagnosis. Prompt diagnosis is imperative because necrotizing infections typically spread rapidly and can result in multiple-organ failure, adult respiratory distress syndrome, and death. Although group A Streptococcus is the most common bacterial isolate, a polymicrobial infection with a variety of Gram-positive, Gram-negative, aerobic, and anaerobic bacteria is more common. Orthopaedic surgeons are often the first physicians to evaluate patients with such infections and therefore need to be familiar with this potentially devastating disease and its management. Prompt diagnosis, immediate administration of broad-spectrum antibiotic coverage, and emergent aggressive surgical debridement of all compromised tissues are critical to reduce the morbidity and mortality of these rapidly progressing infections.

Posterior lateral mass plate fixation of the cervical spine.

Historically, posterior fixation and fusion have been the most popular method of internally stabilizing the cervical spine after injury. Although techniques such as wiring are effective for most injuries, these methods are inadequate in the absence of intact posterior elements or extension and rotation injuries. We review the indications and techniques for posterolateral mass plate fixation that are useful in these difficult fractures.

The topography of the perforating vessels of the deep femoral artery.

This study evaluated the anatomic relationship between the femur and the vessels that arise from the deep femoral artery, that is, the perforating arteries and the nutrient artery. Blue silicone dye was injected through the common femoral artery in 20 fresh human cadavers. An anteromedial and a posterolateral dissection were performed to identify the femoral perforating arteries and the nutrient artery of the femur. The length of the femur and the distances between the tip of the greater trochanter and the perforating arteries and nutrient artery were measured. This study showed that a reliable, clinically applicable topographic relationship exists between the femur and the perforating arteries and the nutrient artery.

Does adult fracture repair recapitulate embryonic skeletal formation?

Bone formation is a continuous process that begins during fetal development and persists throughout life as a remodeling process. In the event of injury, bones heal by generating new bone rather than scar tissue; thus, it can accurately be described as a regenerative process. To elucidate the extent to which fetal skeletal development and skeletal regeneration are similar, we performed a series of detailed expression analyses using a number of genes that regulate key stages of endochondral ossification. They included genes in the indian hedgehog (ihh) and core binding factor 1 (cbfa1) pathways, and genes associated with extracellular matrix remodeling and vascular invasion including vascular endothelial growth factor (VEGF) and matrix metalloproteinase 13 (mmp13). Our analyses suggested that even at the earliest stages of mesenchymal cell condensation, chondrocyte (ihh, cbfa1 and collagen type II-positive) and perichondrial (gli1 and osteocalcin-positive) cell populations were already specified. As chondrocytes matured, they continued to express cbfa1 and ihh whereas cbfa1, osteocalcin and gli1 persisted in presumptive periosteal cells. Later, VEGF and mmp13 transcripts were abundant in chondrocytes as they underwent hypertrophy and terminal differentiation. Based on these expression patterns and available genetic data, we propose a model where Ihh and Cbfa1, together with Gli1 and Osteocalcin participate in establishing reciprocal signal site of injury. The persistence of cbfa1 and ihh, and their targets osteocalcin and gli1, in the callus suggests comparable processes of chondrocyte maturation and specification of a neo-perichondrium occur following injury. VEGF and mmp13 are expressed during the later stages of healing, coincident with the onset of vascularization of the callus and subsequent ossification. Taken together, these data suggest the genetic mechanisms regulating fetal skeletogenesis also regulate adult skeletal regeneration, and point to important regulators of angiogenesis and ossification in bone regeneration.

Minimally invasive plate osteosynthesis: does percutaneous plating disrupt femoral blood supply less than the traditional technique?

OBJECTIVES/HYPOTHESIS: Proximal and distal femur fractures have traditionally been treated with open reduction and internal fixation through a standard lateral approach. New, "minimally invasive" internal fixation techniques, however, have been developed in an effort to devascularize the bone less than the traditional method. The purpose of this study was to determine whether a minimally invasive percutaneous plating technique better preserves bone vascularity relative to the traditional method by comparing the effect of the two approaches on the blood supply of the distal femur using silicone arterial dye injection in a cadaveric model. STUDY DESIGN/METHODS: Ten fresh human cadavers underwent lateral conventional plate osteosynthesis (CPO) through a standard lateral approach on one side and minimally invasive plate osteosynthesis (MIPO) through two three-centimeter incisions on the contralateral side. After injection of silicone dye, a dissection was performed bilaterally to identify the femoral perforating and nutrient arteries. RESULTS: All MIPO specimens showed intact perforating and nutrient arteries, whereas the CPO specimens had a variable incidence of vessel disruption. The MIPO group demonstrated better periosteal perfusion in each of the cadavers and improved medullary perfusion in 70 percent of the MIPO specimens compared with the CPO specimens. CONCLUSION: A percutaneous minimally invasive plating technique disrupts the femoral blood supply less than the traditional open method. Such minimally invasive methods may be more advantageous biologically than the traditional method.