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Concept: Osteology


It is proposed that the external asymmetric formation of callus tissues that forms naturally about an oblique bone fracture can be predicted computationally. We present an analysis of callus formation for two cases of bone fracture healing: idealised and subject-specific oblique bone fractures. Plane strain finite element (FE) models of the oblique fractures were generated to calculate the compressive strain field experienced by the immature callus tissues due to interfragmentary motion. The external formations of the calluses were phenomenologically simulated using an optimisation style algorithm that iteratively removes tissue that experiences low strains from a large domain. The resultant simulated spatial formation of the healing tissues for the two bone fracture cases showed that the calluses tended to form at an angle equivalent to the angle of the oblique fracture line. The computational results qualitatively correlated with the callus formations found in vivo. Consequently, the proposed methods show potential as a means of predicting callus formation in pre-clinical testing.

Concepts: Osteoporosis, Bone fracture, Orthopedic surgery, Bone fractures, Bone healing, Osteology, Fibrocartilage callus, Catagmatic


Failure of bone fracture healing occurs in 5% to 10% of all patients. Nonunion risk is associated with the severity of injury and with the surgical treatment technique, yet progression to nonunion is not fully explained by these risk factors.

Concepts: Osteoporosis, Bone, Bone fracture, Collagen, Orthopedic surgery, Distraction osteogenesis, Bone healing, Osteology


The health of the skeletal system is important for athletes young and old. From the early benefits of exercise on bones to the importance of osteoporosis prevention and treatment, bone health affects the ability to be active throughout life.

Concepts: Bone, Vitamin D, Skeletal system, Glucocorticoid, Intramembranous ossification, Human skeleton, Skeleton, Osteology


Most bone fractures typically heal, although a significant proportion (5%-10%) of fractures fail to heal, resulting in delayed union or persistent nonunion. Some preclinical evidence shows the therapeutic potential of peripheral blood CD34(+) cells, a hematopoietic/endothelial progenitor cell-enriched population, for bone fracture healing; however, clinical outcome following transplantation of CD34(+) cells in patients with fracture has never been reported. We report a phase I/IIa clinical trial regarding transplantation of autologous, granulocyte colony stimulating factor-mobilized CD34(+) cells with atelocollagen scaffold for patients with femoral or tibial fracture nonunion (n = 7). The primary endpoint of this study is radiological fracture healing (union) by evaluating anteroposterior and lateral views at week 12 following cell therapy. For the safety evaluation, incidence, severity, and outcome of all adverse events were recorded. Radiological fracture healing at week 12 was achieved in five of seven cases (71.4%), which was greater than the threshold (18.1%) predefined by the historical outcome of the standard of care. The interval between cell transplantation and union, the secondary endpoint, was 12.6 ± 5.4 weeks (range, 8-24 weeks) for clinical healing and 16.1 ± 10.2 weeks (range, 8-36 weeks) for radiological healing. Neither deaths nor life-threatening adverse events were observed during the 1-year follow-up after the cell therapy. These results suggest feasibility, safety, and potential effectiveness of CD34(+) cell therapy in patients with nonunion.

Concepts: Osteoporosis, Clinical trial, Bone fracture, Orthopedic surgery, Distraction osteogenesis, Adverse event, Bone healing, Osteology


Aminocaproic acid is approved as an anti-fibrinolytic for use in joint replacement and spinal fusion surgeries to limit perioperative blood loss. Previous animal studies have demonstrated a pro-osteogenic effect of aminocaproic acid in spine fusion models. Here, we tested if aminocaproic acid enhances appendicular bone healing and we sought to uncover the effect of aminocaproic acid on osteoprogenitor cells (OPCs) during bone regeneration.

Concepts: Bone fracture, Skeletal system, Orthopedic surgery, Tissue plasminogen activator, Endochondral ossification, Bone healing, Periosteum, Osteology


Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma-induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its soluble form (sIL-6R). Herein, we investigated whether IL-6 classic and trans-signaling play different roles in bone regeneration after severe injury. Twelve-week-old C57BL/6J mice underwent combined femur osteotomy and thoracic trauma. To study the function of IL-6, either an anti-IL-6 antibody, which inhibits both IL-6 classic and trans-signaling, or a soluble glycoprotein 130 fusion protein (sgp130Fc), which selectively blocks trans-signaling, were injected 30 min and 48 h after surgery. Bone healing was assessed using cytokine analyses, flow cytometry, histology, micro-computed tomography, and biomechanical testing. Selective inhibition of IL-6 trans-signaling significantly improved the fracture healing outcome after combined injury, as confirmed by accelerated cartilage-to-bone transformation, enhanced bony bridging of the fracture gap and improved mechanical callus properties. In contrast, global IL-6 inhibition did not affect compromised fracture healing. These data suggest that classic signaling may mediate beneficial effects on bone repair after severe injury. Selective inhibition of IL-6 trans-signaling might have therapeutic potential to treat fracture healing complications in patients with concomitant injuries.

Concepts: Protein, Bone fracture, Fracture, Flow cytometry, Injuries, Orthopedic surgery, Bone healing, Osteology


The development of stimuli-responsive nanomedicines with tunable cargo release is gathering an increased applicability in bone regeneration and precision biomedicine. Yet, the formulation of nanocarriers that explore skeletal-specific stimuli remains remarkably challenging to materialize due to several endogenous and disease-specific barriers that must be considered during particle design stages. Such anatomo-physiological constrains ultimately hinder nanocarriers bioavailability in target bone tissues and impact the overall therapeutic outcome. This review aims to showcase and critically discuss the hurdles encountered upon responsive nanocarriers delivery in the context of skeletal diseases or tissue regeneration scenarios. Such focus is complemented with an in-depth and up-to-date analysis of advances in the development of stimuli-responsive, bone-focused delivery systems. In a holistic perspective, a deeper knowledge of human osteology combined with advances in materials functionalization via simple precision-chemistry is envisioned to incite the manufacture of stimuli-triggered nanomedicines with more realistic potential for clinical translation.

Concepts: Bone, Medicine, Developmental biology, Cellular differentiation, Regeneration, Tissue, Osteology, Osteometric points


Growing evidence supports the critical role of transcriptional mechanisms in promoting the spatial and temporal progression of bone healing. In this review, we evaluate and discuss new transcriptional and post-transcriptional regulatory mechanisms of secondary bone repair, along with emerging evidence for epigenetic regulation of fracture healing.

Concepts: Gene expression, Epigenetics, Bone fracture, Law, Regulation, Bone healing, Periosteum, Osteology


Mechanostimulation by low-magnitude high frequency vibration (LMHFV) has been shown to provoke anabolic effects on the intact skeleton in both mice and humans. However, experimental studies revealed that, during bone fracture healing, the effect of whole-body vibration is profoundly influenced by the estrogen status. LMHFV significantly improved fracture healing in ovariectomized (OVX) mice being estrogen deficient, whereas bone regeneration was significantly reduced in non-OVX, estrogen-competent mice. Furthermore, estrogen receptors α (ERα) and β (ERβ) were differentially expressed in the fracture callus after whole-body vibration, depending on the estrogen status. Based on these data, we hypothesized that ERs may mediate vibration-induced effects on fracture healing. To prove this hypothesis, we investigated the effects of LMHFV on bone healing in mice lacking ERα or ERβ. To study the influence of the ER ligand estrogen, both non-OVX and OVX mice were used. All mice received a femur osteotomy stabilized by an external fixator. Half of the mice were sham-operated or subjected to OVX 4 weeks before osteotomy. Half of each group received LMHFV with 0.3 g and 45 Hz for 20 min per day, 5 days per week. After 21 days, fracture healing was evaluated by biomechanical testing, μCT analysis, histomorphometry and immunohistochemistry. Absence of ERα or ERβ did not affect fracture healing in sham-treated mice. Wildtype (WT) and ERβ-knockout mice similarly displayed impaired bone regeneration after OVX, whereas ERα-knockout mice did not. Confirming previous data, in WT mice, LMHFV negatively affected bone repair in non-OVX mice, whereas OVX-induced compromised healing was significantly improved by vibration. In contrast, vibrated ERα-knockout mice did not display significant differences in fracture healing compared to non-vibrated animals, both in non-OVX and OVX mice. Fracture healing in ERβ-knockout mice was similarly affected by LMHFV as in WT mice. These results suggest that ERα-signaling may be crucial for vibration-induced effects on fracture healing, whereas ERβ-signaling may play a minor role.

Concepts: Osteoporosis, Bone fracture, Effect, Estrogen receptor, Affect, Orthopedic surgery, Bone healing, Osteology


Patients with traumatic vertebral fractures often have major associated postoperative morbidities such as healing failure and kyphosis. Low-intensity pulsed ultrasound (US) has been found to promote bone fracture healing. The objectives of our study were to determine whether low-intensity pulsed US could promote traumatic vertebral fracture healing and to explore its inner mechanisms.

Concepts: Osteoporosis, Bone, Bone fracture, Fracture, Orthopedic surgery, Forensic engineering, Bone healing, Osteology