A Novel Methodology to Estimate Bone Mechanical Properties Using Dual-Energy Imaging to Improve Pedicle Screw Fixation.

OBJECTIVE: To develop a methodology to improve the representation of the mechanical properties of a vertebral finite element model (FEM) based on a new dual-energy (DE) imaging technology to improve pedicle screw fixation. METHODS: Bone-calibrated radiographs were generated with dual-energy imaging technology in order to estimate the mechanical properties of the trabecular bone. Properties were included in regions of interest in four vertebral FEMs representing heterogeneity and homogeneity, as a realistic and reference model, respectively. Biomechanical parameters were measured during screw pull-out testing to evaluate pedicle screw fixation. RESULTS: Simulations with property distributions deduced from dual-energy imaging characterization (heterogeneous models) induced an increase in biomechanical indicators versus with a homogeneous representation, implying different behaviors for the subject-specific models. CONCLUSION: The presented methodology allows a patient-specific representation of bone quality in a FEM using new DE imaging technology. Consideration of individualized bone distribution in a spinal FEM improves the perspective of orthopedic surgical planning over otherwise underestimated results using a homogeneous representation.

Differential Regulation of POC5 by ERα in Human Normal and Scoliotic Cells.

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional spinal deformity. The incidence of AIS in females is 8.4 times higher than in males. Several hypotheses on the role of estrogen have been postulated for the progression of AIS. Recently, Centriolar protein gene POC5 (POC5) was identified as a causative gene of AIS. POC5 is a centriolar protein that is important for cell cycle progression and centriole elongation. However, the hormonal regulation of POC5 remains to be determined. Here, we identify POC5 as an estrogen-responsive gene under the regulation of estrogen receptor ERα in normal osteoblasts (NOBs) and other ERα-positive cells. Using promoter activity, gene, and protein expression assays, we found that the POC5 gene was upregulated by the treatment of osteoblasts with estradiol (E2) through direct genomic signaling. We observed different effects of E2 in NOBs and mutant POC5A429V AIS osteoblasts. Using promoter assays, we identified an estrogen response element (ERE) in the proximal promoter of POC5, which conferred estrogen responsiveness through ERα. The recruitment of ERα to the ERE of the POC5 promoter was also potentiated by estrogen. Collectively, these findings suggest that estrogen is an etiological factor in scoliosis through the deregulation of POC5.

Air leaks: Stapling affects porcine lungs biomechanics.

During thoracic operations, surgical staplers resect cancerous tumors and seal the spared lung. However, post-operative air leaks are undesirable clinical consequences: staple legs wound lung tissue. Subsequent to this trauma, air leaks from lung tissue into the pleural space. This affects the lung's physiology and patients' recovery. The objective is to biomechanically and visually characterize porcine lung tissue with and without staples in order to gain knowledge on air leakage following pulmonary resection. Therefore, a syringe pump filled with air inflates and deflates eleven porcine lungs cyclically without exceeding 10 cmH2O of pressure. Cameras capture stereo-images of the deformed lung surface at regular intervals while a microcontroller simultaneously records the alveolar pressure and the volume of air pumped. The raw images are then used to compute tri-dimensional displacements and strains with the Digital Image Correlation method (DIC). Air bubbles originated at staple holes of inner row from exposed porcine lung tissue due to torn pleural on costal surface. Compared during inflation, left upper or lower lobe resections have similar compliance (slope of the pressure vs volume curve), which are 9% lower than healthy lung compliance. However, lower lobes statistically burst at lower pressures than upper lobes (p-value<0.046) in ex vivo conditions confirming previous clinical in vivo studies. In parallel, the lung deformed mostly in the vicinity of staple holes and presented maximum shear strain near the observed leak location. To conclude, a novel technique DIC provided concrete evidence of the post-operative air leaks biomechanics. Further studies could investigate causal relationships between the mechanical parameters and the development of an air leak.

Biomechanical analysis of the number of implants for the immediate sacroiliac joint fixation.

PURPOSE: The fusion of the sacroiliac joint (SIJ) is the last treatment option for chronic pain resulting from sacroiliitis. With the various implant systems available, there are different possible surgical strategies in terms of the type and number of implants and trajectories. The aim was to quantify the effect of the number of cylindrical threaded implants on SIJ stabilization. METHODS: Six cadaveric pelvises were embedded in resin simulating a double-leg stance. Compression loads were applied to the sacral plate. The pelvises were tested non-instrumented and instrumented progressively with up to three cylindrical threaded implants (12-mm diameter, 60-mm length) with a posterior oblique trajectory. Vertical (VD) and angular (AD) displacements of the SIJ were measured locally using high-precision cameras and digital image correlation. RESULTS: Compared to the non-instrumented initial state, instrumentation with one implant significantly decreased the VD (- 24% ± 15%, p = 0.028), while the AD decreased on average by - 9% (± 15%; p = 0.345). When compared to the one-implant configuration, adding a second implant further statistically decreased VD (- 10% ± 7%, p = 0.046) and AD (- 19% ± 15, p = 0.046). Adding a third implant did not lead to additional stabilization for VD nor AD (p > 0.5). CONCLUSION: Compared to the non-instrumented initial state, the two-implant configuration reduces both vertical and angular displacements the most, while minimizing the number of implants.

Biomechanical analysis of two insertion sites for the fixation of the sacroiliac joint via an oblique lateral approach.

BACKGROUND: The sacroiliac joint is an important source of low back pain. In severe cases, sacroiliac joint fusion is used to reduce pain, but revision rates can reach 30%. The lack of initial mechanical stability may lead to pseudarthrosis, thus not alleviating the patient's symptoms. This could be due to the damage induced to the interosseous ligament during implant insertion. Decoupling instrumentation steps (drilling-tapping and implant insertion) would allow verifying this hypothesis. Moreover, no biomechanical studies have been published on sacroiliac joint fixation with an oblique lateral approach, while it has important clinical advantages over the direct lateral approach. METHODS: Eight cadaveric human pelves with both ischia embedded were tested in three sequential states: intact, drilled-tapped and instrumented with one cylindrical threaded implant with an oblique lateral trajectory. Specimens were assigned one of two insertion sites (distal point; near the posterior superior iliac spine, and proximal point; anterosuperior to the distal point) and tested in compression and flexion-extension. Vertical and angular displacements of the sacroiliac joint were measured locally using digital image correlation methods. FINDINGS: In compression, instrumentation significantly reduced vertical displacements (17% (SD 22%), P = 0.04) but no difference was found for angular displacements or flexion-extension loads (P > 0.05). Drilling-tapping did not change the stability of the sacroiliac joint (P > 0.05); there was no statistical difference between the insertion sites (P > 0.05). INTERPRETATIONS: Insertion of one implant through either the distal or proximal insertion site with an oblique lateral approach significantly reduced vertical displacements of the sacroiliac joint in compression, a predominant load of this joint. RESEARCH ETHICS COMMITTEE: Polytechnique Montreal: CÉR-1617-30.

CFTR deletion affects mouse osteoblasts in a gender-specific manner.

Advancements in research and care have contributed to increase life expectancy of individuals with cystic fibrosis (CF). With increasing age comes a greater likelihood of developing CF bone disease, a comorbidity characterized by a low bone mass and impaired bone quality, which displays gender differences in severity. However, pathophysiological mechanisms underlying this gender difference have never been thoroughly investigated. We used bone marrow-derived osteoblasts and osteoclasts from Cftr+/+ and Cftr-/- mice to examine whether the impact of CF transmembrane conductance regulator (CFTR) deletion on cellular differentiation and functions differed between genders. To determine whether in vitro findings translated into in vivo observations, we used imaging techniques and three-point bending testing. In vitro studies revealed no osteoclast-autonomous defect but impairment of osteoblast differentiation and functions and aberrant responses to various stimuli in cells isolated from Cftr-/- females only. Compared with wild-type controls, knockout mice exhibited a trabecular osteopenic phenotype that was more pronounced in Cftr-/- males than Cftr-/- females. Bone strength was reduced to a similar extent in knockout mice of both genders. In conclusion, we find a trabecular bone phenotype in Cftr-/- mice that was slightly more pronounced in males than females, which is reminiscent of the situation found in patients. However, at the osteoblast level, the pathophysiological mechanisms underlying this phenotype differ between males and females, which may underlie gender differences in the way bone marrow-derived osteoblasts behave in absence of CFTR.

Cyclically controlled vertebral body tethering for scoliosis: an in vivo verification in a pig model of the pressure exerted on vertebral end plates.

STUDY DESIGN: Experimental in vivo study of the pressure exerted on the spine of a pig by a new cyclic anterior vertebral body tethering (AVBT) prototype. OBJECTIVES: To evaluate the relationship between the tether tension and the pressures transmitted onto the vertebral end plates by a cyclic AVBT prototype. AVBT is a recent surgical technique for the treatment of pediatric scoliosis that compresses the convex side of the spine with a sustained tension, to modulate the growth to progressively correct the deformity over time. Previous studies demonstrated that cyclic compression has similar growth modulation capacity but with less detrimental effects on the integrity of the discs and growth plates. METHODS: A 3-month-old healthy Duroc pig was anesthetized and a lateral thoracotomy was performed. The T7-T10 segment was instrumented and compressed during 50 s with the load oscillating (0.2 Hz) from + 30 to - 30% of the following mean tensions: 29, 35, 40, 44, and 49 N. The pressure exerted on T9 superior vertebral end plate was monitored during the cyclic loading. Three repetitions of each test were performed. RESULTS: The resulting mean pressure exerted on the vertebral end plate was linearly correlated with the mean tether tension (r2 = 0.86). Each cycle translated in a hysteresis profile of the measured pressure and tension, with amplitudes varying between ± 11.5 and ± 29.9%. CONCLUSIONS: This experimental study documented the relationship between the tether tension and the pressure. This study confirmed the feasibility of cyclic AVBT principle to transfer varying pressures on the vertebral end plates, which is intended to control vertebral growth, while keeping the spine flexibility and preserving the health of soft tissues such as the intervertebral discs and the growth plate but remained to be further verified. LEVEL OF EVIDENCE: Level IV.

The 17ß-estradiol induced upregulation of the adhesion G-protein coupled receptor (ADGRG7) is modulated by ESRα and SP1 complex.

The physiological role and the regulation of ADGRG7 are not yet elucidated. The functional involvement of this receptor was linked with different physiological process such as reduced body weight, gastrointestinal function and recently, a gene variant in ADGRG7 was observed in patients with adolescent idiopathic scoliosis. Here, we identify the ADGRG7 as an estrogen-responsive gene under the regulation of estrogen receptor ERα in scoliotic osteoblasts and other cells lines. We found that ADGRG7 expression was upregulated in response to estrogen (E2) in adolescent idiopathic scoliosis (AIS) cells. ADGRG7 promoter studies indicate the presence of an ERα response half site in close vicinity of a specificity protein 1 (SP1) binding site. Mutation of the SP1 site completely abrogated the response to E2, indicating its essential requirement. ChIP confirmed the binding of SP1 and ERα to the ADGRG7 promoter. Our results identify the ADGRG7 gene as an estrogen-responsive gene under the control of ERα and SP1 tethered actions, suggesting a possible role of estrogens in the regulation of ADGRG7 This article has an associated First Person interview with the first author of the paper.

Can repeated in vivo micro-CT irradiation during adolescence alter bone microstructure, histomorphometry and longitudinal growth in a rodent model?

In vivo micro-computed tomography (micro-CT) can monitor longitudinal changes in bone mass and microstructure in small rodents but imposing high doses of radiation can damage the bone tissue. However, the effect of weekly micro-CT scanning during the adolescence on bone growth and architecture is still unknown. The right proximal tibia of male Sprague-Dawley rats randomized into three dose groups of 0.83, 1.65 and 2.47 Gy (n = 11/group) were CT scanned at weekly intervals from 4th to 12th week of age. The left tibia was used as a control and scanned only at the last time point. Bone marrow cells were investigated, bone growth rates and histomorphometric analyses were performed, and bone structural parameters were determined for both left and right tibiae. Radiation doses of 1.65 and 2.47 Gy affected bone marrow cells, heights of the proliferative and hypertrophic zones, and bone growth rates in the irradiated tibiae. For the 1.65 Gy group, irradiated tibiae resulted in lower BMD, Tb.Th, Tb.N and a higher Tb.Sp compared with the control tibiae. A decrease in BMD, BV/TV, Tb.Th, Tb.N and an increase in Tb.Sp were observed between the irradiated and control tibiae for the 2.47 Gy group. For cortical bone parameters, no effects were noticed for 1.65 and 0.83 Gy groups, but a lower Ct.Th was observed for 2.47 Gy group. Tibial bone development was adversely impacted and trabecular bone, together with bone marrow cells, were negatively affected by the 1.65 and 2.47 Gy radiation doses. Cortical bone microstructure was affected for 2.47 Gy group. However, bone development and morphometry were not affected for 0.83 Gy group. These findings can be used as a proof of concept for using the reasonable high-quality image acquisition under 0.83 Gy radiation doses during the adolescent period of rats without interfering with the bone development process.

Geometry reconstruction method for patient-specific finite element models for the assessment of tibia fracture risk in osteogenesis imperfecta.

Lower limb deformation in children with osteogenesis imperfecta (OI) impairs ambulation and may lead to fracture. Corrective surgery is based on empirical assessment criteria. The objective was to develop a reconstruction method of the tibia for OI patients that could be used as input of a comprehensive finite element model to assess fracture risks. Data were obtained from three children with OI and tibia deformities. Four pQCT scans were registered to biplanar radiographs, and a template mesh was deformed to fit the bone outline. Cortical bone thickness was computed. Sensitivity of the model to missing slices of pQCT was assessed by calculating maximal von Mises stress for a vertical hopping load case. Sensitivity of the model to ±5 % of cortical thickness measurements was assessed by calculating loads at fracture. Difference between the mesh contour and bone outline on the radiographs was below 1 mm. Removal of one pQCT slice increased maximal von Mises stress by up to 10 %. Simulated ±5 % variation of cortical bone thickness leads to variations of up to 4.1 % on predicted fracture loads. Using clinically available tibia imaging from children with OI, the developed reconstruction method allowed the building of patient-specific finite element models.

Static and dynamic compression application and removal on the intervertebral discs of growing rats.

Fusionless implants are used to correct pediatric progressive spinal deformities, most of them spanning the intervertebral disc. This study aimed at investigating the effects of in vivo static versus dynamic compression application and removal on discs of growing rats. A microloading device applied compression. 48 immature rats (28 d.o.) were divided into two groups (43d, 53d). Each group included four subgroups: control (no surgery), sham (device installed without loading), static (0.2 MPa) and dynamic compressions (0.2 MPa ± 30% with 0.1 Hz). In 43d subgroups, compression was applied for 15 days. In 53d subgroups, compression was followed by 10 days without loading. Disc heights, nucleus/annulus volumetric proportions and nucleus proteoglycan contents were analyzed using one-way ANOVA and post-hoc Tukey comparisons (p < 0.05). Disc heights of 43d and 53d static and dynamic loading rats were lower than shams (p < 0.05). Volumetric proportions remained similar. At 43d, nucleus proteoglycan contents increased in both static and dynamic loading rats. However, at 53d, static loading rats had lower proteoglycan content than dynamic loading rats (p < 0.05). Disc structure is altered following static compression removal, but nucleus proteoglycan content remaining elevated in dynamic group. Dynamic fusionless implants would better preserve disc integrity.

Bone growth resumption following in vivo static and dynamic compression removals on rats.

Mechanical loadings influence bone growth and are used in pediatric treatments of musculoskeletal deformities. This in vivo study aimed at evaluating the effects of static and dynamic compression application and subsequent removal on bone growth, mineralization and neuropathic pain markers in growing rats. Forty-eight immature rats (28 days old) were assigned in two groups (2- and 4 weeks experiment duration) and four subgroups: control, sham, static, and dynamic. Controls had no surgery. A micro-loading device was implanted on the 6th and 8th caudal vertebrae of shams without loading, static loading at 0.2 MPa or dynamic loading at 0.2 MPa ± 30% and 0.1 Hz. In 2-week subgroups, compression was maintained for 15 days prior to euthanasia, while in 4- week subgroups, compression was removed for 10 additional days. Growth rates, histomorphometric parameters and mineralization intensity were quantified and compared. At 2 weeks, growth rates and growth plate heights of loaded groups (static/dynamic)were significantly lower than shams (p b 0.01).However, at 4 weeks, both growth rates and growth plate heights of loaded groups were similar to shams. At 4 weeks, alizarin red intensity was significantly higher in dynamics compared to shams (p b 0.05) and controls (p b 0.01). Both static and dynamic compressions enable growth resumption after loading removal, while preserving growth plate histomorphometric integrity. However, mineralization was enhanced after dynamic loading removal only. Dynamic loading showed promising results for fusionless treatment approaches for musculoskeletal deformities.

The effect of altering the mechanical loading environment on the expression of bone regenerating molecules in cases of distraction osteogenesis.

Distraction osteogenesis (DO) is a surgical technique where gradual and controlled separation of two bony fragments following an osteotomy leads to the induction of new bone formation in the distracted gap. DO is used for limb lengthening, correction of bony deformities, and the replacement of bone loss secondary to infection, trauma, and tumors. Although DO gives satisfactory results in most cases, one major drawback of this technique is the prolonged period of time the external fixator has to be kept on until the newly formed bone consolidates thus leading to numerous complications. Numerous attempts at accelerating bone formation during DO have been reported. One specific approach is manipulation of the mechanical environment during DO by applying changes in the standard protocol of distraction. Attempts at changing this mechanical environment led to mixed results. Increasing the rate or applying acute distraction, led to poor bone formation in the distracted zone. On the other hand, the addition of compressive forces (such as weight bearing, alternating distraction with compression or by over-lengthening, and then shortening) has been reported to increase bone formation. It still remains unclear why these alterations may lead to changes in bone formation. While the cellular and molecular changes occurring during the standard DO protocol, specifically increased expression of transforming growth factor-ß1, platelet-derived growth factor, insulin-like growth factor, basic fibroblast growth factor, vascular endothelial growth factor, and bone morphogenic proteins have been extensively investigated, the literature is sparse on the changes occurring when this protocol is altered. It is the purpose of this article to review the pertinent literature on the changes in the expression of various proteins and molecules as a result of changes in the mechanical loading technique in DO and try to define potential future research directions.

In vivo dynamic loading reduces bone growth without histomorphometric changes of the growth plate.

This in vivo study aimed at investigating the effects of dynamic compression on the growth plate. Rats (28 days old) were divided into three dynamically loaded groups, compared with two groups (control, sham). A device was implanted on the 6th and 8th caudal vertebrae for 15 days. Controls (n = 4) did not undergo surgery. Shams (n = 4) were operated but not loaded. Dynamic groups had sinusoidal compression with a mean value of 0.2 MPa: 1.0 Hz and ± 0.06 MPa (group a, n = 4); 0.1 Hz and ± 0.2 MPa (group b, n = 4); 1.0 Hz and ± 0.14 MPa (group c, n = 3). Growth rates (µm/day) of dynamic groups (a) and (b) were lower than shams (p < 0.01). Growth plate heights, hypertrophic cell heights and proliferative cell counts per column did not change in dynamic (a) and (b) groups compared with shams (p > 0.01). Rats from dynamic group (c) had repeated inflammations damaging tissues; consequently, their analysis was unachievable. Increasing magnitude or frequency leads to growth reduction without histomorphometric changes. However, the combined augmentation of magnitude and frequency alter drastically growth plate integrity. Appropriate loading parameters could be leveraged for developing novel growth modulation implants to treat skeletal deformities.