Magnetic resonance imaging for three-dimensional printing of the bony orbit: is clinical use imminent?

The aim of this study was to examine the accuracy of three dimensionally (3D) printed models of the bony orbit derived from magnetic resonance imaging (MRI) for the purpose of preoperative plate bending in the setting of orbital blowout fracture. Retrospective computed tomography (CT) and MRI data from patients with suspected orbital fractures were used. Virtual models were manually generated and analysed for spatial accuracy of the fracture margins. 3D-printed models were produced and orbital fan plates bent by a single operator. The plates were then digitized and analysed for spatial discrepancy using reverse engineering software. Seven orbital blowout fractures were evident in six orbits. Analysis of the virtual models revealed high congruence between blowout fracture margins on CT and MRI (n=7, average deviation 0.85mm). Three zygomaticomaxillary complex fractures were seen, for which MRI did not demonstrate the same accuracy. For plates bent to the 3D-printed models of blowout fractures (n=6), no significant difference was found between those bent to CT versus those bent to MRI when compared for average surface and average border deviation (Wilcoxon signed rank test). Orbital blowout fractures can be defined on MRI with clinically acceptable accuracy. 3D printing of orbital biomodels from MRI for bending reconstructive plates is an acceptable and accurate technique.

Is there a bone-nail specific entry point? Automated fit quantification of tibial nail designs during the insertion for six different nail entry points.

Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of tibia. Selection of the correct nail insertion point is important for axial alignment of bone fragments and to avoid iatrogenic fractures. However, the standard entry point (SEP) may not always optimise the bone-nail fit due to geometric variations of bones. This study aimed to investigate the optimal entry for a given bone-nail pair using the fit quantification software tool previously developed by the authors. The misfit was quantified for 20 bones with two nail designs (ETN and ETN-Proximal Bend) related to the SEP and 5 entry points which were 5 mm and 10 mm away from the SEP. The SEP was the optimal entry point for 50% of the bones used. For the remaining bones, the optimal entry point was located 5 mm away from the SEP, which improved the overall fit by 40% on average. However, entry points 10 mm away from the SEP doubled the misfit. The optimised bone-nail fit can be achieved through the SEP and within the range of a 5 mm radius, except posteriorly. The study results suggest that the optimal entry point should be selected by considering the fit during insertion and not only at the final position.

Assessing the bilateral geometrical differences of the tibia--are they the same?

Contralateral bones are often used in many medical applications but it is assumed that their bilateral differences are insignificant. Previous studies used a limited number of distance measurements in quantifying the corresponding differences; therefore, little is known about their bilateral 3D surface asymmetries. The aim of the study is to develop a comprehensive method to quantify geometrical asymmetries between the left and right tibia in order to provide first results on whether the contralateral tibia can be used as an equivalent reference. In this study, 3D bone models were reconstructed from CT scans of seven tibiae pairs, and 34 variables consisting of 2D and 3D measurements were measured from various anatomical regions. All 2D measurements, and lateral plateau and distal subchondral bone surface measurements showed insignificant differences (p>0.05), but the rest of the surfaces showed significant differences (p<0.05). Our results suggest that the contralateral tibia can be used as a reference especially in surgical applications such as articular reconstructions since the bilateral differences in the subchondral bone surfaces were less than 0.3mm. The method can also be potentially transferable to other relevant studies that require the accurate quantification of bone bilateral asymmetries.

Can the contra-lateral limb be used as a control with respect to analyses of bone remodelling?

Bone loss may result from remodelling initiated by implant stress protection. Quantifying remodelling requires bone density distributions which can be obtained from computed tomography scans. Pre-operative scans of large animals however are rarely possible. This study aimed to determine if the contra-lateral bone is a suitable control for the purpose of quantifying bone remodelling. CT scans of 8 pairs of ovine tibia were used to determine the likeness of left and right bones. The deviation between the outer surfaces of the bone pairs was used to quantify geometric similarity. The density differences were determined by dividing the bones into discrete volumes along the shaft of the tibia. Density differences were also determined for fractured and contra-lateral bone pairs to determine the magnitude of implant related remodelling. Left and right ovine tibiae were found to have a high degree of similarity with differences of less than 1.0mm in the outer surface deviation and density difference of less than 5% in over 90% of the shaft region. The density differences (10-40%) as a result of implant related bone remodelling were greater than left-right differences. Therefore, for the purpose of quantifying bone remodelling in sheep, the contra-lateral tibia may be considered an alternative to a pre-operative control.

Computational investigations of mechanical failures of internal plate fixation.

This paper investigated the biomechanics of two clinical cases of bone fracture treatments. Both fractures were treated with the same locking compression plate but with different numbers of screws as well as different plate materials. The fracture treated with 12 screws (rigid fixation) failed at 7 weeks with the plate breaking; the fracture with six screws (flexible fixation) endured the entire healing process. It was hypothesized that the plate failure in the unsuccessful case was due to the material fatigue induced by stress concentration in the plate. As the two clinical cases had different fracture locations and different plate materials, finite element simulations were undertaken for each fractured bone fixed by both a rigid and a flexible method. This enabled comparisons to be made between the rigid and flexible fixation methods. The fatigue life was assessed for each fixation method. The results showed that the stress in the rigid fixation methods could be significantly higher than that in flexible fixation methods. The fatigue analyses showed that, with the stress level in flexible fixation (i.e. with fewer screws), the plate was able to endure 2000 days, and that the plate in rigid fixation could fail by fatigue fracture in 20 days. The paper concludes that the rigid fixation method resulted in serious stress concentrations in the plate, which induced fatigue failure. The flexible fixation gave sufficient stability and was better for fracture healing.

Quantitative fit assessment of tibial nail designs using 3D computer modelling.

Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of the tibia in adults. The bends in modern tibial nails allow for an easier insertion, enhance the 'bone-nail construct' stability, and reduce axial malalignments of the main fragments. Anecdotal clinical evidence indicates that current nail designs do not fit optimally for patients of Asian origin. The aim of this study was to develop a method to quantitatively assess the anatomical fitting of two different nail designs for Asian tibiae by utilising 3D computer modelling. We used 3D models of two different tibial nail designs (ETN (Expert Tibia Nail) and ETN-Proximal-Bend, Synthes), and 20 CT-based 3D cortex models of Japanese cadaver tibiae. With the aid of computer graphical methods, the 3D nail models were positioned inside the medullary cavity of the intact 3D tibia models. The anatomical fitting between nail and bone was assessed by the extent of the nail protrusion from the medullary cavity into the cortical bone, in a real bone this might lead to axial malalignments of the main fragments. The fitting was quantified in terms of the total surface area, and the maximum distance by which the nail was protruding into the cortex of the virtual bone model. In all 20 bone models, the total area of the nail protruding from the medullary cavity was smaller for the ETN-Proximal-Bend (average 540 mm(2)) compared to the ETN (average 1044 mm(2)). Also, the maximum distance of the nail protruding from the medullary cavity was smaller for the ETN-Proximal-Bend (average 1.2mm) compared to the ETN (average 2.7 mm). The differences were statistically significant (p<0.05) for both the total surface area and the maximum distance measurements. By utilising computer graphical methods it was possible to conduct a quantitative fit assessment of different nail designs. The ETN-Proximal-Bend shows a statistical significantly better intramedullary fit with less cortical protrusion than the original ETN. In addition to the application in implant design, the developed method could potentially be suitable for pre-operative planning enabling the surgeon to choose the most appropriate nail design for a particular patient.

A new approach for assigning bone material properties from CT images into finite element models.

Generation of subject-specific finite element (FE) models from computed tomography (CT) datasets is of significance for application of the FE analysis to bone structures. A great challenge that remains is the automatic assignment of bone material properties from CT Hounsfield Units into finite element models. This paper proposes a new assignment approach, in which material properties are directly assigned to each integration point. Instead of modifying the dataset of FE models, the proposed approach divides the assignment procedure into two steps: generating the data file of the image intensity of a bone in a MATLAB program and reading the file into ABAQUS via user subroutines. Its accuracy has been validated by assigning the density of a bone phantom into a FE model. The proposed approach has been applied to the FE model of a sheep tibia and its applicability tested on a variety of element types. The proposed assignment approach is simple and illustrative. It can be easily modified to fit users' situations.

Customization of a generic 3D model of the distal femur using diagnostic radiographs.

A method for the customization of a generic 3D model of the distal femur is presented. The customization method involves two steps: acquisition of calibrated orthogonal planar radiographs; and linear scaling of the generic model based on the width of a subject's femoral condyles as measured on the planar radiographs. Planar radiographs of seven intact lower cadaver limbs were obtained. The customized generic models were validated by comparing their surface geometry with that of CT-reconstructed reference models. The overall mean error was 1.2 mm. The results demonstrate that uniform scaling as a first step in the customization process produced a base model of accuracy comparable to other models reported in the literature.

Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans and is characterized by neuronal loss, neurofibrillary tangles and beta-amyloid deposition. The interaction between neurotrophins and their tyrosine kinase (trk) receptors is important for cellular differentiation and survival. Interestingly, marked reductions in neurotrophins and receptors have been reported in AD. The cause of the decrease in these molecules remains unclear. However, the role of beta-amyloid (A beta) appears central in understanding the mechanisms controlling neurotrophin/trk expression. In this study we exposed SHSY5Y neuroblastoma cells to A beta or hydrogen peroxide and measured the expression of trk B/truncated trk B, and brain-derived neurotrophic factor (BDNF)/NT4 at the protein and molecular level. We show that A beta or hydrogen peroxide (H(2)O(2)) induces oxidative stress and cell cytotoxicity. The exposure of cells to A beta results in an increased trk B expression with a concurrent reduction in truncated trk B levels. H(2)O(2) exposure decreased both trk B and truncated trk B levels at the cell surface. At the molecular level trk B RNA increased in the presence of A beta and was unaffected by H(2)O(2). Similarly, BDNF and NT4 levels increased in the presence of A beta. Pre-treatment of cells with the anti-oxidant melatonin returns trk receptor expression, mRNA and BDNF/NT4 secretion to normal levels. These results are significant as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.

Oxidative stress modulates tyrosine kinase receptor A and p75 receptor (low-affinity nerve growth factor receptor) expression in SHSY5Y neuroblastoma cells.

The interaction of neurotrophins and their tyrosine kinase receptors (trks) is essential for differentiation and survival of brain cells. In Alzheimer's disease (AD), the number of neurotrophins and receptors is markedly decreased. The cause of this reduction is unclear, but the role of beta-amyloid (Abeta) seems central in understanding the mechanisms controlling neurotrophin and trk expression. In the study reported here, we exposed SHSY5Y neuroblastoma cells to Abeta or hydrogen peroxide (H(2)O(2)) and measured the expression of trk-A and p75 at the protein and molecular levels. Both Abeta and H(2)O(2) induced oxidative stress (measured by a decrease in cellular glutathione), which decreased trk-A levels and increased p75 levels, decreased messenger RNA (mRNA) levels of both receptors, and increased nerve growth factor (NGF) secretion. Pretreatment of cells with the antioxidant melatonin returned levels of protein expression, mRNA, and NGF secretion to normal. These results are significant, as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.

Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression.

Increasing evidence supports an essential role for interleukin-6 (IL-6) in the development, differentiation, as well as de- and re-generation of neurons in the central nervous system (CNS). Both IL-6 and its specific receptor (IL-6R) are expressed on neurons and glial cells including astrocytes. In this study, we have analyzed the responses of primary rat astrocytes of various brain regions to IL-6 with respect to morphological changes and neurotrophin expression. Since IL-6 alone failed to initiate effects on astrocytes, we have examined whether the soluble IL-6R (sIL-6R) can modulate the responsiveness of to IL-6 in these cells. For this purpose, we used a highly active fusion protein of IL-6 and sIL-6R, which is designated Hyper-IL-6 (H-IL-6). We show that treatment of cultured astrocytes with Hyper-IL-6 promotes region-specific morphological changes of GFAP-positive astrocytes from typical stellate- to fibrous-like cells. In addition, we find that Hyper-IL-6 induces expression of neurotrophins (NTs) of the nerve growth factor (NGF)-family in a dose-dependent manner. Interestingly, astrocytes of various brain regions show differing patterns of cytokine-induced NT expression: NGF is maximally induced in cortex and hippocampus, NT-3 in hippocampus, and NT-4/5 in cortex and cerebellum. In summary, our results indicate that IL-6 in conjunction with sIL-6R regulates specific neurotrophin expression in astrocytes in a brain region dependent manner. Thus, the IL-6 system provides a local supply of neurotrophins that participate in diverse CNS functions such as protection of neurons from insults, neuronal survival, and neuro-immune responses.

Expression of functional trk tyrosine kinase receptors after T cell activation.

Increasing evidence indicates that nerve growth factor (NGF), in addition to its neurotrophic actions, exerts specific effects on cells of the immune system. This report show that the CD4-positive T cell line 9/6 expresses trk protooncogene, the signal transducing receptor unit for NGF, after TCR-mediated activation by Ag and APC. This receptor is of functional importance because interaction of NGF with Ag-stimulated 9/6 T cells induced the transcriptional activation of the c-fos gene, a hallmark of the biochemical response to NGF. Our findings that neither mitogen nor Ag stimulation induced the expression of the low affinity NGF receptor in 9/6 T cells indicate that trk alone is sufficient to mediate biologic activity of NGF in T lymphocytes.

Expression of low-affinity NGF receptor and trkB mRNA in human SH-SY5Y neuroblastoma cells.

We have used the human neuroblastoma cell line SH-SY5Y as a model system to investigate the expression and regulation of the receptors for brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) family of neurotrophins. We demonstrate that SH-SY5Y cells express transcripts encoding the low-affinity NGF receptor (LNGFR) and trkB, the signal transducing receptor unit for BDNF. Interaction of BDNF with SH-SY5Y cells increased the transcription of the c-fos gene, showing that these molecules encode functional BDNF receptors. Our findings that differentiating agents such as retinoids and cAMP analogs increased the expression of LNGFR, but decreased trkB mRNA levels, suggest that LNGFR and trkB have different roles during neuronal differentiation.