In JoVE (1)

Other Publications (23)

Articles by Simon Y. Tang in JoVE

 JoVE Bioengineering

An In Vitro Organ Culture Model of the Murine Intervertebral Disc

1Department of Biomedical Engineering, Washington University in St. Louis, 2Department of Biology, Washington University in St. Louis, 3Department of Orthopaedic Surgery, Washington University in St. Louis, 4Department of Materials Science and Mechanical Engineering, Washington University in St. Louis

JoVE 55437

Other articles by Simon Y. Tang on PubMed

Trabecular Microfracture and the Influence of Pyridinium and Non-enzymatic Glycation-mediated Collagen Cross-links

Bone. Dec, 2005  |  Pubmed ID: 16140600

The propensity of individual trabeculae to fracture (microfracture) may be important clinically since it could be indicative of bone fragility. Whether or not an overloaded trabecula fractures is determined in part by its structural ductility, a mechanical property that describes how much deformation a trabecula can sustain. The overall goal of this study was to determine the structural ductility of individual trabeculae and the degree to which it is influenced by pyridinium and non-enzymatic collagen cross-links. Vertically oriented rodlike trabeculae were taken from the thoracic vertebral bodies of 32 cadavers (16 male and 16 female, 54 - 94 years of age). A total of 221 trabeculae (4 - 9 per donor) were tested to failure in tension using a micro-tensile loading device. A subset of 76 samples was analyzed to determine the concentration of hydroxylysyl-pyridinoline (HP) and lysyl-pyridinoline (LP) cross-links as well as pentosidine, a marker of non-enzymatic glycation. Structural ductility (defined as the ultimate strain of the whole trabecula) ranged from 1.8% to 20.2% strain (8.8 +/- 3.7%, mean +/- SD) and did not depend on age (P = 0.39), sex (P = 0.57), or thickness of the sample at the point of failure (P = 0.36). Pentosidine was the only marker of collagen cross-linking measured that was found to be correlated with structural ductility (P = 0.01) and explained about 9% of the observed variance. We conclude that the ductility of individual trabeculae varies tremendously, can be substantial, and is weakly influenced by non-enzymatic glycation.

Evaluation of a Simplified Therapeutic Intervention Scoring System (TISS-28) and the Modified Early Warning Score (MEWS) in Predicting Physiological Deterioration During Inter-facility Transport

Resuscitation. Jan, 2008  |  Pubmed ID: 17728045

There is an emerging demand for inter-facility transport (IFT) of patients in recent years following changes in the healthcare framework in Hong Kong but this carries certain risks. Anticipation of possible deterioration of patients is important for patient safety and therefore risk stratification of patients before transport is important.

Effects of Collagen Crosslinking on Tissue Fragility

Clinical Biomechanics (Bristol, Avon). Jan, 2008  |  Pubmed ID: 17910987

Knowledge of Inter-facility Transport Among Emergency Nurses in Hong Kong: a Questionnaire Survey

International Emergency Nursing. Jul, 2008  |  Pubmed ID: 18627800

Inter-facility transport (IFT) is a dynamic process and its quality largely depends on pre-transport preparation, emergency equipment support and recognition of possible en route adverse events. This study aims to evaluate knowledge of IFT among emergency nurses of three Accident and Emergency Departments in Hong Kong.

Bisphosphonate Treatment Modifies Canine Bone Mineral and Matrix Properties and Their Heterogeneity

Bone. Mar, 2010  |  Pubmed ID: 19925895

Bone loss and alterations in bone quality are major causes leading to bone fragility in postmenopausal women. Although bisphosphonates are well known to reduce bone turnover and prevent bone loss in postmenopausal osteoporosis, their effects on other bone properties are not fully characterized. Changes in bone mineral and matrix properties may contribute to the anti-fracture efficacy observed with bisphosphonate treatments. The aim of this work was to analyze the effect of a 1-year treatment with either alendronate or risedronate, at low and high doses, on spatially resolved bone material and compositional properties that could contribute to the fracture efficacy of these agents. Distal tibias from 30 normal beagles that had been treated daily for 1 year with oral doses of vehicle (Veh), alendronate (Aln) at 0.2 or 1 mg/kg, and risedronate (Ris) at 0.1 or 0.5 mg/kg were analyzed by Fourier Transform Infrared imaging (FTIRI) to assess the changes in both mineral and matrix properties in discrete bone areas. The widths at half maximum of the pixel histograms for each FTIRI parameter were used to assess the heterogeneity of the bone tissue. Aln and Ris increased the mineral content and the collagen maturity mainly in cancellous bone and at the endocortical surface. Significant differences were observed in the mineral content and in the hydroxyapatite crystallinity distribution in bone tissue, which can contribute to reduced ductility and micro-crack accumulation. No significant differences were observed between low and high dose nor between Aln and Ris treatments. These results show that pharmacologic suppression of bone turnover increases the mineral and matrix bone tissue maturity in normal cancellous and endocortical bone areas where bone turnover is higher. These positive effects for decreased fracture risk are also associated with a loss of bone heterogeneity that could be one factor contributing to increased bone tissue brittleness and micro-crack accumulation.

In Situ Materials Characterization Using the Tissue Diagnostic Instrument

Polymer Testing. Apr, 2010  |  Pubmed ID: 20582333

An understanding of the mechanical behavior of polymers is critical towards the design, implementation, and quality control of such materials. Yet experiments and method for the characterization of material properties of polymers remain challenging due the need to reconcile constitutive assumptions with experimental conditions. Well-established modes of mechanical testing, such as unconfined compression or uniaxial tension, require samples with specific geometries and carefully controlled orientations. Moreover, producing specimens that conform to such specifications often requires a considerable amount of sample material. In this study we validate a micromechanical indentation device, the Tissue Diagnostic Instrument (TDI), which implements a cyclic indentation method to determine the material properties of polymers and elastomeric materials. Measurements using the TDI require little or no sample preparation, and they allow the testing of sample materials in situ. In order to validate the use of the TDI, we compared measurements of modulus determined by the TDI to those obtained by unconfined compression tests and by uniaxial tension tests within the limit of small stresses and strains. The results show that the TDI measurements were significantly correlated with both unconfined compression (p<0.001; r(2) = 0.92) and uniaxial tension tests (p<0.001; r(2)=0.87). Moreover, the measurements across all three modes of testing were statistically indistinguishable from each other (p=0.92; ANOVA) and demonstrate that TDI measurements can provide a surrogate for the conventional methods of mechanical characterization.

Local Tissue Properties of Human Osteoarthritic Cartilage Correlate with Magnetic Resonance T(1) Rho Relaxation Times

Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. Sep, 2011  |  Pubmed ID: 21445940

The objective of this study is to examine the local relationship between T(1ρ) relaxation times and the mechanical behavior of human osteoarthritic articular cartilage using high-resolution magnetic resonance imaging (MRI) and local in situ microindentation. Seven human tibial plateaus were obtained from patients who underwent total knee arthroplasty due to severe osteoarthritis (OA). Three to six sites were selected from each sample for visual classification using the ICRS Outerbridge scale (a total of 36 sites). Samples were imaged by MR, and the local distribution of T(1ρ) relaxation times were obtained at these selected sites. The elastic and viscoelastic characteristics of the tissue were quantified nondestructively using dynamic microindentation to measure peak dynamic modulus, energy dissipation, and phase angle. Measured Outerbridge scores, MR T(1ρ) relaxation times, and mechanical properties were highly heterogeneous across each cartilage surface. Site-specific measures of T(1ρ) relaxation times correlated significantly with the phase angle (p < 0.001; R = 0.908), a viscoelastic mechanical behavior of the cartilage. The novel combination of high-resolution MR imaging and microindentation allows the investigation of the local relationship between quantitative MRI and biomechanical properties in highly heterogeneous OA cartilage. These findings suggest that MRI T(1ρ) can provide a functional assessment of articular cartilage.

Age-related Changes in the Plasticity and Toughness of Human Cortical Bone at Multiple Length Scales

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2011  |  Pubmed ID: 21873221

The structure of human cortical bone evolves over multiple length scales from its basic constituents of collagen and hydroxyapatite at the nanoscale to osteonal structures at near-millimeter dimensions, which all provide the basis for its mechanical properties. To resist fracture, bone's toughness is derived intrinsically through plasticity (e.g., fibrillar sliding) at structural scales typically below a micrometer and extrinsically (i.e., during crack growth) through mechanisms (e.g., crack deflection/bridging) generated at larger structural scales. Biological factors such as aging lead to a markedly increased fracture risk, which is often associated with an age-related loss in bone mass (bone quantity). However, we find that age-related structural changes can significantly degrade the fracture resistance (bone quality) over multiple length scales. Using in situ small-angle X-ray scattering and wide-angle X-ray diffraction to characterize submicrometer structural changes and synchrotron X-ray computed tomography and in situ fracture-toughness measurements in the scanning electron microscope to characterize effects at micrometer scales, we show how these age-related structural changes at differing size scales degrade both the intrinsic and extrinsic toughness of bone. Specifically, we attribute the loss in toughness to increased nonenzymatic collagen cross-linking, which suppresses plasticity at nanoscale dimensions, and to an increased osteonal density, which limits the potency of crack-bridging mechanisms at micrometer scales. The link between these processes is that the increased stiffness of the cross-linked collagen requires energy to be absorbed by "plastic" deformation at higher structural levels, which occurs by the process of microcracking.

Characterization of the Effects of X-ray Irradiation on the Hierarchical Structure and Mechanical Properties of Human Cortical Bone

Biomaterials. Dec, 2011  |  Pubmed ID: 21885114

Bone comprises a complex structure of primarily collagen, hydroxyapatite and water, where each hierarchical structural level contributes to its strength, ductility and toughness. These properties, however, are degraded by irradiation, arising from medical therapy or bone-allograft sterilization. We provide here a mechanistic framework for how irradiation affects the nature and properties of human cortical bone over a range of characteristic (nano to macro) length-scales, following x-ray exposures up to 630 kGy. Macroscopically, bone strength, ductility and fracture resistance are seen to be progressively degraded with increasing irradiation levels. At the micron-scale, fracture properties, evaluated using insitu scanning electron microscopy and synchrotron x-ray computed micro-tomography, provide mechanistic information on how cracks interact with the bone-matrix structure. At sub-micron scales, strength properties are evaluated with insitu tensile tests in the synchrotron using small-/wide-angle x-ray scattering/diffraction, where strains are simultaneously measured in the macroscopic tissue, collagen fibrils and mineral. Compared to healthy bone, results show that the fibrillar strain is decreased by ∼40% following 70 kGy exposures, consistent with significant stiffening and degradation of the collagen. We attribute the irradiation-induced deterioration in mechanical properties to mechanisms at multiple length-scales, including changes in crack paths at micron-scales, loss of plasticity from suppressed fibrillar sliding at sub-micron scales, and the loss and damage of collagen at the nano-scales, the latter being assessed using Raman and Fourier Transform Infrared spectroscopy and a fluorometric assay.

Alterations in T2 Relaxation Magnetic Resonance Imaging of the Ovine Intervertebral Disc Due to Nonenzymatic Glycation

Spine. Feb, 2012  |  Pubmed ID: 21857410

An in vitro study using ovine intervertebral discs to correlate the effects of increasing advanced glycation end-products (AGEs) with disc hydration evaluated by magnetic resonance imaging (MRI).

Matrix Metalloproteinase-13 is Required for Osteocytic Perilacunar Remodeling and Maintains Bone Fracture Resistance

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. Sep, 2012  |  Pubmed ID: 22549931

Like bone mass, bone quality is specified in development, actively maintained postnatally, and disrupted by disease. The roles of osteoblasts, osteoclasts, and osteocytes in the regulation of bone mass are increasingly well defined. However, the cellular and molecular mechanisms by which bone quality is regulated remain unclear. Proteins that remodel bone extracellular matrix, such as the collagen-degrading matrix metalloproteinase (MMP)-13, are likely candidates to regulate bone quality. Using MMP-13-deficient mice, we examined the role of MMP-13 in the remodeling and maintenance of bone matrix and subsequent fracture resistance. Throughout the diaphysis of MMP-13-deficient tibiae, we observed elevated nonenzymatic cross-linking and concentric regions of hypermineralization, collagen disorganization, and canalicular malformation. These defects localize to the same mid-cortical bone regions where osteocyte lacunae and canaliculi exhibit MMP-13 and tartrate-resistant acid phosphatase (TRAP) expression, as well as the osteocyte marker sclerostin. Despite otherwise normal measures of osteoclast and osteoblast function, dynamic histomorphometry revealed that remodeling of osteocyte lacunae is impaired in MMP-13(-/-) bone. Analysis of MMP-13(-/-) mice and their wild-type littermates in normal and lactating conditions showed that MMP-13 is not only required for lactation-induced osteocyte perilacunar remodeling, but also for the maintenance of bone quality. The loss of MMP-13, and the resulting defects in perilacunar remodeling and matrix organization, compromise MMP-13(-/-) bone fracture toughness and postyield behavior. Taken together, these findings demonstrate that osteocyte perilacunar remodeling of mid-cortical bone matrix requires MMP-13 and is essential for the maintenance of bone quality.

Load Regulates Bone Formation and Sclerostin Expression Through a TGFβ-dependent Mechanism

PloS One. 2013  |  Pubmed ID: 23308287

Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGFβ acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGFβ pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGFβ pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGFβ sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGFβ signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGFβ is required for the mechanosensitive regulation of Sclerostin, which is induced by TGFβ in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGFβ pathway to regulate Sclerostin expression and the deposition of new bone.

Regulation of Postnatal Bone Homeostasis by TGFβ

BoneKEy Reports. Jan, 2013  |  Pubmed ID: 24404376

Perhaps more so than any other tissue, bone has pivotal mechanical and biological functions. Underlying the ability of bone to execute these functions, whether providing structural support or preserving mineral homeostasis, is the dynamic remodeling of bone matrix. Cells within bone integrate multiple stimuli to balance the deposition and resorption of bone matrix. Transforming growth factor-β (TGFβ) uniquely coordinates bone cell activity to maintain bone homeostasis. TGFβ regulates the differentiation and function of both osteoblasts and osteoclasts, from lineage recruitment to terminal differentiation, to balance bone formation and resorption. TGFβ calibrates the synthesis and material quality of bone matrix and bone's responsiveness to applied mechanical loads. Therefore, by coupling the activity of bone forming and resorbing cells, and by sensing, responding to and defining physical cues, TGFβ integrates physical and biochemical stimuli to maintain bone homeostasis. Disruption of TGFβ signaling has significant consequences on bone mass and quality. Alternatively, TGFβ is a powerful lever that has the potential to yield therapeutic benefit in cases where bone homeostasis needs to be recalibrated.

How Tough is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. Jun, 2014  |  Pubmed ID: 24420672

The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level, we attribute the loss in toughness to a decrease in the stabilizing enzymatic cross-links and an increase in nonenzymatic cross-links, which may break prematurely, inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales.

Comparison of Different Intubation Techniques Performed Inside a Moving Ambulance: a Manikin Study

Hong Kong Medical Journal = Xianggang Yi Xue Za Zhi. Aug, 2014  |  Pubmed ID: 24914074

OBJECTIVE. Airway management and endotracheal intubation may be required urgently when a patient deteriorates in an ambulance or aircraft during interhospital transfer or in a prehospital setting. The objectives of this study were: (1) to compare the effectiveness of conventional intubation by Macintosh laryngoscope in a moving ambulance versus that in a static ambulance; and (2) to compare the effectiveness of inverse intubation and GlideScope laryngoscopy with conventional intubation inside a moving ambulance. DESIGN. Comparative experimental study. SETTING. The experiment was conducted in an ambulance provided by the Auxiliary Medical Service in Hong Kong. PARTICIPANTS. A group of 22 doctors performed endotracheal intubation on manikins with Macintosh laryngoscope in a static and moving ambulance. In addition, they performed conventional Macintosh intubation, inverse intubation with Macintosh laryngoscope, and GlideScope intubation in a moving ambulance in both normal and simulated difficult airways. MAIN OUTCOME MEASURES. The primary outcome was the rate of successful intubation. The secondary outcomes were time taken for intubation, subjective glottis visualisation grading, and eventful intubation (oesophageal intubation, intubation time >60 seconds, and incisor breakage) with different techniques or devices. RESULTS. In normal airways, conventional Macintosh intubation in a static ambulance (95.5%), conventional intubation in a moving ambulance (95.5%), as well as GlideScope intubation in a moving ambulance (95.5%) were associated with high success rates; the success rate of inverse intubation was comparatively low (54.5%; P=0.004). In difficult airways, conventional Macintosh intubation in a static ambulance (86.4%), conventional intubation in a moving ambulance (90.9%), and GlideScope intubation in a moving ambulance (100%) were associated with high success rates; the success rate of inverse intubation was comparatively lower (40.9%; P=0.034). CONCLUSIONS. En-route intubation in an ambulance by conventional Macintosh laryngoscopy is superior to inverse intubation unless the cephalad access is impossible. GlideScope laryngoscopy appears to be associated with lower rates of eventful intubation in difficult airways and has better laryngoscopic view versus inverse intubation.

The High-throughput Phenotyping of the Viscoelastic Behavior of Whole Mouse Intervertebral Discs Using a Novel Method of Dynamic Mechanical Testing

Journal of Biomechanics. Jul, 2015  |  Pubmed ID: 26004435

Intervertebral disc (IVD) degeneration is highly correlated with lower back pain, and thus understanding the mechanisms of IVD degeneration is critical for the treatment of this disease. Utilizing mouse models to probe the mechanisms of degeneration is especially attractive due to the ease of manipulating mouse models and the availability of transgenics. Yet characterizing the mechanical behavior of mice IVDs remain challenging due to their minute size (approximately 540 μm in height and 1080 μm(2) in cross sectional area). We have thus developed a simple method to dynamically characterize the mechanical properties of intact mouse IVDs. The IVDs were dissected with the endplates intact, and dynamically compressed in the axial direction at 1% and 5% peak strains at 1 Hz. Utilizing this novel approach, we examined the effects of in vitro ribosylation and trypsin digestion for 24 or 72 h on the viscoelastic behavior of the whole murine IVD. Trypsin treatment resulted in a decrease of proteoglycans and loss of disc height, while ribosylation had no effect on structure or proteoglycan composition. The 72 h ribosylation group exhibited a stiffening of the disc, and both treatments significantly reduced viscous behavior of the IVDs, with the effects being more pronounced at 5% strain. Here we demonstrate a novel high-throughput method to mechanically characterize murine IVDs and detect strain-dependent differences in the elastic and the viscous behavior of the treated IVDs due to ribose and trypsin treatments.

Multiscale Predictors of Femoral Neck In Situ Strength in Aging Women: Contributions of BMD, Cortical Porosity, Reference Point Indentation, and Nonenzymatic Glycation

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. Dec, 2015  |  Pubmed ID: 26060094

The diagnosis of fracture risk relies almost solely on quantifying bone mass, yet bone strength is governed by factors at multiple scales including composition and structure that contribute to fracture resistance. Furthermore, aging and conditions such as diabetes mellitus alter fracture incidence independently of bone mass. Therefore, it is critical to incorporate other factors that contribute to bone strength in order to improve diagnostic specificity of fracture risk. We examined the correlation between femoral neck fracture strength in aging female cadavers and areal bone mineral density, along with other clinically accessible measures of bone quality including whole-bone cortical porosity (Ct.Po), bone material mechanical behavior measured by reference point indentation (RPI), and accumulation of advanced glycation end-products (AGEs). All measurements were found to be significant predictors of femoral neck fracture strength, with areal bone mineral density (aBMD) being the single strongest correlate (aBMD: r = 0.755, p < 0.001; Ct.Po: r = -0.500, p < 0.001; RPI: r = -0.478, p < 0.001; AGEs: r = -0.336, p = 0.016). RPI-derived measurements were not correlated with tissue mineral density or local cortical porosity as confirmed by micro-computed tomography (μCT). Multiple reverse stepwise regression revealed that the inclusion of aBMD and any other factor significantly improve the prediction of bone strength over univariate predictions. Combining bone assays at multiple scales such as aBMD with tibial Ct.Po (r = 0.835; p < 0.001), tibial difference in indentation depth between the first and 20th cycle (IDI) (r = 0.883; p < 0.001), or tibial AGEs (r = 0.822; p < 0.001) significantly improves the prediction of femoral neck strength over any factor alone, suggesting that this personalized approach could greatly enhance bone strength and fracture risk assessment with the potential to guide clinical management strategies for at-risk populations.

Alendronate Treatment Alters Bone Tissues at Multiple Structural Levels in Healthy Canine Cortical Bone

Bone. Dec, 2015  |  Pubmed ID: 26253333

Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.

Microstructural and Compositional Contributions Towards the Mechanical Behavior of Aging Human Bone Measured by Cyclic and Impact Reference Point Indentation

Bone. Jun, 2016  |  Pubmed ID: 27021150

The assessment of fracture risk often relies primarily on measuring bone mineral density, thereby accounting for only a single pathology: the loss of bone mass. However, bone's ability to resist fracture is a result of its biphasic composition and hierarchical structure that imbue it with high strength and toughness. Reference point indentation (RPI) testing is designed to directly probe bone mechanical behavior at the microscale in situ, although it remains unclear which aspects of bone composition and structure influence the results at this scale. Therefore, our goal in this study was to investigate factors that contribute to bone mechanical behavior measured by cyclic reference point indentation, impact reference point indentation, and three-point bending. Twenty-eight female cadavers (ages 57-97) were subjected to cyclic and impact RPI in parallel at the unmodified tibia mid-diaphysis. After RPI, the middiaphyseal tibiae were removed, scanned using micro-CT to obtain cortical porosity (Ct.Po.) and tissue mineral density (TMD), then tested using three-point bending, and lastly assayed for the accumulation of advanced glycation end-products (AGEs). Both the indentation distance increase from cyclic RPI (IDI) and bone material strength index from impact RPI (BMSi) were significantly correlated with TMD (r=-0.390, p=0.006; r=0.430, p=0.002; respectively). Accumulation of AGEs was significantly correlated with IDI (r=0.281, p=0.046), creep indentation distance (CID, r=0.396, p=0.004), and BMSi (r=-0.613, p<0.001). There were no significant relationships between tissue TMD or AGEs accumulation with the quasi-static material properties. Toughness decreased with increasing tissue Ct.Po. (r=-0.621, p<0.001). Other three-point bending measures also correlated with tissue Ct.Po. including the bending modulus (r=-0.50, p<0.001) and ultimate stress (r=-0.56, p<0.001). The effects of Ct.Po. on indentation were less pronounced with IDI (r=0.290, p=0.043) and BMSi (r=-0.299, p=0.037) correlated modestly with tissue Ct.Po. These results suggest that RPI may be sensitive to bone quality changes relating to collagen.

A 5 NW Quasi-Linear CMOS Hot-Electron Injector for Self-Powered Monitoring of Biomechanical Strain Variations

IEEE Transactions on Biomedical Circuits and Systems. Dec, 2016  |  Pubmed ID: 27214911

Piezoelectricity-driven hot-electron injectors (p-HEI) are used for self-powered monitoring of mechanical activity in biomechanical implants and structures. Previously reported p-HEI devices operate by harvesting energy from a piezoelectric transducer to generate current and voltage references which are then used for initiating and controlling the process of hot-electron injection. As a result, the minimum energy required to activate the device is limited by the power requirements of the reference circuits. In this paper we present a p-HEI device that operates by directly exploiting the self-limiting capability of an energy transducer when driving the process of hot-electron injection in a pMOS floating-gate transistor. As a result, the p-HEI device can activate itself at input power levels less than 5 nW. Using a prototype fabricated in a 0.5- [Formula: see text] bulk CMOS process we validate the functionality of the proposed injector and show that for a fixed input power, its dynamics is quasi-linear with respect to time. The paper also presents measurement results using a cadaver phantom where the fabricated p-HEI device has been integrated with a piezoelectric transducer and is used for self-powered monitoring of mechanical activity.

Longitudinal Changes in the Structure and Inflammatory Response of the Intervertebral Disc Due to Stab Injury in a Murine Organ Culture Model

Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. Aug, 2016  |  Pubmed ID: 27273204

Despite the significant public health impact of intervertebral disc (IVD) degeneration and low back pain, it remains challenging to investigate the multifactorial molecular mechanisms that drive the degenerative cascade. Organ culture model systems offer the advantage of allowing cells to live and interact with their native extracellular matrix, while simultaneously reducing the amount of biological variation and complexity present at the organismal level. Murine organ cultures in particular also allow the use of widely available genetically modified animals with molecular level reporters that would reveal insights on the degenerative cascade. Here, we utilize an organ culture system of murine lumbar functional spinal units where we are able to maintain the cellular, metabolic, and structural, and mechanical stability of the whole organ over a 21-day period. Furthermore, we describe a novel approach in organ culture by using tissues from animals with an NF-κB-luc reporter in combination with a mechanical injury model, and are able to show that proinflammatory factors and cytokines such as NF-κB and IL-6 produced by IVD cells can be monitored longitudinally during culture in a stab injury model. Taken together, we utilize a murine organ culture system that maintains the cellular and tissue level behavior of the intervertebral disc and apply it to transgenic animals that allow the monitoring of the inflammatory profile of IVDs. This approach could provide important insights on the molecular and metabolic mediators that regulate the homeostasis of the IVD. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1431-1438, 2016.

A Novel Technique for the Contrast-enhanced MicroCT Imaging of Murine Intervertebral Discs

Journal of the Mechanical Behavior of Biomedical Materials. Oct, 2016  |  Pubmed ID: 27341292

Disc degeneration is one of the leading factors that contribute to low back pain. Thus, the further understanding of the mechanisms contributing to degeneration of the intervertebral disc degeneration is critical for the development of therapies and strategies for treating low back pain. Rodent models are attractive for conducting mechanistic studies particularly because of the availability of genetically modified animals. However, current imaging technologies such as magnetic resonance imaging, do not have the ability to resolve spatial features at the tens- to single- micrometer scale. We propose here a contrast-enhanced microCT technique to conduct high-resolution imaging of the rodent intervertebral discs at 10µm spatial resolution. Based on the iodinated-hydrophilic contrast agent Ioversol, we are able to conduct high resolution imaging on rat and mouse intervertebral discs. Leveraging the hydrophilic characteristic of the contrast agent, we are able to discriminate the annulus fibrosus from the water-rich nucleus pulposus. Moreover, this technique allows for the quantitative measurement of disc morphologies and volumes, and we demonstrate the versatility of this technique on cultured live intervertebral discs. Coupled with our semi-automated segmentation technique, we are able to quantify the intervertebral disc volumes with a high degree of reproducibility. The contrast-enhanced microCT images were qualitatively and quantitatively indistinguishable from the traditional histological assessment of the same sample. Furthermore, stereological measures compared well between histology and microCT images. Taken together, the results reveal that rat and mouse intervertebral discs can be imaged longitudinally in vitro at high resolutions, with no adverse effects on viability and features of the intervertebral disc.

Novel Augmentation Technique for Patellar Tendon Repair Improves Strength and Decreases Gap Formation: A Cadaveric Study

Clinical Orthopaedics and Related Research. Dec, 2016  |  Pubmed ID: 27492687

Patellar tendon ruptures commonly are repaired using transosseous patellar drill tunnels with modified-Krackow sutures in the patellar tendon. This simple suture technique has been associated with failure rates and poor clinical outcomes in a modest proportion of patients. Failure of this repair technique can result from gap formation during loading or a single catastrophic event. Several augmentation techniques have been described to improve the integrity of the repair, but standardized biomechanical evaluation of repair strength among different techniques is lacking.

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