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1.  Functionally-Detected Cognitive Impairment in High School Football Players without Clinically-Diagnosed Concussion 
Journal of Neurotrauma  2014;31(4):327-338.
Head trauma and concussion in football players have recently received considerable media attention. Postmortem evidence suggests that accrual of damage to the brain may occur with repeated blows to the head, even when the individual blows fail to produce clinical symptoms. There is an urgent need for improved detection and characterization of head trauma to reduce future injury risk and promote development of new therapies. In this study we examined neurological performance and health in the presence of head collision events in high school football players, using longitudinal measures of collision events (the HIT™ System), neurocognitive testing (ImPACT™), and functional magnetic resonance imaging MRI (fMRI). Longitudinal assessment (including baseline) was conducted in 11 young men (ages 15–19 years) participating on the varsity and junior varsity football teams at a single high school. We expected and observed subjects in two previously described categories: (1) no clinically-diagnosed concussion and no changes in neurological behavior, and (2) clinically-diagnosed concussion with changes in neurological behavior. Additionally, we observed players in a previously undiscovered third category, who exhibited no clinically-observed symptoms associated with concussion, but who demonstrated measurable neurocognitive (primarily visual working memory) and neurophysiological (altered activation in the dorsolateral prefrontal cortex [DLPFC]) impairments. This new category was associated with significantly higher numbers of head collision events to the top-front of the head, directly above the DLPFC. The discovery of this new category suggests that more players are suffering neurological injury than are currently being detected using traditional concussion-assessment tools. These individuals are unlikely to undergo clinical evaluation, and thus may continue to participate in football-related activities, even when changes in brain physiology (and potential brain damage) are present, which will increase the risk of future neurological injury.
PMCID: PMC3922228  PMID: 20883154
behavioral assessment; cognitive function; human studies; magnetic resonance imaging; traumatic brain injury
2.  Oligomers Modulate Interfibril Branching and Mass Transport Properties of Collagen Matrices 
Mass transport within collagen-based matrices is critical to tissue development, repair, and pathogenesis as well as the design of next generation tissue engineering strategies. This work shows how collagen precursors, specified by intermolecular cross-link composition, provide independent control of collagen matrix mechanical and transport properties. Collagen matrices were prepared from tissue-extracted monomers or oligomers. Viscoelastic behavior was measured in oscillatory shear and unconfined compression. Matrix permeability and diffusivity were measured using gravity-driven permeametry and integrated optical imaging, respectively. Both collagen types showed an increase in stiffness and permeability hindrance with increasing collagen concentration (fibril density); however, different physical property-concentration relationships were noted. Diffusivity wasn’t affected by concentration for either collagen type over the range tested. In general, oligomer matrices exhibited a substantial increase in stiffness and only a modest decrease in transport properties when compared to monomer matrices prepared at the same concentration. The observed differences in viscoelastic and transport properties were largely attributed to increased levels of interfibril branching within oligomer matrices. The ability to relate physical properties to relevant microstructure parameters, including fibril density and interfibril branching, is expected to advance the understanding of cell-matrix signaling as well as facilitate model-based prediction and design of matrix-based therapeutic strategies.
PMCID: PMC3778042  PMID: 23842082
collagen matrix; oligomer; monomer; mass transport; permeability; diffusivity
3.  Contribution of cytoskeletal elements to the axonal mechanical properties 
Microtubules, microfilaments, and neurofilaments are cytoskeletal elements that affect cell morphology, cellular processes, and mechanical structures in neural cells. The objective of the current study was to investigate the contribution of each type of cytoskeletal element to the mechanical properties of axons of dorsal root and sympathetic ganglia cells in chick embryos.
Microtubules, microfilaments, and neurofilaments in axons were disrupted by nocodazole, cytochalasin D, and acrylamide, respectively, or a combination of the three. An atomic force microscope (AFM) was then used to compress the treated axons, and the resulting corresponding force-deformation information was analyzed to estimate the mechanical properties of axons that were partially or fully disrupted.
We have found that the mechanical stiffness was most reduced in microtubules-disrupted-axons, followed by neurofilaments-disrupted- and microfilaments-disrupted-axons. This suggests that microtubules contribute the most of the mechanical stiffness to axons.
PMCID: PMC3846871  PMID: 24007256
Axon; Elastic modulus; Atomic force microscope; Cytoskeleton
4.  A three-dimensional finite element analysis of finger joint stresses in the MCP joint while performing common tasks 
Hand (New York, N.Y.)  2012;7(3):341-345.
The goal of this study was to develop a three-dimensional finite element model of the metacarpophalangeal (MCP) joint to characterize joint contact stresses incurred during common daily activities. The metacarpal and proximal phalanx were modeled using a COMSOL-based finite element analysis. Muscle forces determined from a static force analysis of two common activities (pen grip and carrying a weight) were applied to the simulation to characterize the surface stress distributions at the MCP joint. The finite element analysis predicted that stresses as high as 1.9 MPa, similar in magnitude to stresses experienced at the hip, may be experienced by the subchondral bone in the MCP joint. The internal structure and material properties of the phalanges were found to play a significant role in both the magnitude and distribution of stresses, but the dependence on cancellous bone modulus was not as severe as predicted by previous two dimensional models.
PMCID: PMC3418372  PMID: 23997746
FEA; Finite element analysis; Hand strength; Osteoarthritis; Rheumatoid arthritis; Joint replacement
5.  In vitro and in vivo evaluation of orthopedic interface repair using a tissue scaffold with a continuous hard tissue-soft tissue transition 
Tendon tears produce pain and decrease joint stability; each year, over 1.1 million rotator cuff tendon surgical procedures are performed worldwide. However, surgical success is highly variable, and the inability of the procedure to drive the regeneration of the normal tendon-bone interface has been identified as a key factor in surgical failure. This study focuses on the development, in vitro evaluation, and in vivo assessment of a tissue scaffold derived from bovine cancellous bone with the potential to direct regeneration of a bone-soft tissue interface. The scaffold is a highly porous scaffold with a continuous hard tissue-soft tissue transition that facilitates load transfer across the interface and contains all of the extracellular matrix components of the orthopedic interface. This study demonstrated the in vitro characterization of the mechanical properties and successful in vivo assessment using an ovine model.
PMCID: PMC3689086  PMID: 23782505
Tendon repair; Soft tissue-bone interface; Rotator cuff tenotemy
6.  Development of Subject-Specific Geometric Spine Model through Use of Automated Active Contour Segmentation and Kinematic Constraint-Limited Registration 
Journal of Digital Imaging  2010;24(5):926-942.
This paper describes the development of a patient-specific spine model through use of active contour segmentation and registration of intraoperative imaging of porcine vertebra augmented with kinematic constraints. The geometric active contours are fully automated and lead to a discrete representation of the image segmentation results. After determining errors within the segmentations, application of reliability theory allows the selection of active contour parameters to obtain best-fit segmentations from a stack of 2D images. The segmented images are then used in conjunction with C-arm fluoroscope images to simulate the result of intraoperative patient-specific model registration including patient and/or structure motion between preoperative and intraoperative scans. The results are validated through comparison of the error within the patient-specific model generated through use of the C-arm images with a model acquired directly from MRI images of the spine after motion. The results are applicable to the development of a wide variety of patient-specific geometric and biomechanical models.
PMCID: PMC3180553  PMID: 20882395
Segmentation; template geometry; patient-specific model; spine; active contour; fluoroscopy; kinematic constraints; imaging; image error; registration
7.  Compression Induces Acute Demyelination and Potassium Channel Exposure in Spinal Cord 
Journal of Neurotrauma  2010;27(6):1109-1120.
Crush to the mammalian spinal cord leads to primary mechanical damage followed by a series of secondary biomolecular events. The chronic outcomes of spinal cord injuries have been well detailed in multiple previous studies. However, the initial mechanism by which constant displacement injury induces conduction block is still unclear. We therefore investigated the anatomical factors that may directly contribute to electrophysiological deficiencies in crushed cord. Ventral white matter strips from adult guinea pig spinal cord were compressed 80%, either briefly or continuously for 30 min. Immunofluorescence imaging and coherent anti-Stokes Raman spectroscopy (CARS) were used to visualize key pathological changes to ion channels and myelin. Compression caused electrophysiological deficits, including compound action potential (CAP) decline that was injury-duration-dependent. Compression further induced myelin retraction at the nodes of Ranvier. This demyelination phenomenon exposed a subclass of voltage-gated potassium channels (Kv1.2). Application of a potassium channel blocker, 4-aminopyridine (4-AP), restored the CAP to near pre-injury levels. To further investigate the myelin detachment phenomenon, we constructed a three-dimensional finite element model (FEM) of the axon and surrounding myelin. We found that the von Mises stress was highly concentrated at the paranodal junction. Thus, the mechanism of myelin retraction may be associated with stress concentrations that cause debonding at the axoglial interface. In conclusion, our findings implicate myelin disruption and potassium channel pathophysiology as the culprits causing compression-mediated conduction block. This result highlights a potential therapeutic target for compressive spinal cord injuries.
PMCID: PMC2943505  PMID: 20373847
acute spinal cord injury; demyelination; potassium ion channel; sustained compression
8.  The Role of Glucose, Serum, and Three-Dimensional Cell Culture on the Metabolism of Bone Marrow-Derived Mesenchymal Stem Cells 
Stem Cells International  2011;2011:429187.
Mesenchymal stem cells (MSCs) have become a critical addition to all facets of tissue engineering. While most in vitro research has focused on their behavior in two-dimensional culture, relatively little is known about the cells' behavior in three-dimensional culture, especially with regard to their metabolic state. To evaluate MSC metabolism during twodimensional culture, murine bone marrow-derived MSCs were cultured for one week using twelve different medium compositions, varying in both glucose and fetal bovine serum (FBS) concentrations. The results indicate that glucose concentration was the more important factor in sustaining cell growth and viability. To evaluate metabolic state during three-dimensional culture, MSCs were cultured for one week using two different medium compositions and two different concentrations of collagen gel matrix. The medium compositions only varied in glucose concentration. The results indicate that glucose and extracellular matrix were significant factors in the metabolic response of the cells. However, cells cultured in low density collagen exhibited considerable cell death, likely because of physical contraction of the collagen hydrogel which was not observed in the higher density collagen. These findings will be useful to the development of in vitro cell culture models that properly mimic in vivo physiological processes.
PMCID: PMC3096318  PMID: 21603146
9.  Effects of Reduced Oxygen and Glucose Levels on Ocular Cells in vitro: Implications for Tissue Models 
Cells, Tissues, Organs  2009;191(2):141-151.
An important goal of tissue engineering is the development of better in vitro tissue models for the study and treatment of diseases, especially those that are difficult to model in animals, such as glaucoma. In order to properly interpret experimental results designed to mimic in vivo conditions, it is necessary to characterize the metabolic state of the in vitro culture. The goal of this study was to determine how porcine lamina cribrosa cells (PLC), porcine scleral fibroblasts (PSC) and rat astrocytes (RAS) respond metabolically to reduced glucose and oxygen levels compared to normal in vitro culture conditions. Throughout the culture period, cell number and the levels of glucose, lactate, pyruvate and glutamate were characterized. Cell number in the PLC and PSC was more sensitive to glucose level than oxygen, while the RAS exhibited sensitivities to both variables. While the pyruvate and glutamate levels did not vary substantially between groups, glucose consumption and lactate production were dependent on culture condition. In addition, the ΔL/ΔG ratio was dependent on glucose and oxygen levels, but not cell type at early time points. By day 7, however, the RAS exhibited ratios consistently lower than the other cell types. The results of this study serve as a basis for future studies into the degenerative matrix remodeling in the glaucomatous optic nerve head, and may prove insightful for other tissue engineering applications.
PMCID: PMC2855277  PMID: 19641288
Aerobic cell metabolism; Anaerobic metabolism; Glaucoma; Sclera; Lamina cribrosa; Fibroblasts; Astrocytes
10.  Toward a Continuous Intravascular Glucose Monitoring System 
Sensors (Basel, Switzerland)  2010;11(1):409-424.
Proof-of-concept studies that display the potential of using a glucose-sensitive hydrogel as a continuous glucose sensor are presented. The swelling ratio, porosity, and diffusivity of the hydrogel increased with glucose concentration. In glucose solutions of 50, 100, 200, and 300 mg/dL, the hydrogel swelling ratios were 4.9, 12.3, 15.9, and 21.7, respectively, and the swelling was reversible. The impedance across the hydrogel depended solely on the thickness and had an average increase of 47 Ω/mm. The hydrogels exposed to a hyperglycemic solution were more porous than the hydrogels exposed to a normal glycemic solution. The diffusivity of 390 Da MW fluorescein isothiocyanate in hydrogels exposed to normal and hyperglycemic solutions was examined using fluorescence recovery after photobleaching and was found to be 9.3 × 10−14 and 41.4 × 10−14 m2/s, respectively, compared to 6.2 × 10−10 m2/s in glucose solution. There was no significant difference between the permeability of hydrogels in normal and hyperglycemic glucose solutions with averages being 5.26 × 10−17 m2 and 5.80 × 10−17 m2, respectively, which resembles 2–4% agarose gels. A prototype design is presented for continuous intravascular glucose monitoring by attaching a glucose sensor to an FDA-approved stent.
PMCID: PMC3274116  PMID: 22344366
glucose monitoring; hydrogels; biosensors; polymers; continuous; intravascular; stent, wireless
11.  Increased osteoblast cell density on nanostructured PLGA-coated nanostructured titanium for orthopedic applications 
There are more than 30,000 orthopedic implant revision surgeries necessary each year in part due to poor implant fixation with juxtaposed bone. A further emphasis on the current problems associated with insufficient bone implant performance is the fact that many patients are receiving hip implants earlier in life, remaining active older, and that the human lifespan is continuously increasing. Collectively, it is clear that there is a strong clinical need to improve implant performance through proper, prolonged fixation. For these reasons, the objective of the present in vitro study was to improve the performance of titanium (Ti), one of the most popular orthopedic implant materials. Accordingly, the proliferative response of osteoblasts (bone-forming cells) on novel nanostructured Ti/PLGA (poly-lactic-co-glycolic acid) composites was examined. This study showed that nano-topography can be easily applied to Ti (through anodization) and porous PLGA (through NaOH chemical etching) to enhance osteoblast cell proliferation which may lead to better orthopedic implant performance. This straight forward application of nano-topography on current bone implant materials represents a new direction in the design of enhanced biomaterials for the orthopedic industry.
PMCID: PMC2676665  PMID: 18019847
osseointegration; nano-scale topography; PLGA; titanium; tissue engineering; orthopedic implants
12.  Decreased fibroblast and increased osteoblast adhesion on nanostructured NaOH-etched PLGA scaffolds 
To facilitate locomotion and support the body, the skeleton relies on the transmission of forces between muscles and bones through complex junctions called entheses. The varying mechanical and biological properties of the enthesis make healing this avascular tissue difficult; hence the need for an engineered alternative. Cells in situ interact with their environment on the nano-scale which suggests that engineered approaches to enthesis regeneration should include such biologically-inspired nano-scale surface features. The present in vitro study investigated the effects of etching poly-lactic-co-glycolic acid (PLGA) scaffolds to produce nano-topography on the adhesion of fibroblasts and osteoblasts, two integral enthesis cell types. Nano-topography was produced on PLGA by etching the scaffolds in NaOH. Results showed that etching PLGA with NaOH to create nano-scale surface features decreased fibroblast adhesion while it increased osteoblast adhesion; criteria critical for the spatial control of osteoblast and fibroblast adhesion for a successful enthesis tissue engineering material. Thus, the results of this study showed for the first time collective evidence that PLGA can be either treated with NaOH or not on ends of an enthesis tissue engineering construct to spatially increase osteoblast and fibroblast adhesion, respectively.
PMCID: PMC2676656  PMID: 18019837
nano-topography; enthesis; tissue engineering; scaffold; porosity
13.  Novel Quantitative Biosystem for Modeling Physiological Fluid Shear Stress on Cells▿  
The response of microbes to changes in the mechanical force of fluid shear has important implications for pathogens, which experience wide fluctuations in fluid shear in vivo during infection. However, the majority of studies have not cultured microbes under physiological fluid shear conditions within a range commonly encountered by microbes during host-pathogen interactions. Here we describe a convenient batch culture biosystem in which (i) the levels of fluid shear force can be varied within physiologically relevant ranges and quantified via mathematical models and (ii) large numbers of cells can be planktonically grown and harvested to examine the effect of fluid shear levels on microbial genomic and phenotypic responses. A quantitative model based on numerical simulations and in situ imaging analysis was developed to calculate the fluid shear imparted by spherical beads of different sizes on bacterial cell cultures grown in a rotating wall vessel (RWV) bioreactor. To demonstrate the application of this model, we subjected cultures of the bacterial pathogen Salmonella enterica serovar Typhimurium to three physiologically-relevant fluid shear ranges during growth in the RVW and demonstrated a progressive relationship between the applied fluid shear and the bacterial genetic and phenotypic responses. By applying this model to different cell types, including other bacterial pathogens, entire classes of genes and proteins involved in cellular interactions may be discovered that have not previously been identified during growth under conventional culture conditions, leading to new targets for vaccine and therapeutic development.
PMCID: PMC1800738  PMID: 17142365

Results 1-13 (13)