269 results found
Snider EJ, Kubelick KP, Tweed K, et al., 2018, Improving Stem Cell Delivery to the Trabecular Meshwork Using Magnetic Nanoparticles, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Feola AJ, Nelson ES, Myers J, et al., 2018, The Impact of Choroidal Swelling on Optic Nerve Head Deformation, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 59, Pages: 4172-4181, ISSN: 0146-0404
Keller KE, Bhattacharya SK, Borras T, et al., 2018, Consensus recommendations for trabecular meshwork cell isolation, characterization and culture, EXPERIMENTAL EYE RESEARCH, Vol: 171, Pages: 164-173, ISSN: 0014-4835
Wang K, Li G, Read AT, et al., 2018, The relationship between outflow resistance and trabecular meshwork stiffness in mice, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Snider EJ, Vannatta RT, Schildmeyer L, et al., 2018, Characterizing differences between MSCs and TM cells: Toward autologous stem cell therapies for the glaucomatous trabecular meshwork, JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Vol: 12, Pages: 695-704, ISSN: 1932-6254
Mulvihill JJE, Raykin J, Snider EJ, et al., 2018, Development of a Platform for Studying 3D Astrocyte Mechanobiology: Compression of Astrocytes in Collagen Gels, ANNALS OF BIOMEDICAL ENGINEERING, Vol: 46, Pages: 365-374, ISSN: 0090-6964
Campbell IC, Sherwood JM, Overby DR, et al., 2017, Quantification of Scleral Biomechanics and Collagen Fiber Alignment., Glaucoma. Methods in Molecular Biology., Editors: Jakobs, Publisher: Humana Press, Pages: 135-159
The stiffness of the sclera is important in several ocular disorders, and there is hence a need to quantify the biomechanical properties of this tissue. Here, we present two methods for measuring the stiffness of scleral ocular tissues: ocular compliance testing and digital image correlation strain mapping. In tandem with these approaches, we provide two methods to spatially quantify the anisotropic alignment of collagen fibers making up the sclera, using second harmonic generation microscopy and small-angle light scattering. Together, these approaches allow specimen-specific measurement of tissue stiffness and collagen alignment, which are key factors in determining how the eye responds to mechanical loads.
Perea D, Guiu J, Hudry B, et al., 2017, Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia., EMBO Journal, Vol: 36, Pages: 3029-3045, ISSN: 0261-4189
Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homoeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease.
Wang K, Johnstone MA, Xin C, et al., 2017, Estimating Human Trabecular Meshwork Stiffness by Numerical Modeling and Advanced OCT Imaging, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 58, Pages: 4809-4817, ISSN: 0146-0404
Nelson ES, Mulugeta L, Feola A, et al., 2017, The impact of ocular hemodynamics and intracranial pressure on intraocular pressure during acute gravitational changes, JOURNAL OF APPLIED PHYSIOLOGY, Vol: 123, Pages: 352-363, ISSN: 8750-7587
Chang JYH, Chow LW, Dismuke WM, et al., 2017, Peptide-functionalized fluorescent particles for in situ detection of nitric oxide via peroxynitrite-mediated nitration, Advanced Healthcare Materials, Vol: 6, ISSN: 2192-2640
Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half-life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio-inspired peptide-based NO sensor is developed, which detects NO-derived oxidants, predominately peroxynitrite-mediated nitration of tyrosine residues. It is demonstrated that these peptide-based NO sensors can detect peroxynitrite-mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide-conjugated fluorescent particle immunoassay, peroxynitrite-mediated nitration activity with a detection limit of ≈100 × 10−9m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell-based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.
Campbell IC, Hannon BG, Read AT, et al., 2017, Quantification of the efficacy of collagen cross-linking agents to induce stiffening of rat sclera (vol 14, 20170014, 2017), Journal of the Royal Society Interface, Vol: 14, ISSN: 1742-5662
The concept of scleral stiffening therapies has emerged as a novel theoretical approach for treating the ocular disorders glaucoma and myopia. Deformation of specific regions of the posterior eye is innately involved in the pathophysiology of these diseases, and thus targeted scleral stiffening could resist these changes and slow or prevent progression of these diseases. Here, we present the first systematic screen and direct comparison of the stiffening effect of small molecule collagen cross-linking agents in the posterior globe, namely using glyceraldehyde, genipin and methylglyoxal (also called pyruvaldehyde). To establish a dose–response relationship, we used inflation testing to simulate the effects of increasing intraocular pressure in freshly harvested rat eyes stiffened with multiple concentrations of each agent. We used digital image correlation to compute the mechanical strain in the tissue as a metric of stiffness, using a novel treatment paradigm for screening relative stiffening by incubating half of each eye in cross-linker and using the opposite half as an internal control. We identified the doses necessary to increase stiffness by approximately 100%, namely 30 mM for glyceraldehyde, 1 mM for genipin and 7 mM for methylglyoxal, and we also identified the range of stiffening it was possible to achieve with such agents. Such findings will inform development of in vivo studies of scleral stiffening to treat glaucoma and myopia.
Stowell C, Burgoyne CF, Tamm ER, et al., 2017, Biomechanical aspects of axonal damage in glaucoma: A brief review, EXPERIMENTAL EYE RESEARCH, Vol: 157, Pages: 13-19, ISSN: 0014-4835
Tamm ER, Ethier CR, 2017, Biological aspects of axonal damage in glaucoma: A brief review, EXPERIMENTAL EYE RESEARCH, Vol: 157, Pages: 5-12, ISSN: 0014-4835
Feola AJ, Coudrillier B, Mulvihill J, et al., 2017, Deformation of the Lamina Cribrosa and Optic Nerve Due to Changes in Cerebrospinal Fluid Pressure, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 58, Pages: 2070-2078, ISSN: 0146-0404
Raykin J, Snider E, Bheri S, et al., 2017, A modified gelatin zymography technique incorporating total protein normalization, ANALYTICAL BIOCHEMISTRY, Vol: 521, Pages: 8-10, ISSN: 0003-2697
Raykin J, Forte TE, Wang R, et al., 2017, Characterization of the mechanical behavior of the optic nerve sheath and its role in spaceflight-induced ophthalmic changes, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 16, Pages: 33-43, ISSN: 1617-7959
Tam LC, Reina-Torres E, Sherwood JM, et al., 2017, Enhancement of outflow facility in the murine eye by targeting selected tight-junctions of Schlemm's canal endothelia, Scientific Reports, Vol: 7, ISSN: 2045-2322
The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm’s canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.
Coudrillier B, Campbell IC, Read AT, et al., 2016, Effects of Peripapillary Scleral Stiffening on the Deformation of the Lamina Cribrosa, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 57, Pages: 2666-2677, ISSN: 0146-0404
Feola AJ, Myers JG, Raykin J, et al., 2016, Finite Element Modeling of Factors Influencing Optic Nerve Head Deformation Due to Intracranial Pressure, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 57, Pages: 1901-1911, ISSN: 0146-0404
Stockslager MA, Samuels BC, Allingham RR, et al., 2016, System for Rapid, Precise Modulation of Intraocular Pressure, toward Minimally-Invasive In Vivo Measurement of Intracranial Pressure, PLOS ONE, Vol: 11, ISSN: 1932-6203
Brady MA, Talvard L, Vella A, et al., 2015, Bio-inspired design of a magnetically active trilayered scaffold for cartilage tissue engineering, Journal of Tissue Engineering and Regenerative Medicine, Vol: 11, Pages: 1298-1302, ISSN: 1932-6254
An important topic in cartilage tissue engineering is the development of biomimetic scaffolds which mimic the depth/dependent material properties of the native tissue. We describe an advanced trilayered nanocomposite hydrogel (ferrogel) with a gradient in compressive modulus from the top to the bottom layers (p<0.05) of the construct. Further, the scaffold was able to respond to remote external stimulation,exhibiting an elastic, depth/dependent strain gradient. When bovine chondrocytes were seeded into the ferrogels and cultured for up to 14 days, there was good cell viability and a biochemical gradient was measured with sulfated glycosaminoglycan increasing with depth from the surface. This novel construct provides tremendous scope for tailoring location/specific cartilage replacement tissue; by varying the density of magnetic nanoparticles, concentration of base hydrogel and number of cells, physiologically relevant depth/dependent gradients may be attained.
Braakman ST, Moore JE, Ethier CR, et al., 2015, Transport across Schlemm's canal endothelium and the blood-aqueous barrier, Experimental Eye Research, Vol: 146, Pages: 17-21, ISSN: 0014-4835
The majority of trabecular outflow likely crosses Schlemm's canal (SC) endothelium through micron-sized pores, and SC endothelium provides the only continuous cell layer between the anterior chamber and episcleral venous blood. SC endothelium must therefore be sufficiently porous to facilitate outflow, while also being sufficiently restrictive to preserve the blood-aqueous barrier and prevent blood and serum proteins from entering the eye. To understand how SC endothelium satisfies these apparently incompatible functions, we examined how the diameter and density of SC pores affects retrograde diffusion of serum proteins across SC endothelium, i.e. from SC lumen into the juxtacanalicular tissue (JCT). Opposing retrograde diffusion is anterograde bulk flow velocity of aqueous humor passing through pores, estimated to be approximately 5 mm/s. As a result of this relatively large through-pore velocity, a mass transport model predicts that upstream (JCT) concentrations of larger solutes such as albumin are less than 1% of the concentration in SC lumen. However, smaller solutes such as glucose are predicted to have nearly the same concentration in the JCT and SC. In the hypothetical case that, rather than micron-sized pores, SC formed 65 nm fenestrae, as commonly observed in other filtration-active endothelia, the predicted concentration of albumin in the JCT would increase to approximately 50% of that in SC. These results suggest that the size and density of SC pores may have developed to allow SC endothelium to maintain the blood-aqueous barrier while simultaneously facilitating aqueous humor outflow.
Boussommier-Calleja A, Li G, Wilson A, et al., 2015, Physical factors affecting outflow facility measurements in mice, Investigative Ophthalmology & Visual Science, Vol: 56, Pages: 8331-8339, ISSN: 1552-5783
Purpose: Mice are commonly used to study conventional outflow physiology. This study examined how physical factors (hydration, temperature, and anterior chamber [AC] deepening) influence ocular perfusion measurements in mice.Methods: Outflow facility (C) and pressure-independent outflow (Fu) were assessed by multilevel constant pressure perfusion of enucleated eyes from C57BL/6 mice. To examine the effect of hydration, seven eyes were perfused at room temperature, either immersed to the limbus in saline and covered with wet tissue paper or exposed to room air. Temperature effects were examined in 12 eyes immersed in saline at 20°C or 35°C. Anterior chamber deepening was examined in 10 eyes with the cannula tip placed in the anterior versus posterior chamber (PC). Posterior bowing of the iris (AC deepening) was visualized by three-dimensional histology in perfusion-fixed C57BL/6 eyes and by spectral-domain optical coherence tomography in living CD1 mice.Results: Exposure to room air did not significantly affect C, but led to a nonzero Fu that was significantly reduced upon immersion in saline. Increasing temperature from 20°C to 35°C increased C by 2.5-fold, more than could be explained by viscosity changes alone (1.4-fold). Perfusion via the AC, but not the PC, led to posterior iris bowing and increased outflow.Conclusions: Insufficient hydration contributes to the appearance of pressure-independent outflow in enucleated mouse eyes. Despite the large lens, AC deepening may artifactually increase outflow in mice. Temperature-dependent metabolic processes appear to influence conventional outflow regulation. Physical factors should be carefully controlled in any outflow studies involving mice.
Ethier CR, Morrison JC, Clark AF, 2015, Introduction to special issue on glaucomatous optic neuropathy: In vivo models and techniques, EXPERIMENTAL EYE RESEARCH, Vol: 141, Pages: 1-2, ISSN: 0014-4835
Nguyen TD, Ethier CR, 2015, Biomechanical assessment in models of glaucomatous optic neuropathy, EXPERIMENTAL EYE RESEARCH, Vol: 141, Pages: 125-138, ISSN: 0014-4835
Amin HD, Ethier CR, 2015, Differential effects of tyrosine-rich amelogenin peptide on chondrogenic and osteogenic differentiation of adult chondrocytes, Cell and Tissue Research, Vol: 364, Pages: 219-224, ISSN: 1432-0878
Current approaches to treat osteoarthritis (OA) are insufficient. Autologous chondrocyte implantation (ACI) has been used for the past decade to treat patients with OA or focal cartilage defects. However, a number of complications have been reported post-ACI, including athrofibrosis and symptomatic hypertrophy. Thus, a long term ACI strategy should ideally incorporate methods to ‘prime’ autologous chondrocytes to form cartilage-specific matrix and suppress hypertrophic mineralization. The objective of this study was to examine the effects of tyrosine rich amelogenin peptide (TRAP; an isoform of the develop mental protein amelogenin) on human articular cartilage cell (HAC) chondrogenic differentiation and hypertrophic mineralization in vitro. Effects of chemically synthesized TRAP on HAC chondrogenic differentiation were determined by assessing: (i) sGAG production; (ii) Alcian blue staining for proteoglycans; (iii) Collagen type II immunostaining; and (iv) Expression of the chondrogenic genes SOX9, ACAN and COL2A1. Hypertrophic mineralization was assayed by: (i) ALP expression; (ii) Alizarin red staining for Ca+2 -rich bone nodules; (iii) OC immunostaining; and (iv) Expression of the Osteogenic/Hypertrophic genes Ihh and BSP. Chemically synthesized TRAP was found to suppress terminal osteogenic differentiation of HACs cultured in hype rtrophic mineralization-like conditions, an effect mediated via down regulation of the Ihh gene. Moreover, TRAP was found to augment chondrogenic differentiation of HACs via induction of SOX9 gene expression when cells were cultured in pro-chondrogenic media. The results obtained from this proof of concept study motivate further studies on the use of TRAP as part of a preconditioning regimen in autologous chondrocyte implantation procedures for OA patients and patients suffering from focal cartilage defects.
Vargas-Pinto R, Lai J, Gong H, et al., 2015, Finite element analysis of the pressure-induced deformation of Schlemm's canal endothelial cells, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 14, Pages: 851-863, ISSN: 1617-7959
Chang JYH, Stamer WD, Bertrand J, et al., 2015, Role of nitric oxide in murine conventional outflow physiology, American Journal of Physiology - Cell Physiology, Vol: 309, Pages: C205-C214, ISSN: 0363-6143
Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Exogenous nitric oxide (NO) decreases IOP by increasing outflow facility, but whether endogenous NO production contributes to the physiological regulation of outflow facility is unclear. Outflow facility was measured by pressure-controlled perfusion in ex vivo eyes from C57BL/6 wild-type (WT) or transgenic mice expressing human endothelial NO synthase (eNOS) fused to green fluorescent protein (GFP) superimposed on the endogenously expressed murine eNOS (eNOS-GFPtg). In WT mice, exogenous NO delivered by 100 μM S-nitroso-N-acetylpenicillamine (SNAP) increased outflow facility by 62 ± 28% (SD) relative to control eyes perfused with the inactive SNAP analog N-acetyl-d-penicillamine (NAP; n = 5, P = 0.016). In contrast, in eyes from eNOS-GFPtg mice, SNAP had no effect on outflow facility relative to NAP (−9 ± 4%, P = 0.40). In WT mice, the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10 μM) decreased outflow facility by 36 ± 13% (n = 5 each, P = 0.012), but 100 μM l-NAME had no detectable effect on outflow facility (−16 ± 5%, P = 0.22). An eNOS-selective inhibitor (cavtratin, 50 μM) decreased outflow facility by 19 ± 12% in WT (P = 0.011) and 39 ± 25% in eNOS-GFPtg (P = 0.014) mice. In the conventional outflow pathway of eNOS-GFPtg mice, eNOS-GFP expression was localized to endothelial cells lining Schlemm's canal and the downstream vessels, with no apparent expression in the trabecular meshwork. These results suggest that endogenous NO production by eNOS within endothelial cells of Schlemm's canal or downstream vessels contributes to the physiological regulation of aqueous humor outflow facility in mice, representing a viable strategy to more successfully lower IOP in glaucoma.
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