Implementation and application of a Monte Carlo model for an in vivo micro computed tomography system.

Micro computed tomography (µCT) scanners are used to create high-resolution images and to quantify properties of the scanned objects. While modern µCT scanners benefit from the cone beam geometry, they are compromised by scatter radiation. This work aims to develop a Monte Carlo (MC) model of a µCT scanner in order to characterize the scatter radiation in the detector plane. The EGS++ framework with the MC code EGSnrc was used to simulate the particle transport through the main components of the XtremeCT (SCANCO Medical AG, Switzerland). The developed MC model was based on specific information of the manufacturer and was validated against measurements. The primary and the scatter radiation were analyzed and by implementing a dedicated tracing method, the scatter radiation was subdivided into different scatter components. The comparisons of measured and simulated transmission values for different absorber and filter combinations result in a mean difference of 0.2% ±â€¯1.4%, with a maximal local difference of 3.4%. The reconstructed image of the phantom based on measurements agrees well with the image reconstructed using the MC model. The local contribution of scattered radiation is up to 10% of the total radiation in the detector plane and most of the scattered particles result from interactions in the scanned object. The MC simulations show that scatter radiation contains information about the structure of the object. In conclusion, a MC model for a µCT scanner was successfully validated and applied to analyze the characteristics of the scatter radiation for a µCT scanner.

Outcome of intravitreal dexamethasone implant for the treatment of ranibizumab-resistant macular edema secondary to retinal vein occlusion.

To assess the effect of intravitreal dexamethasone implant (Ozurdex) for the treatment of macular edema secondary to retinal vein occlusion (RVO) resistant to repeated intravitreal ranibizumab injection. Retrospective review of 11 patients (11 eyes) with ranibizumab-resistant macular edema secondary to RVO. Macular edema was considered refractory to ranibizumab if no change of the pattern of macular fluid on optical coherence tomography and no change of best-corrected visual acuity (BCVA) was observed after at least three consecutive monthly injections, excluding the loading dose. A single Ozurdex injection was performed and BCVA and central foveal thickness (CFT) were reviewed 2, 3, and 6 months after treatment. Mean BCVA improved significantly from 0.51 logarithm of the minimal angle of resolution (log MAR) at baseline to 0.3 log MAR (p = 0.03) at 2 months and 0.29 log MAR (p = 0.003) at 3 months. There was no significant difference in the BCVA between baseline at 6 months (p = 0.62). Mean CFT reduced significantly from 538 µm at baseline to 281 µm at 2 months (p = 0.00003), 281 µm at 3 months (p = 0.00003), and 445 µm at 6 months (p = 0.03). Treatment with Ozurdex results in improvement of BCVA and reduction of CFT in patients with ranibizumab refractory macular edema due to RVO at 3 months. However, it seems that the visual acuity gain may not last up to 6 months, so that a re-injection before this time point could be considered.

20 g PPV with indocyanine green-assisted ILM peeling versus 23 g PPV with brilliant blue G-assisted ILM peeling for epiretinal membrane.

To compare the anatomical and visual outcomes of 20 gauge (g) pars plana vitrectomy (PPV) with indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling and 23 g PPV with brilliant blue G (BBG)-assisted ILM peeling for idiopathic epiretinal membrane (ERM). 38 eyes of 38 patients with idiopathic ERM were included. They were divided in two groups: group 1 (18 eyes) underwent 20 g PPV with ICG-assisted ILM peeling and group 2 (20 eyes) 23 g PPV with BBG-assisted ILM peeling. Postoperative best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared. Average BCVA in group 1 improved significantly from 0.60 logarithm of the minimal angle of resolution (log MAR) at baseline to 0.3 log MAR postoperatively. Average BCVA in group 2 improved significantly from 0.60 log MAR at baseline to 0.3 log MAR postoperatively. Mean CMT reduced significantly from 473 to 375 µm in group 1 and from 486 to 396 µm in group 2. There were no significant differences in the BCVA and CMT between the groups. Both surgical methods appeared to be safe and provided similar anatomical and visual outcomes.

Diagnostic Accuracy of Quantitative and Qualitative Phase-Contrast Imaging for the ex Vivo Characterization of Human Coronary Atherosclerotic Plaques.

PURPOSE: To investigate the accuracy of x-ray grating interferometry phase-contrast (PC) imaging for the characterization of human coronary artery plaque. MATERIALS AND METHODS: PC and conventional absorption computed tomographic (CT) imaging was performed ex vivo in this institutional review board-approved study in 40 human coronary artery segments by using a synchrotron radiation source. Qualitative analyses and calculations of image quality (McNemar test), plaque components (McNemar test), and plaque classification (Cohen κ test) according to the American Heart Association classification were performed in 38 plaques detected at histopathologic examination (reference standard). Quantitative measurements of plaque components (ie, collagen, lipids, smooth muscle, and calcifications) were compared among PC and absorption images by using analysis of variance for repeated measures with post hoc Bonferroni correction. RESULTS: Image quality was superior in PC (median image score, 1) in all cases (100%) compared with absorption imaging (median image score, 3) (P < .001). Plaque components were detected by means of PC without significant differences (seven of seven calcifications, 22 of 22 plaques with collagen and smooth muscle cells, P > .99; 29 of 29 plaques with lipids, P = .10) with histopathologic findings, whereas absorption imaging was used to detect calcifications (seven of seven, P > .99) without statistical differences only (nine of 29 plaques with lipids, 0 of 22 plaques with collagen and smooth muscle cells, P < .001). Accuracy for plaque stage assessment with PC (early vs advanced) was 100%, and characterization was correct in 33 of 38 plaques (87%), while conventional absorption imaging allowed correct characterization of seven plaques only (18%, P < .001). PC CT numbers were significantly different (P < .05) for all plaque components (mean for calcifications, 1236 HU ± 69; collagen, 78 HU ± 24; lipids, -18 HU ± 23; and smooth muscle cells, 34 HU ± 12), whereas absorption images showed significant differences (P < .001) between calcifications (1336 HU ± 241) and other plaque components, but not for collagen (22 HU ± 13), lipids (-15 HU ± 14), and smooth muscle (13 HU ± 9) (P > .99). CONCLUSION: PC imaging allows accurate characterization of human coronary artery plaques and quantitative assessment of plaque components, thereby outperforming absorption imaging.

Multiple scattering tomography.

Multiple scattering represents a challenge for numerous modern tomographic imaging techniques. In this Letter, we derive an appropriate line integral that allows for the tomographic reconstruction of angular resolved scattering distributions, even in the presence of multiple scattering. The line integral is applicable to a wide range of imaging techniques utilizing various kinds of probes. Here, we use x-ray grating interferometry to experimentally validate the framework and to demonstrate additional structural sensitivity, which exemplifies the impact of multiple scattering tomography.

Combining Monte Carlo methods with coherent wave optics for the simulation of phase-sensitive X-ray imaging.

Phase-sensitive X-ray imaging shows a high sensitivity towards electron density variations, making it well suited for imaging of soft tissue matter. However, there are still open questions about the details of the image formation process. Here, a framework for numerical simulations of phase-sensitive X-ray imaging is presented, which takes both particle- and wave-like properties of X-rays into consideration. A split approach is presented where we combine a Monte Carlo method (MC) based sample part with a wave optics simulation based propagation part, leading to a framework that takes both particle- and wave-like properties into account. The framework can be adapted to different phase-sensitive imaging methods and has been validated through comparisons with experiments for grating interferometry and propagation-based imaging. The validation of the framework shows that the combination of wave optics and MC has been successfully implemented and yields good agreement between measurements and simulations. This demonstrates that the physical processes relevant for developing a deeper understanding of scattering in the context of phase-sensitive imaging are modelled in a sufficiently accurate manner. The framework can be used for the simulation of phase-sensitive X-ray imaging, for instance for the simulation of grating interferometry or propagation-based imaging.

Living-engineered valves for transcatheter venous valve repair.

BACKGROUND: Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential. METHODS: Tri- and bicuspid venous valves (n=27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone-marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. RESULTS: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase. CONCLUSIONS: Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.

Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model.

Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs.

Engineering of living autologous human umbilical cord cell-based septal occluder membranes using composite PGA-P4HB matrices.

Interventional closure of intracardiac wall defects using occluder devices has evolved as a highly attractive treatment option. However, incomplete and delayed healing reactions often result in a major risk of residual defects, thromboembolism, or device fractures. Biodegradable living tissue engineered occluder membranes (TEOMs) could provide autologous thromboresistant implants with growth and remodeling capacities. PGA-P4HB composite matrices were seeded with human umbilical cord-derived cells or vascular-derived control cells and exposed to static (n = 19) or dynamic (n = 13) conditioning. Harvested TEOMs were integrated into occluder frameworks, exposed to crimping and delivered into pre-formed defects of juvenile porcine hearts. Dynamically conditioned TEOM constructs showed higher collagen formation in histology than static constructs with significantly higher stiffness moduli in uniaxial tensile testing. Grating interferometry revealed substantial but inhomogeneous cone-like degradation of the composite matrices in dynamic conditioning. The crimping and delivery procedures resulted in no significant changes in macroscopy, histo-morphology, cellular viability, DNA or hydroxyproline content, and scanning electron microscopy findings. Here, we present the in vitro fabrication, crimping and experimental delivery of living human umbilical cord-cell derived TEOMs based on composite matrices as a potential future autologous therapy of intracardiac wall defects.

Ocular photodynamic therapy--standard applications and new indications. Part 2. Review of the literature and personal experience.

Photodynamic therapy (PDT) has become a well-established treatment for vascular forms of age-related macular degeneration (AMD). The implementation of evidence-based medicine principles into the treatment regimen of AMD seems to be immensly important, since AMD continues to be the most frequent cause of blindness among patients older than 65 years in industrialized countries. Numerous randomized prospective studies demonstrated high levels of evidence for the efficacy of various treatment approaches such as laser photocoagulation, PDT, subretinal surgery or novel anti-angiogenic drugs [Arch Ophthalmol 2006;124:597-599]. The high evidence shown by these studies supported the rationale to use PDT also in additional, less frequent, vasoproliferative diseases. Although these 'case series' and 'individual case control studies' have a low level of evidence, they give us important information for treatment decisions in these rare conditions. The goal of this survey is to review the current literature regarding PDT in vasoproliferative and exudative ocular diseases outside AMD. Many studies modified the treatment parameters of PDT to address the specific pathology of the underlying disease. Table 1 summarizes the diseases and treatment parameters that are described in this part 2, the entire table of this review is included in part 1 (www.karger.com/doi/10.1159/ 000101922).

Accessory optical device for the Heidelberg retina angiograph (HRA classic) to perform angiography of the vitreous cavity and the anterior eye segment.

The Heidelberg retina angiograph (HRA) classic enables fluorescein angiography (FA) and indocyanine green angiography (ICG-A) of the retina and choroid. The goal of this study was to design an accessory device to adapt the HRA classic for application on structures anterior to the retina. The optical device consisted of a cylindrical two-piece plastic frame holding a magnifying lens commonly used with the indirect ophthalmoscope. A 60-diopters lens was inserted in this frame to enable the angiography of the anterior segment. A less strong lens of 30 diopters was used for the visualization of pathologic findings in the vitreous cavity. We designed an easy-to-use and low-cost device to adapt the HRA classic for angiography of the fundus, vitreous cavity and anterior segment in the same session and without delay. FA and ICG-A images of two patients with rubeosis iridis and of one patient with choroidal melanoma are described.

Ocular photodynamic therapy--standard applications and new indications (part 1). Review of the literature and personal experience.

Ocular photodynamic therapy (PDT) was introduced as a novel treatment for neovascular forms of age-related macular degeneration and choroidal neovascularization (CNV) secondary to pathologic myopia in the mid/end 1990s. The current treatment recommendations are based on the results of two large, prospective, multicenter, randomized clinical trials (Treatment of Age-Related Macular Degeneration with Photodynamic Therapy and Verteporfin in Photodynamic Therapy Studies) and thousands of patients have been treated worldwide over the last years. Meanwhile, PDT has been performed in several other ocular pathologies with some remarkable results, however, with most reports being case reports and small case series without statistical significance. These extended applications include CNV secondary to choroiditis and retinochoroiditis, angioid streaks, central serous chorioretinopathy, retinal angiomatous proliferation, parafoveal telangiectasia or CNV associated with macular dystrophy and idiopathic CNV, as well as diseases without CNV, such as choroidal hemangioma, retinal hamartoma, choroidal melanoma, chronic central serous chorioretinopathy, angiomatous lesions secondary to systemic diseases, rubeosis iridis or neovascular glaucoma. To date, with the introduction of anti-VEGF therapy, the role of PDT will certainly change. However, it is reasonable to believe that it will maintain an important role in combination therapy due to its unique properties of selective vascular targeting. Therefore, it is essential for the ophthalmologist to be familiar with the extended applications and their modifications of treatment parameters. This review will summarize the standard and experimental applications of PDT based on our own results and the literature.

Current treatment modalities for exudative retinal hamartomas secondary to tuberous sclerosis: review of the literature.

BACKGROUND: Retinal hamartoma is a common finding in tuberous sclerosis, but the symptomatic changes of this lesion have rarely been described. This evidence-based review evaluated the incidence of symptomatic retinal hamartoma and compared possible treatment modalities. METHODS: We carried out a review of the literature using MEDLINE. Older publications not listed in MEDLINE were obtained from the reference list of currently published papers. RESULTS: Three observational case series with a follow-up of up to 34 years included 93 patients and reported progression from a flat to a more elevated lesion without visual symptoms in nine patients (9.7%). Additional symptomatic changes were described in 11 case reports published over a period of three decades. The symptomatic alterations were caused by an enlarged tumour with leakage, macular oedema, accumulating lipoid exudates, serous retinal detachment (n = 8/11) and vitreous haemorrhage (n = 4/11). Most symptomatic cases involved a retinal hamartoma type 1 (n = 6/8). Spontaneous resolution of symptomatic exudative hamartomas occurred in three patients within 4 weeks, although a delayed resorption of subretinal fluid caused permanent visual impairment in one patient. Investigational reports described a slow resorption of subretinal fluid after argon laser photocoagulation (n = 2), although recurrent laser applications induced choroidal neovascularization and destruction of the neurosensory retina (n = 1). A vitrectomy was used to remove a vitreous haemorrhage in another reported patient. In one case, complete resorption of subretinal fluid and an increase in visual acuity was observed within 2 weeks after a single treatment with photodynamic therapy (PDT). No complications were noted during a follow-up of 4 years. CONCLUSIONS: Symptomatic changes are very rare in retinal hamartomas secondary to tuberous sclerosis. Spontaneous resolution of subretinal fluid may occur within 4 weeks. If a macular oedema with increasing lipoid exudates persists over a period of 6 weeks, treatment should be considered. Although previous reports demonstrated possible visual stabilization after argon laser photocoagulation, vision-threatening complications can occur. Current treatment strategies may include PDT based on favourable anatomical and functional results.

Retinal branch artery occlusion following injection of hyaluronic acid (Restylane).

The authors report a retinal branch artery occlusion occurring after facial injection of a dermal filler. The superior temporal artery showed occlusion due to a clearly visible long and fragmented embolus suggestive of gel and clearly distinguishable from calcific or cholesterol emboli. The authors suppose that hyaluronic acid gel was embolized in the patient. The embolized material is supposed to enter the ocular circulation through retrograde arteriolar flow after intra-arterial injection into one of the peripheral branches of the ophthalmic artery. If there is any evidence of a visual problem after facial injection of a dermal filler, prompt consultation of an ophthalmologist is recommended.

Effect of photodynamic therapy on the function of the outer blood-retinal barrier in an in vitro model.

BACKGROUND: Photodynamic therapy (PDT) is a well established clinical treatment for age-related macular degeneration (AMD), and comprises intravenous injection of verteporfin and subsequent application of a non-thermal laser beam to the area of AMD to induce selective vascular occlusion. Since there is evidence that PDT may cause outer blood-retinal barrier (BRB) breakdown and possibly RPE cell alteration, we investigated the effect of PDT on the BRB function of the RPE in an in vitro model. METHODS: Twenty-one monolayers of human RPE cells were cultured on semipermeable membranes until a stable barrier function was achieved as determined by transepithelial electrical resistance (TER) and sodium fluorescein permeability. To test the effect of PDT on the outer BRB function, non-thermal laser (692 nm), verteporfin or a combination of both were applied. TER assessment prior to and after PDT was utilized to identify changes in barrier function of the RPE in this in vitro model. Finally, monolayers of RPE cells were evaluated by transmission electron microscopy (TEM). RESULTS: No significant TER decrease was observed after application of non-thermal laser alone or after administration of verteporfin in therapeutic concentrations, but combination of these modalities resulted in significantly decreased TER within 4 h. Except for intercellular blisters, no damage to the RPE was evident in TEM. Verteporfin added at concentrations higher than therapeutic doses (2 mg/ml) resulted in an immediate decrease in TER and damage to the RPE cells. CONCLUSION: The combination of a therapeutic concentration of verteporfin and application of non-thermal laser resulted in a morphologically and functionally detectable breakdown of the outer BRB function of the RPE without any damage to the RPE cells themselves in vitro. However, increasing the concentration of verteporfin can result in RPE cell damage.

Autofluorescence and angiographic findings of retinal astrocytic hamartomas in tuberous sclerosis.

OBJECTIVE: To describe fundus autofluorescence (AF), fluorescein angiography (FA) and indocyanine green angiography (ICGA) in different types of retinal astrocytic hamartomas in tuberous sclerosis (Morbus Bourneville-Pringle). METHODS: Two eyes with 8 lesions, i.e. type 1 (n = 7) and type 3 (n = 1), were examined. AF pictures were taken prior to injection, FA and ICGA images were obtained in the early and the late phase. To achieve additional cases, a systematic literature review with exten- sive Internet and library search was performed. RESULTS: Strong AF was seen in type 2 and type 3 retinal astrocytic hamartomas, whereas type 1 lesions blocked the physiologic fundus AF. Fluorescence angiography of all types of lesions revealed hypofluorescence in early frames and hyperfluorescence originating from leakage in late frames. ICGA showed a subtle blockade in type 1, a total blockade in type 2 and in the central part and a partial blockade in the peripheral part in type 3 lesions. CONCLUSIONS: Retinal astrocytic hamartomas in tuberous sclerosis can be easily detected by angiography, especially type 1 lesions which are difficult to visualize by funduscopy. Early- and late-phase fluorescein angiography and ICGA are helpful to differentiate the three lesion types.