Retinal function after intravitreal injection of autologous bone marrow-derived mesenchymal stromal cells in advanced glaucoma.

PURPOSE: To report electroretinographic (ERG) findings in advanced glaucoma treated with a single intravitreal injection of bone marrow-derived mesenchymal stem cells (MSCs). METHODS: Intravitreal injection of autologous MSCs (1 × 106 cells) was performed in 2 eyes from 2 patients with open-angle glaucoma in advanced stage of optic neuropathy (ClinicalTrials.gov, NCT02330978, 01.05.2015): cup/disk ratio worse than 0.9, visual field mean deviation index lower than - 15 dB, visual acuity of light perception, but controlled intraocular pressure. ERG tests were recorded at baseline and week 1, 4 and 48 after injection, using DTL electrodes following the ISCEV standard: After dark adaptation, ERG was elicited using white flashes of 0.01 cd.s/m2 and 3.0 cd.s/m2, followed by 10-min light adaptation (30 cd/m2) and stimuli of 3.0 cd.s/m2 and 30 Hz flicker. RESULTS: Patients did not show improvement on visual acuity or visual field after treatment. At baseline, ERG responses showed typical findings for advanced glaucoma, with a- and b-wave amplitude and latency within normative range, but reduced photopic negative responses. No noteworthy changes were observed on ERG responses for both cases up to 1 week after treatment, but at day 15, one patient showed retinal detachment with proliferative vitreoretinopathy and was removed from the trial. The other patient kept ERG responses stable throughout study period. CONCLUSION: Although no ERG response changes were observed after MSCs injection in one case, the complication observed on the second one, along with the lack of visual function improvement, warrants further studies involving modified MSCs to treat ocular disorders, including glaucoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02330978- missed in pdf.

Bevacizumab versus triamcinolone for persistent diabetic macular edema: a randomized clinical trial.

PURPOSE: To evaluate 24-week visual acuity and anatomic outcomes of two "pro re nata" (prn) treatment strategies (intravitreal bevacizumab [IVB] prn versus intravitreal triamcinolone acetonide [IVT] prn) in patients with persistent diabetic macular edema (pDME) after 24 weeks of prn-IVB. METHODS: One hundred eyes with center-involving DME were enrolled and treated with prn-IVB for 24 weeks; at week 24, eyes with pDME (central subfield thickness [CST] on spectral domain optical coherence tomography > 300 µm) were randomized to IVB monthly prn (group I; prn-IVB) or IVT every 3 months prn (group II; prn-IVT) and eyes in which the CST was ≤ 300 µm were assigned to continue prn-IVB (group III). RESULTS: Seventy-four eyes completed a 48-week study period. At week 24, 65 (79.3%) eyes still had DME with CST > 300 µm and, therefore, were randomized to prn-IVB (group I, n = 33) or prn-IVT (group II, n = 32); the remaining 17 (20.7%) eyes had CST ≤ 300 µm and were assigned to continued treatment with prn-IVB (group III). At baseline, mean CST (µm) ± standard error of the mean (SEM) was 447.2 ± 24.4, 478.0 ± 19.7, and 386.0 ± 21.0 in groups I, II, and III, respectively (p > 0.05). At week 48, there was no significant difference in mean CST between groups I and II (369.9 ± 23.3 and 426.0 ± 26.1, respectively; p = 0.9995). A significant reduction in mean CST, compared with baseline, was noted at weeks 28 (p = 0.0002) and 44 (p = 0.0002) in group II. Group I did not show a significant reduction in mean CST compared with baseline at any study visit. There were no significant differences in mean CST between groups I and II at any study visit. At baseline, mean ± SEM best-corrected visual acuity (BCVA) (logMAR) was 0.50 ± 0.00, 0.60 ± 0.10, and 0.50 ± 0.10 in groups I, II, and III, respectively (p > 0.05). At week 48, there was no statistically significant difference in mean BCVA between groups I and II (0.50 ± 0.10 and 0.80 ± 0.10, respectively; p = 0.4473). There was no significant improvement in mean BCVA, as compared with baseline, at any study follow-up visit in any of the groups. Group II demonstrated significantly lower BCVA after 24 weeks of IVT (at week 48) compared with baseline (p = 0.0435). There was no significant difference in mean BCVA between groups I and II at any time-point. CONCLUSION: In eyes with pDME after 24 weeks of treatment with prn-IVB, there was no difference between continued treatment with prn-IVB versus a treatment switch to prn-IVT with respect to mean BCVA or mean CST at week 48. However, BCVA was stable in the prn-IVB group, while prn-IVT was associated with BCVA reduction from baseline and a higher risk of IOP elevation.

Ex vivo evaluation of intravitreal mesenchymal stromal cell viability using bioluminescence imaging.

BACKGROUND: Bone marrow-derived mesenchymal stromal cell (MSC) therapy is a promising treatment for several degenerative ocular diseases; however, no reproducible method of monitoring these cells into the eye has been established. The aim of this study was to describe successful bioluminescence imaging (BLI) to detect viable luciferase-expressing MSC in the eye. METHODS: Human donor MSC in culture were transduced with 50 µl luciferase lentiviral vector (three viral particles/cell) prior to intraocular injection. Twenty-one right eyes of 21 rabbits were evaluated through BLI after receiving 1 × 106 luciferase-expressing MSC intravitreally. Contralateral eyes were injected with vehicle (phosphate-buffered saline (PBS)) and were used as controls. At seven different time points (1 h to 60 days), D-luciferin (40 mg/ml, 300 µl PBS) was injected in subsets of six enucleated eyes for evaluation of radiance decay through BLI analysis. CD90 and CD73 immunofluorescence was studied in selected eyes. RESULTS: Eyes injected with MSC showed high BLI radiance immediately after D-luciferin injection and progressive decay until 60 days. Mean BLI radiance measures from eyes with luciferase-expressing MSC were significantly higher than controls from 8 h to 30 days. At the thirtieth day, positive CD90- and CD73-expressing cells were observed only in the vitreous cavity of eyes injected with MSC. CONCLUSIONS: Viable MSC were identified in the vitreous cavity 1 month after a single injection. Our results confirmed BLI as a useful and reliable method to detect MSC injected into the eye globe.

SAFETY AND FEASIBILITY OF A NOVEL 25-GAUGE BIODEGRADABLE IMPLANT OF DEXAMETHASONE FOR TREATMENT OF MACULAR EDEMA ASSOCIATED WITH RETINAL VEIN OCCLUSION: A PHASE I CLINICAL TRIAL.

PURPOSE: To evaluate the safety and feasibility of a 25-gauge biodegradable implant containing 350 µg of dexamethasone (DDS-25) for the treatment of decreased vision due to macular edema associated with central or branch retinal vein occlusion. METHODS: Prospective, nonrandomized, open-label, Phase I clinical trial, including 10 patients with decreased vision (best-corrected early treatment diabetic retinopathy study visual acuity of 20/40 or worse) due to macular edema associated with central retinal vein occlusion (n = 4) or branch retinal vein occlusion (n = 6) for more than 4 months. Comprehensive ophthalmic evaluation, including best-corrected visual acuity, spectral domain optical coherence tomography (Spectralis Heidelberg Engineering) for determination of central subfield thickness, full-field electroretinography (ISCEV standard ERG), and fluorescein angiography, was performed at baseline, and 1, 4, 12, and 24 weeks after intravitreal DDS-25 insertion. RESULTS: Mean best-corrected visual acuity was 0.72 ± 0.1 logMAR (20/100) at baseline and improved by 7 early treatment diabetic retinopathy study letters to 0.58 ± 0.08 logMAR (20/80 + 1) at 24 weeks (P = 0.049), with 3 central retinal vein occlusion and 3 branch retinal vein occlusion patients improving between 1 and 4 early treatment diabetic retinopathy study lines. Significant central subfield thickness reduction was observed at 24 weeks compared with baseline (P = 0.011); mean ± standard error (range) central subfield thickness (µm) was 461.2 ± 41.3 (288-701) at baseline, and 439.6 ± 40.4 (259-631), 442.5 ± 44.6 (255-632), 354.6 ± 31.2 (228-537), and 316.5 ± 26.4 (226-441) at 1, 4, 12, and 24 weeks, respectively. No significant changes in electroretinography responses or area of retinal nonperfusion were observed during 24 weeks of follow-up. There was no significant change in mean intraocular pressure at any of the study visits compared with baseline. One patient had mild anterior chamber inflammation (1-5 cells) at one week after DDS-25 insertion. CONCLUSION: In this Phase I study demonstrating the feasibility of intravitreal DDS-25 insertion for the treatment of decreased vision due to macular edema associated with retinal vein occlusion, no safety concerns were observed. A larger prospective randomized study with longer follow-up is warranted to confirm these findings.

Quality of life in patients with retinitis pigmentosa submitted to intravitreal use of bone marrow-derived stem cells (Reticell -clinical trial).

INTRODUCTION: Retinitis pigmentosa (RP) is a severe neurodegenerative disease of the retina that can lead to blindness. Even without treatment, a clinical study with the use of stem cells is currently underway and the results are being evaluated. In the present report we assess the vision-related quality of life in patients with RP submitted to intravitreal use of bone marrow-derived stem cells. METHOD: The study included 20 patients with RP submitted to intravitreal use of bone marrow-derived stem cells. We evaluate the vision-related quality of life (VRQOL) of patients using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). Patients were scheduled to answer the questionnaire before treatment and 3 and 12 months after treatment. RESULTS: All patients completed the survey as scheduled. There was a statistically significant improvement (P<0.05) in the quality of life of patients 3 months after treatment, whereas by the 12th month there was no statistically significant difference from baseline. CONCLUSIONS: Cell therapy with intravitreal use of bone marrow-derived stem cells can improve the quality of life of patients with RP, although the improvement is lost with time. A larger number of cases will be necessary to evaluate the repercussions of this therapy on the quality of life of these patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01560715 . Registered March 19, 2012.

Neuroprotective effects of intravitreal triamcinolone acetonide and dexamethasone implant in rabbit retinas after pars plana vitrectomy and silicone oil injection.

PURPOSE: To investigate potential retinal neuroprotective effects of intravitreal triamcinolone acetonide and dexamethasone implant in rabbits after pars plana vitrectomy and intravitreal silicone oil injection. METHODS: The right eyes of 84 rabbits, divided into 3 groups of 28 rabbits each, underwent standard 3-port pars plana vitrectomy with silicone oil (SO group), silicone oil and intravitreal dexamethasone implant (SO/DEX group), or silicone oil and triamcinolone acetonide (SO/TA group). The retina from the left eye of each rabbit served as a control. The animals were killed at 4 weeks after surgery. Qualitative and quantitative histopathologic analyses were performed 4 weeks after surgery, and investigation for apoptosis was performed using the Tunel assay. RESULTS: Intravitreal triamcinolone acetonide and dexamethasone implant were associated with increased retinal neuronal survival, primarily in the outer nuclear layer, inner nuclear layer, and ganglion cell layer. In the SO group, the cell density in eyes that underwent PPV/SO was 31% lower in the outer nuclear layer, 33% lower in the inner nuclear layer, and 45% lower in the ganglion cell layer compared to control eyes (p < 0.05 for all PPV/SO versus control comparisons). Compared to eyes that underwent PPV/SO, the cell density in eyes treated with triamcinolone was 27% higher in the outer nuclear layer, 66% higher in the inner nuclear layer, and 100% higher in the ganglion cell layer (p < 0.05 for all triamcinolone versus PPV/SO comparisons). Compared to eyes that underwent PPV/SO, the cell density in eyes treated with dexamethasone was 46% higher in the outer nuclear layer, 62% higher in the inner nuclear layer, and 77% higher in the ganglion cell layer (p < 0.05 for all dexamethasone versus PPV/SO comparisons). Analyses using the Tunnel assay demonstrated apoptotic bodies in all eyes in the SO group, compared with none of the eyes in the SO/TA and SO/DEX groups. The presence of cell nuclei stained with 49,6-diamidino-2-phenylindole (DAPI) was demonstrated in all groups. CONCLUSION: In this experimental model of neuroprotection, increased retinal neuronal survival was seen in the steroid-treated groups compared with the controls.

Determination of triamcinolone acetonide in silicone oil and aqueous humor of vitrectomized rabbits' eyes: Application for a pharmacokinetic study with intravitreal triamcinolone acetonide injections (Kenalog® 40).

A simple and accurate method including liquid-liquid extraction and protein precipitation procedures from silicone oil and aqueous humor samples followed by high-performance liquid chromatography (HPLC-UV) was developed and validated to determine the pharmacokinetic profile of triamcinolone acetonide in silicone oil and aqueous humor of rabbits' eyes submitted to the pars plana vitrectomy surgery. The method was successfully applied to quantify the drug remaining in silicone oil and aqueous humor (LOQ range of 1µg/mL). The triamcinolone acetonide remained in silicone oil and aqueous humor of vitrectomized rabbits' eyes for four weeks after the intravitreal injections.

Vitreous pharmacokinetics and retinal safety of intravitreal preserved versus non-preserved triamcinolone acetonide in rabbit eyes.

PURPOSE: To compare the intravitreal pharmacokinetic profile of a triamcinolone acetonide formulation containing the preservative benzyl alcohol (TA-BA) versus a preservative-free triamcinolone acetonide formulation (TA-PF), and evaluate potential signs of toxicity to the retina. METHODS: A total of 60 New Zealand male white rabbits, divided into two groups, were studied. In the TA-BA group, 30 rabbits received an intravitreal injection of TA-BA (4 mg/0.1 ml) into the right eye. In the TA-PF group, 30 rabbits received an intravitreal injection of TA-PF (4 mg/0.1 ml) into the right eye. The intravitreal drug levels were determined in 25 animals from each group by high-performance liquid chromatography (HPLC). The potential for toxicity associated with the intravitreal triamcinolone injections was evaluated in five randomly selected animals from each group by electroretinography (ERG) and by light microscopy. RESULTS: Median intravitreal concentrations of TA-BA (µg/ml) were 1903.1, 1213.0, 857.8, 442.0, 248.6 at 3, 7, 14, 21 and 28 days after injection. Intravitreal concentrations of TA-PF (µg/ml) were 1032.9, 570.1, 516.6, 347.9, 102.8 at 3, 7, 14, 21 and 28 days after injection. The median intravitreal triamcinolone concentration was significantly higher in the TA-BA compared to the TA-PF group at 7 days post-injection (p < 0.05). There was no significant difference between the two groups in median triamcinolone concentration at the other time points evaluated. There was no evidence of toxic effects on the retina in either group based on ERG or histological analyses. CONCLUSIONS: Following a single intravitreal injection, the median concentration of triamcinolone acetonide is significantly higher in the TA-BA compared to the TA-PF group at 7 days post-injection. No toxic reactions in the retina were observed in either group.

Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial.

PURPOSE: To evaluate the short-term (10 months) safety of a single intravitreal injection of autologous bone marrow-derived mononuclear cells in patients with retinitis pigmentosa or cone-rod dystrophy. METHODS: A prospective, Phase I, nonrandomized, open-label study including 3 patients with retinitis pigmentosa and 2 patients with cone-rod dystrophy and an Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/200 or worse. Evaluations including best-corrected visual acuity, full-field electroretinography, kinetic visual field (Goldman), fluorescein and indocyanine green angiography, and optical coherence tomography were performed at baseline and 1, 7, 13, 18, 22, and 40 weeks after intravitreal injection of 10 × 10(6) autologous bone marrow-derived mononuclear cells (0.1 mL) into 1 study eye of each patient. RESULTS: No adverse event associated with the injection was observed. A 1-line improvement in best-corrected visual acuity was measured in 4 patients 1 week after injection and was maintained throughout follow-up. Three patients showed undetectable electroretinography responses at all study visits, while 1 patient demonstrated residual responses for dark-adapted standard flash stimulus (a wave amplitude approximately 35 µV), which remained recordable throughout follow-up, and 1 patient showed a small response (a wave amplitude approximately 20 µV) recordable only at Weeks 7, 13, 22, and 40. Visual fields showed no reduction (with a Goldman Standard V5e stimulus) for any patient at any visit. No other changes were observed on optical coherence tomography or fluorescein and indocyanine green angiograms. CONCLUSION: Intravitreal injection of autologous bone marrow-derived mononuclear cells in eyes with advanced retinitis pigmentosa or cone-rod dystrophy was associated with no detectable structural or functional toxicity over a period of 10 months. Further studies are required to investigate the role, if any, of autologous bone marrow-derived mononuclear cell therapy in the management of retinal dystrophies.

Ocular findings in a patient with Castleman's disease before and after treatment with immunosuppression and plasmapheresis.

A 12-year-old girl with a 3-month history of epistaxis and Castleman's disease presented with blurred vision in both eyes for 2 weeks. Indirect ophthalmoscopy revealed a blurred optic disc margin, venous engorgement and tortuosity, intraretinal hemorrhages and cotton wool spots, and serous detachment of the neurosensory retina in the posterior pole of each eye. Fluorescein angiography and laboratory tests revealed abnormalities consistent with the clinical examination. Six months following institution of immunosuppressive treatment, cryoglobulin levels decreased and visual acuity and funduscopic abnormalities were markedly improved. However, a few microaneurysms, retinal hemorrhages, and venous engorgement and tortuosity persisted. One month after the cessation of immunosuppressive treatment, symptoms related to the hyperviscosity syndrome recurred and the patient was treated with one session of plasmapheresis. One month after the plasmapheresis, the patient's symptoms resolved, laboratory values were normal, visual acuity was 20/15 in both eyes, and the funduscopic examination of each eye was unremarkable.

Terapia celular nas doenças oftalmológicas / Cell therapy in ophthalmology diseases

Avanços no campo das células-tronco proporcionaram muita perspectiva para uso destas células na regeneração dos tecidos oculares danificados por doenças as quais não possuem tratamento disponível até o momento. Terapia baseada com células-tronco para regeneração e reparo ocular constitui uma esperança para a restauração da função visual em indivíduos com tecido oculares irreversivelmente danificados por doença ou trauma. Até o presente momento, somente as células LESC para o reparo da córnea apresentam aplicação clínica reconhecida no campo da oftalmologia. Experiências adquiridas com esta abordagem poderão potencialmente ajudar com o desenho de terapias baseadas em células-tronco para regenerar outros tecidos oculares particularmente a retina. Utilização de células-tronco adultas para tratamento de doenças degenerativas da retina tem sido testada e também sua viabilidade para utilização em humanos. Apesar de muitos problemas práticos, existe um otimismo geral entre a comunidade médica e científica que a terapia baseada nas células-tronco para restaurar a função visual pode tornar-se realidade em um futuro não muito distante. Neste manuscrito, foi realizada uma revisão do estado atual e limitações na aplicação de células-tronco para terapia ocular e consideramos as perspectivas futuras de seu uso na restauração da visão.

Advances in the field of stem cell therapy have provided promising results in the regeneration of tissues damaged by eye diseases for which treatment is so far unavailable. Therapy based on stem cells to regenerate and repair is a hope for the restoration of visual function in individuals with ocular tissue irreversibly damaged by disease or trauma. Until now, only limbal epithelial stem cells have a recognized clinical application in ophthalmology for the repair of the cornea. Experience gained with this approach, may potentially help with the design of therapies based on stem cells to regenerate other eye tissues, in particular the retina. The use of adult stem cells to treat degenerative diseases of the retina has been tested in animals, as has their feasibility for use in humans. Although many practical problems exist, there is general optimism among the medical and scientific community that therapy based on stem cells to restore visual function can become a reality in the not too distant future. This article reviews the current status and limitations of the application of stem cell therapy in the eye and considers future prospects of its use in the restoration of vision.

20-gauge transconjunctival pars plana vitrectomy.

This article describes a transconjunctival technique for pars plana vitrectomy using 20-gauge instruments. Sclerotomies are performed directly through the conjunctiva, Tenon's capsule, and sclera with a 19-gauge microvitreoretinal blade. A sutureless 20-gauge infusion cannula is then inserted and pars plana vitrectomy is performed in a standardized fashion using 20-gauge instruments. Each sclerotomy and its corresponding conjunctival incision is closed with a single stitch using a 7-0 polyglactin suture. This transconjunctival technique is a reasonable alternative surgical approach to minimize surgical trauma of tissues (eg, conjunctiva) and hasten postoperative recovery without the additional risks and costs associated with 25-gauge pars plana vitrectomy.

Pharmacokinetic and toxicity investigations of a new intraocular lens with a dexamethasone drug delivery system: a pilot study.

AIM: To investigate the short-term safety and pharmacokinetic behavior of a new intraocular lens containing a dexamethasone drug delivery system (IOL-DDS) in rabbit eyes. METHODS: A modified polymethylmethacrylate IOL containing a biodegradable dexamethasone DDS was implanted into the posterior chamber of the right eyes of 9 New Zealand white rabbits. Serial slitlamp and indirect ophthalmoscopic examinations (including grading of intraocular inflammation) were performed. After 3, 6 and 9 days, the rabbits were euthanized and the globes were removed for histological examination and for determination of dexamethasone levels in the aqueous humor and in the vitreous. Analysis of dexamethasone concentrations was performed by ELISA. RESULTS: Therapeutic concentrations of dexamethasone were detectable in the aqueous and vitreous of the study eyes throughout the 9-day period in all tested animals. The mean aqueous dexamethasone concentration (ng/ml, +/- SD) was 1,015.42 (+/- 43.05), 970.11 (+/- 32.47) and 757.58 (+/- 30.19) and the mean vitreous concentration (ng/ml, +/- SD) was 399.82 (+/- 38.05), 287.38 (+/-34.47) and 268.15 (+/- 32.00) at 3, 6 and 9 days after the surgical procedure, respectively. No corneal or retinal histological changes were observed during the study period. CONCLUSION: The IOL-DDS is effective in delivering therapeutic concentrations of dexamethasone to the aqueous and vitreous, without acute damage to the cornea and retina. Further controlled studies in the same animal model are under way to determine the potential value of this lens in the prevention and treatment of inflammation following cataract surgery.

Neuroprotective effects of intramuscular ketamine in rabbit retinas after pars plana vitrectomy and silicone oil injection.

PURPOSE: To investigate potential retinal neuroprotective effects of intramuscular ketamine in rabbits after pars plana vitrectomy (PPV) and intravitreal silicone oil injection (SOI). METHODS: Twelve New Zealand rabbits (weight, 2.0-2.5 kg) underwent PPV with SOI in the right eye. Postoperatively, six rabbits received a daily intramuscular injection of ketamine for 4 weeks (ketamine-operated eyes), and six rabbits received a daily intramuscular injection of saline (saline-operated eyes). The retina from the left eye of each rabbit served as a control (ketamine-control and saline-control eyes). The animals were euthanized at 4 weeks after surgery. Qualitative and quantitative analyses were performed using the Zeiss Axiophot microscope and KS 400 software. RESULTS: Qualitative analysis using light microscopy demonstrated more extensive edema and cell disorganization in saline-operated retinas than in ketamine-operated, ketamine-control, and saline-control retinas. Quantitatively, the cell densities (cell/mm) in the outer nuclear layer (ONL), inner nuclear layer (INL), and ganglion cell layer (GCL) in saline-operated retinas were significantly (P < 0.05) lower than those in these layers in ketamine-operated, ketamine-control, and saline-control retinas. The cell density in the ONL in saline-operated retinas was 52% lower than that in ketamine-operated retinas, 55% lower than that in ketamine-control retinas, and 56% lower than that in saline-control retinas. The cell density in the INL in saline-operated retinas was 44% lower than that in ketamine-operated retinas, 48% lower than that in ketamine-control retinas, and 49% lower than that in saline-control retinas. The cell density in the GCL in saline-operated retinas was 60% lower than that in ketamine-operated retinas, 64% lower than that in ketamine-control retinas, and 64% lower than that in saline-control retinas. CONCLUSION: PPV with SOI was associated with retinal cell death and disorganization in rabbit eyes. Intramuscular ketamine administration provided protection against these effects.

Fragmatome lifting: surgical option for intraocular lens and foreign body removal.

A new technique for intraocular lens (IOL) and foreign body removal using the fragmatome is described. Removal of the formed vitreous, including cortical vitreous, was performed using a conventional vitrectomy probe. The fragmatome tip was placed on the center of the anterior surface of both the IOL optics and the foreign bodies, and active 250 mm Hg vacuum suction was applied. IOLs and foreign bodies were easily held and manipulated after being aspirated into the fragmatome tip, avoiding the use of a forceps or other grasping instrument that may damage the retina. Fragmatome lifting is a reasonable treatment option for IOL and nonmagnetic foreign body removal.