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Dohlman, Claes

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Dohlman

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Claes

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Dohlman, Claes
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    Colocalization of Galectin-3 With CD147 Is Associated With Increased Gelatinolytic Activity in Ulcerating Human Corneas
    (The Association for Research in Vision and Ophthalmology, 2018) Cruzat, Andrea; Gonzalez-Andrades, Miguel; Mauris, Jérôme; Abusamra, Dina; Chidambaram, Preethi; Kenyon, Kenneth R.; Chodosh, James; Dohlman, Claes; Argueso, Pablo
    Purpose Galectin-3 is a carbohydrate-binding protein known to promote expression of matrix metalloproteinases, a hallmark of ulceration, through interaction with the extracellular matrix metalloproteinase inducer CD147. The aim of this study was to investigate the distribution of galectin-3 in corneas of patients with ulcerative keratitis and to determine its relationship to CD147 and the presence of gelatinolytic activity. Methods: This was an observational case series involving donor tissue from 13 patients with active corneal ulceration and 6 control corneas. Fixed-frozen sections of the corneas were processed to localize galectin-3 and CD147 by immunofluorescence microscopy. Gelatinolytic activity was detected by in situ zymography. Results: Tissue from patients with active corneal ulceration showed a greater galectin-3 immunoreactivity in basal epithelia and stroma compared with controls. Immunofluorescence grading scores revealed increased colocalization of galectin-3 and CD147 in corneal ulcers at the epithelial–stromal junction and within fibroblasts. Quantitative analysis using the Manders' colocalization coefficient demonstrated significant overlap in corneas from patients with ulcerative keratitis (M1 = 0.29; M2 = 0.22) as opposed to control corneas (M1 = 0.01, P < 0.01; M2 = 0.02, P < 0.05). In these experiments, there was a significant positive correlation between the degree of galectin-3 and CD147 colocalization and the presence of gelatinolytic activity. Conclusions: Our results indicate that concomitant stimulation and colocalization of galectin-3 with CD147 are associated with increased gelatinolytic activity in the actively ulcerating human cornea and suggest a mechanism by which galectin-3 may contribute to the degradation of extracellular matrix proteins during ulceration.
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    Reliable intraocular pressure measurement using automated radio-wave telemetry
    (Dove Medical Press, 2014) Paschalis, Eleftherios I; Cade, Fabiano; Melki, Samir; Pasquale, Louis; Dohlman, Claes; Ciolino, Joseph
    Purpose To present an autonomous intraocular pressure (IOP) measurement technique using a wireless implantable transducer (WIT) and a motion sensor. Methods: The WIT optical aid was implanted within the ciliary sulcus of a normotensive rabbit eye after extracapsular clear lens extraction. An autonomous wireless data system (AWDS) comprising of a WIT and an external antenna aided by a motion sensor provided continuous IOP readings. The sensitivity of the technique was determined by the ability to detect IOP changes resulting from the administration of latanoprost 0.005% or dorzolamide 2%, while the reliability was determined by the agreement between baseline and vehicle (saline) IOP. Results: On average, 12 diurnal and 205 nocturnal IOP measurements were performed with latanoprost, and 26 diurnal and 205 nocturnal measurements with dorzolamide. No difference was found between mean baseline IOP (13.08±2.2 mmHg) and mean vehicle IOP (13.27±2.1 mmHg) (P=0.45), suggesting good measurement reliability. Both antiglaucoma medications caused significant IOP reduction compared to baseline; latanoprost reduced mean IOP by 10% (1.3±3.54 mmHg; P<0.001), and dorzolamide by 5% (0.62±2.22 mmHg; P<0.001). Use of latanoprost resulted in an overall twofold higher IOP reduction compared to dorzolamide (P<0.001). Repeatability was ±1.8 mmHg, assessed by the variability of consecutive IOP measurements performed in a short period of time (≤1 minute), during which the IOP is not expected to change. Conclusion: IOP measurements in conscious rabbits obtained without the need for human interactions using the AWDS are feasible and provide reproducible results.
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    Low-Cost and Readily Available Tissue Carriers for the Boston Keratoprosthesis: A Review of Possibilities
    (Hindawi Publishing Corporation, 2013) Cruzat, Andrea; Tauber, Allyson; Shukla, Anita; Paschalis, Eleftherios I.; Pineda, Roberto; Dohlman, Claes
    The Boston keratoprosthesis (B-KPro), currently the most commonly used artificial cornea worldwide, can provide rapid visual rehabilitation for eyes with severe corneal opacities not suitable for standard corneal transplantation. However, the B-KPro presently needs a corneal graft as a tissue carrier. Although corneal allograft tissue is readily available in the United States and other developed countries with established eye banks, the worldwide need vastly exceeds supply. Therefore, a simple, safe, and inexpensive alternative to corneal allografts is desirable for the developing world. We are currently exploring reasonable alternative options such as corneal autografts, xenografts, noncorneal autologous tissues, and laboratory-made tissue constructs, as well as modifications to corneal allografts, such as deep-freezing, glycerol-dehydration, gamma irradiation, and cross-linking. These alternative tissue carriers for the B-KPro are discussed with special regard to safety, practicality, and cost for the developing world.
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    A Novel Implantable Glaucoma Valve Using Ferrofluid
    (Public Library of Science, 2013) Paschalis, Eleftherios I.; Chodosh, James; Sperling, Ralph A.; Salvador-Culla, Borja; Dohlman, Claes
    Purpose To present a novel design of an implantable glaucoma valve based on ferrofluidic nanoparticles and to compare it with a well-established FDA approved valve. Setting: Massachusetts Eye & Ear Infirmary, Boston, USA. Methods: A glaucoma valve was designed using soft lithography techniques utilizing a water-immiscible magnetic fluid (ferrofluid) as a pressure-sensitive barrier to aqueous flow. Two rare earth micro magnets were used to calibrate the opening and closing pressure. In-vitro flow measurements were performed to characterize the valve and to compare it to Ahmed™ glaucoma valve. The reliability and predictability of the new valve was verified by pressure/flow measurements over a period of three months and X-ray diffraction (XRD) analysis over a period of eight weeks. In vivo assessment was performed in three rabbits. Results: In the in vitro experiments, the opening and closing pressures of the valve were 10 and 7 mmHg, respectively. The measured flow/pressure response was linearly proportional and reproducible over a period of three months (1.8 µl/min at 12 mmHg; 4.3 µl/min at 16 mmHg; 7.6 µl/min at 21 mmHg). X-ray diffraction analysis did not show oxidization of the ferrofluid when exposed to water or air. Preliminary in vivo results suggest that the valve is biocompatible and can control the intraocular pressure in rabbits. Conclusions: The proposed valve utilizes ferrofluid as passive, tunable constriction element to provide highly predictable opening and closing pressures while maintaining ocular tone. The ferrofluid maintained its magnetic properties in the aqueous environment and provided linear flow to pressure response. Our in-vitro tests showed reliable and reproducible results over a study period of three months. Preliminary in-vivo results were very promising and currently more thorough investigation of this device is underway.
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    Biocompatibility and biofilm inhibition of N,N-hexyl,methyl-polyethylenimine bonded to Boston Keratoprosthesis materials
    (Elsevier BV, 2011) Behlau, Irmgard; Mukherjee, Koushik; Todani, Amit; Tisdale, Ann S.; Cade, Fabiano; Wang, Liqiang; Leonard, Elizabeth M.; Zakka, Fouad R.; Gilmore, Michael; Jakobiec, Frederick A.; Dohlman, Claes; Klibanov, Alexander M.
    The biocompatibility and antibacterial properties of N,N-hexyl,methyl-polyethylenimine (HMPEI) covalently attached to the Boston Keratoprosthesis (B-KPro) materials was evaluated. By means of confocal and electron microscopies, we observed that HMPEI-derivatized materials exert an inhibitory effect on biofilm formation by Staphylococcus aureus clinical isolates, as compared to the parent poly(methyl methacrylate) (PMMA) and titanium. There was no additional corneal epithelial cell cytotoxicity of HMPEI-coated PMMA compared to that of control PMMA in tissue cultures in vitro. Likewise, no toxicity or adverse reactivity was detected with HMPEI-derivatized PMMA or titanium compared to those of the control materials after intrastromal or anterior chamber implantation in rabbits in vivo.
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    Effect of Penetrating Keratoplasty and Keratoprosthesis Implantation on the Posterior Segment of the Eye
    (The Association for Research in Vision and Ophthalmology, 2016) Črnej, Alja; Omoto, Masahiro; Dohlman, Thomas H.; Gonzalez-Andrades, Miguel; Paschalis, Eleftherios I.; Cruzat, Andrea; Vu, T. H. Khanh; Doorenbos, Marianne; Chen, Dong; Dohlman, Claes; Dana, Reza
    Purpose To compare the effects of post-penetrating keratoplasty (PK) and post-keratoprosthesis (KPro) surgery-related inflammation on the posterior segment of the eye and to assess inhibition of tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) on these effects. Methods: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or miniature KPro (m-KPro) implantation. Intraocular pressure (IOP) was measured via an intracameral pressure sensor; tissues were harvested and analyzed 8 weeks after surgery. Expression of TNFα and IL-1β in the retina was analyzed using real-time quantitative (q)PCR. Optic nerve degeneration (axon count, circularity, and area) was assessed quantitatively using ImageJ software. After m-KPro implantation, mice were treated with saline, anti-TNFα, or anti-IL-1β antibody, and axonal loss was assessed after 10 weeks. Results: Mean IOP was within normal limits in the operated and fellow eyes in all groups. The mRNA expression of TNFα and IL-1β was highest in m-KPro groups with either syngeneic or an allogeneic carrier. We observed optic nerve degeneration in both allogeneic PK and m-KPro implanted eyes with an allogeneic carrier. However, TNFα blockade significantly reduced axonal loss by 35%. Conclusions: Allogeneic PK and m-KPro implants with an allogeneic carrier lead to chronic inflammation in the posterior segment of the eye, resulting in optic nerve degeneration. In addition, blockade of TNFα prevents axonal degeneration in this preclinical model of allogeneic m-KPro (alloKPro) implantation.
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    Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function
    (Nature Publishing Group, 2016) Gonzalez-Andrades, Miguel; Alonso-Pastor, Luis; Mauris, Jerome; Cruzat, Andrea; Dohlman, Claes; Argueso, Pablo
    The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro. However, these assays are mostly based on monolayer systems that fail to reproduce the differentiation processes associated to multilayered systems. Here, we describe a straightforward in vitro wound assay to evaluate the healing and restoration of barrier function in stratified human corneal epithelial cells. In this assay, circular punch injuries lead to the collective migration of the epithelium as coherent sheets. The closure of the wound was associated with the restoration of the transcellular barrier and the re-establishment of apical intercellular junctions. Altogether, this new model of wound healing provides an important research tool to study the mechanisms leading to barrier function in stratified epithelia and may facilitate the development of future therapeutic applications.
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    Titanium Coating of the Boston Keratoprosthesis
    (The Association for Research in Vision and Ophthalmology, 2016) Salvador-Culla, Borja; Jeong, Kyung Jae; Kolovou, Paraskevi Evi; Chiang, Homer H.; Chodosh, James; Dohlman, Claes; Kohane, Daniel
    Purpose We tested the feasibility of using titanium to enhance adhesion of the Boston Keratoprosthesis (B-KPro), ultimately to decrease the risk of implant-associated complications. Methods: Cylindrical rods were made of poly(methyl methacrylate) (PMMA), PMMA coated with titanium dioxide (TiO2) over a layer of polydopamine (PMMATiO2), smooth (Ti) and sandblasted (TiSB) titanium, and titanium treated with oxygen plasma (Tiox and TiSBox). Topography and surface chemistry were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Adhesion force between rods and porcine corneas was measured ex vivo. Titanium sleeves, smooth and sandblasted, were inserted around the stem of the B-KPro and implanted in rabbits. Tissue adhesion to the stem was assessed and compared to an unmodified B-Kpro after 1 month. Results: X-ray photoelectron spectroscopy demonstrated successful deposition of TiO2 on polydopamine-coated PMMA. Oxygen plasma treatment did not change the XPS spectra of titanium rods (Ti and TiSB), although it increased their hydrophilicity. The materials did not show cell toxicity. After 14 days of incubation, PMMATiO2, smooth titanium treated with oxygen plasma (Tiox), and sandblasted titanium rods (TiSB, TiSBox) showed significantly higher adhesion forces than PMMA ex vivo. In vivo, the use of a TiSB sleeve around the stem of the B-KPro induced a significant increase in tissue adhesion compared to a Ti sleeve or bare PMMA. Conclusions: Sandblasted titanium sleeves greatly enhanced adherence of the B-KPro to the rabbit cornea. This approach may improve adhesion with the donor cornea in humans as well. Translational Relevance This approach may improve adhesion with donor corneas in humans.
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    Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye
    (The Association for Research in Vision and Ophthalmology, 2017) Zhou, Chengxin; Robert, Marie-Claude; Kapoulea, Vassiliki; Lei, Fengyang; Stagner, Anna; Jakobiec, Frederick A.; Dohlman, Claes; Paschalis, Eleftherios I.
    Purpose Tumor necrosis factor (TNF)-α is upregulated in eyes following corneal alkali injury and contributes to corneal and also retinal damage. Prompt TNF-α inhibition by systemic infliximab ameliorates retinal damage and improves corneal wound healing. However, systemic administration of TNF-α inhibitors carries risk of significant complications, whereas topical eye-drop delivery is hindered by poor ocular bioavailability and the need for patient adherence. This study investigates the efficacy of subconjunctival delivery of TNF-α antibodies using a polymer-based drug delivery system (DDS). Methods: The drug delivery system was prepared using porous polydimethylsiloxane/polyvinyl alcohol composite fabrication and loaded with 85 μg of infliximab. Six Dutch-belted pigmented rabbits received ocular alkali burn with NaOH. Immediately after the burn, subconjunctival implantation of anti-TNF-α DDS was performed in three rabbits while another three received sham DDS (without antibody). Rabbits were followed with photography for 3 months. Results: After 3 months, the device was found to be well tolerated by the host and the eyes exhibited less corneal damage as compared to eyes implanted with a sham DDS without drug. The low dose treatment suppressed CD45 and TNF-α expression in the burned cornea and inhibited retinal ganglion cell apoptosis and optic nerve degeneration, as compared to the sham DDS treated eyes. Immunolocalization revealed drug penetration in the conjunctiva, cornea, iris, and choroid, with residual infliximab in the DDS 3 months after implantation. Conclusions: This reduced-risk biologic DDS improves corneal wound healing and provides retinal neuroprotection, and may be applicable not only to alkali burns but also to other inflammatory surgical procedures such as penetrating keratoplasty and keratoprosthesis implantation.
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    A Drug Delivery System for Administration of Anti–TNF-α Antibody
    (The Association for Research in Vision and Ophthalmology, 2016) Robert, Marie-Claude; Frenette, Mathieu; Zhou, Chengxin; Yan, Yueran; Chodosh, James; Jakobiec, Frederick A.; Stagner, Anna M.; Vavvas, Demetrios; Dohlman, Claes; Paschalis, Eleftherios I.
    Purpose To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti–TNF-α antibody administration. Methods: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100–300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti–TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. Results: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti–TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. Conclusions: Sustained local delivery of anti–TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. Translational Relevance The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.