-
Marine Drugs Feb 2022Neuroprotection in glaucoma using epoetin beta (EPOβ) has yielded promising results. Our team has developed chitosan-hyaluronic acid nanoparticles (CS/HA) designed to...
Neuroprotection in glaucoma using epoetin beta (EPOβ) has yielded promising results. Our team has developed chitosan-hyaluronic acid nanoparticles (CS/HA) designed to carry EPOβ into the ocular globe, improving the drug's mucoadhesion and retention time on the ocular surface to increase its bioavailability. In the present in vivo study, we explored the possibility of delivering EPOβ to the eye through subconjunctival administration of chitosan-hyaluronic acid-EPOβ (CS/HA-EPOβ) nanoparticles. Healthy Wistar Hannover rats ( = 21) were split into 7 groups and underwent complete ophthalmological examinations, including electroretinography and microhematocrit evaluations before and after the subconjunctival administrations. CS/HA-EPOβ nanoparticles were administered to the right eye (OD), and the contralateral eye (OS) served as control. At selected timepoints, animals from each group ( = 3) were euthanized, and both eyes were enucleated for histological evaluation (immunofluorescence and HE). No adverse ocular signs, no changes in the microhematocrits (≈45%), and no deviations in the electroretinographies in both photopic and scotopic exams were observed after the administrations ( < 0.05). Intraocular pressure remained in the physiological range during the assays (11-22 mmHg). EPOβ was detected in the retina by immunofluorescence 12 h after the subconjunctival administration and remained detectable until day 21. We concluded that CS/HA nanoparticles could efficiently deliver EPOβ into the retina, and this alternative was considered biologically safe. This nanoformulation could be a promising tool for treating retinopathies, namely optic nerve degeneration associated with glaucoma.
Topics: Animals; Chitosan; Drug Carriers; Drug Delivery Systems; Erythropoietin; Eye; Hyaluronic Acid; Male; Nanoparticles; Rats; Rats, Wistar; Recombinant Proteins; Retina; Time Factors
PubMed: 35200680
DOI: 10.3390/md20020151 -
Proceedings of the Royal Society of... Jan 1933
PubMed: 19989087
DOI: No ID Found -
Journal of Controlled Release :... Jan 2018Thermodynamically and chemically stable RNA nanoparticles derived from the three-way junction (3WJ) of the pRNA from bacteriophage phi29 DNA packaging motor were...
Thermodynamically and chemically stable RNA nanoparticles derived from the three-way junction (3WJ) of the pRNA from bacteriophage phi29 DNA packaging motor were examined previously for ocular delivery. It was reported that, after subconjunctival injection, RNA nanoparticles with tri-way shape entered the corneal cells but not the retinal cells, whereas particle with four-way shape entered both corneal and retinal cells. The present study evaluated ocular delivery of RNA nanoparticles with various shapes and sizes, and assessed the effect of thermosensitive hydrogels (poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid); PLGA-PEG-PLGA) for increasing the retention of RNA nanoparticles in the eye. Fluorescence imaging of mouse eyes and fluorescence microscopy of dissected eye tissues from the conjunctiva, cornea, retina, and sclera were performed to determine the distribution and clearance of the nanoparticles in the eyes after subconjunctival injection in vivo. RNA nanoparticles entered the cells of the conjunctiva, cornea, retina, and sclera after subconjunctival delivery. The clearance of RNA pentagon was slower than both RNA square and triangle of the same designed edge length (10nm) in the eye, and the clearance of RNA squares of the longer edge lengths (10 and 20nm) was slower than RNA square of the shorter edge length (5nm), thus indicating that the size could affect ocular pharmacokinetics of the nanoparticles. At 24h after the injection, approximately 6-10% of the fluorescence signal from the larger nanoparticles in the study (RNA square of 20nm edge length and RNA pentagon of 10nm edge length) remained in the eye, and up to 70% of the retinal cells contained the nanoparticles. The results suggest that the larger nanoparticles were "gulped" in conjunctival, corneal, retinal, and scleral cells, similar to the behavior observed in macrophages. Additionally, the combination of RNA nanoparticles with the thermosensitive polymers increased the retention of the nanoparticles in the eye.
Topics: Animals; Eye; Hydrogels; Injections; Mice, Hairless; Mice, Inbred C57BL; Nanoparticles; Polyethylene Glycols; Polyglactin 910; RNA
PubMed: 29170141
DOI: 10.1016/j.jconrel.2017.11.028 -
Stem Cell Research & Therapy Oct 2023T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due...
BACKGROUND
T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC).
METHODS
A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 10 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells.
RESULTS
Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice.
CONCLUSIONS
Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.
Topics: Humans; Animals; Mice; Conjunctivitis, Allergic; Conjunctiva; Cytokines; Disease Models, Animal; Mesenchymal Stem Cells; Umbilical Cord
PubMed: 37784129
DOI: 10.1186/s13287-023-03484-4 -
American Journal of Ophthalmology Case... Sep 2022To report a case of recurrent malignant melanoma suspected to have arisen from intrascleral melanocytic cells.
PURPOSE
To report a case of recurrent malignant melanoma suspected to have arisen from intrascleral melanocytic cells.
OBSERVATIONS
En bloc removal of melanoma was performed with iridocyclectomy in a 46-year-old Caucasian male. Histopathologic examination confirmed a diagnosis of malignant melanoma in the subconjunctival space, which was presumed to have arisen from the sclera and extended both intraocularly and subconjunctivally. 15 years later, a pigmented limbal lesion near the site of the previous iridocyclectomy was excised by lamellar sclerectomy. Histopathology showed a proliferation of pigment-containing cells with atypical nuclei consistent with recurrent melanoma.
CONCLUSIONS AND IMPORTANCE
We report a case of recurrent melanoma that we suspect arose from intrascleral melanocytes, extended both intraocularly and subconjunctivally, and recurred 15 years following initial excision.
PubMed: 35677815
DOI: 10.1016/j.ajoc.2022.101562 -
Taiwan Journal of Ophthalmology 2022Unilateral proptosis secondary to ectopic lacrimal gland tissue is rare. The most common site of ectopic lacrimal gland tissue is at the bulbar conjunctiva and limbal...
Unilateral proptosis secondary to ectopic lacrimal gland tissue is rare. The most common site of ectopic lacrimal gland tissue is at the bulbar conjunctiva and limbal area. Although uncommon, intraorbital ectopic lacrimal gland tissue may mimic other ominous symptoms of intraorbital neoplasm in childhood. We present a rare case of intraconal ectopic lacrimal gland tissue in a 14-year-old girl with intermittent proptosis since childhood associated with subconjunctival hemorrhage and excruciating pain. She underwent lateral orbitotomy with orbital mass excision that resulted in good outcomes and no recurrence was seen at 6 months after the surgery.
PubMed: 35399977
DOI: 10.4103/tjo.tjo_49_20 -
International Journal of Ophthalmology 2023To investigate the effectiveness and safety of subconjunctival injection of conbercept in the treatment of corneal neovascularization (CNV).
AIM
To investigate the effectiveness and safety of subconjunctival injection of conbercept in the treatment of corneal neovascularization (CNV).
METHODS
The data on 10 consecutively recruited patients with CNV who received a subconjunctival conbercept (1 mg) once, and measured the area, length, and diameter of neovascularization before and after (1d, 1, 2wk, and 1mo) treatment as well as the occurrence of systemic and ocular complications after treatment were analyzed.
RESULTS
There was a statistically significant reduction in the area of CNV one day after treatment (mean±SD: 38.46±11.36 mm), compared with before treatment (42.46±12.80 mm, <0.01). There was also a statistically significant reduction in the length (3.86±1.80 mm 4.64±1.77 mm, <0.01) and diameter (0.044±0.022 0.060±0.026, <0.05) of CNV, one week after treatment comparing to before treatment. The reduction in all three parameters was maximized at two weeks after treatment (area: 29.49±8.83 mm, <0.001; length: 3.50±1.88 mm, <0.001; and diameter: 0.038±0.017 mm, <0.01). No severe systemic or ocular complication was observed during the study.
CONCLUSION
During the observation period of one-month, subconjunctival injection of conbercept is an effective and safe method for the reduction of CNV. It may be effective as a preoperative drug for neovascular corneal transplantation.
PubMed: 37332556
DOI: 10.18240/ijo.2023.06.06 -
Ophthalmology Science Dec 2021To uncover the mechanism of subconjunctival outflow in human patients.
PURPOSE
To uncover the mechanism of subconjunctival outflow in human patients.
DESIGN
Cross-sectional study.
SUBJECTS/PARTICIPANTS AND/OR CONTROLS
Fifteen subjects receiving subconjunctival anesthesia prior to intravitreal injection for routine clinical care.
METHODS
Anterior segment OCT (AS-OCT) was performed in patients with various instances of conjunctival edema or subconjunctival fluid. Other subjects received a subconjunctival mixture of 0.005% indocyanine green and 2% lidocaine. After subconjunctival injection of the tracer/anesthetic mixture, blebs and associated outflow pathways were angiographically imaged and the time for appearance recorded. The pattern and structure of outflow pathways were studied using AS-OCT. Angiographic and AS-OCT results were compared to trabecular/conventional outflow imaging which demonstrates veins.
MAIN OUTCOME MEASURES
Ocular surface lymphangiography and AS-OCT images.
RESULTS
AS-OCT of the conjunctiva in a normal eye demonstrated thin non-edematous conjunctiva with absent intraconjunctival lumens or subconjunctival fluid. Subjects with a history of trabeculectomy, subconjunctival drug injection, or chemosis demonstrated thickened conjunctiva and intraconjunctival luminal pathways that contained valve-like structures. Tracer-based studies in patients demonstrated blebs with irregular subconjunctival bleb-related outflow patterns that arose in a time-dependent fashion. These angiographic pathways were luminal on OCT, sausage-shaped, and contained intraluminal valve-like structures. This was in contrast to trabecular/conventional outflow imaging where pathways were classically Y-shaped, of even-caliber, and lacked valve-like structures.
DISCUSSION
Outflow pathways were seen in cases of conjunctival edema and after subconjunctival tracer injection. These pathways were lymphatic based upon pattern and structural study. Better understanding of bleb-related lymphatic outflow may lead to improved bleb-requiring glaucoma surgeries and subconjunctival drug delivery.
PubMed: 35005679
DOI: 10.1016/j.xops.2021.100080 -
Stem Cell Research & Therapy Jan 2021Mesenchymal stem cells (MSCs) have unique and beneficial properties and are currently used to treat a broad variety of diseases. These properties include the potential... (Review)
Review
Mesenchymal stem cells (MSCs) have unique and beneficial properties and are currently used to treat a broad variety of diseases. These properties include the potential for differentiation into other cell types, secretion of different trophic factors that promote a regenerative microenvironment, anti-inflammatory actions, selective migration to damaged tissues, and non-immunogenicity. MSCs are effective for the treatment of ocular surface diseases such as dry eye, corneal burns, and limbal stem cell deficiency (LSCD), both in experimental models and in humans. LSCD is a pathological condition in which damage occurs to the limbal epithelial stem cells, or their niche, that are responsible for the continuous regeneration of the corneal epithelium. If LSCD is extensive and/or severe, it usually causes corneal epithelial defects, ulceration, and conjunctival overgrowth of the cornea. These changes can result in neovascularization and corneal opacity, severe inflammation, pain, and visual loss. The effectiveness of MSCs to reduce corneal opacity, neovascularization, and inflammation has been widely studied in different experimental models of LSCD and in some clinical trials; however, the methodological disparity used in the different studies makes it hard to compare outcomes among them. In this regard, the MSC route of administration used to treat LSCD and other ocular surface diseases is an important factor. It should be efficient, minimally invasive, and safe. So far, intravenous and intraperitoneal injections, topical administration, and MSC transplantation using carrier substrata like amniotic membrane (AM), fibrin, or synthetic biopolymers have been the most commonly used administration routes in experimental models. However, systemic administration carries the risk of potential side effects and transplantation requires surgical procedures that could complicate the process. Alternatively, subconjunctival injection is a minimally invasive and straightforward technique frequently used in ophthalmology. It enables performance of local treatments using high cell doses. In this review, we provide an overview of the current status of MSC administration by subconjunctival injection, analyzing the convenience, safety, and efficacy for treatment of corneal failure due to LSCD in different experimental models. We also provide a summary of the clinical trials that have been completed, are in progress, or being planned.
Topics: Cornea; Corneal Diseases; Epithelium, Corneal; Humans; Limbus Corneae; Mesenchymal Stem Cells; Stem Cell Transplantation; Stem Cells
PubMed: 33441175
DOI: 10.1186/s13287-020-02129-0 -
Journal of Ophthalmology 2014Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine...
Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model. Methods. LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature. Results. Focal melphalan significantly reduced retinal tumor size (P < 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P = 0.017) and at 3 weeks after injection (P = 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration. Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.
PubMed: 24734170
DOI: 10.1155/2014/829879