July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Topical corneal application of mescenchymal stem cell-derived exosomes: an evaluation of feasibility, distribution, and safety of administration
Author Affiliations & Notes
  • Hon Shing Ong
    Corneal and External Diseases, Ophthalmology, Singapore National Eye Centre, Singapore, Singapore
    Tissue Engineering and Stem Cells, Singapore Eye Research Institute, Singapore
  • Gary Hin-Fai Yam
    Tissue Engineering and Stem Cells, Singapore Eye Research Institute, Singapore
  • Tze-Wei Goh
    Tissue Engineering and Stem Cells, Singapore Eye Research Institute, Singapore
  • Sai Kiang Lim
    Institute of Molecular Biology, A*Star, Singapore
  • Jodhbir S Mehta
    Corneal and External Diseases, Ophthalmology, Singapore National Eye Centre, Singapore, Singapore
    Tissue Engineering and Stem Cells, Singapore Eye Research Institute, Singapore
  • Footnotes
    Commercial Relationships   Hon Shing Ong, None; Gary Hin-Fai Yam, None; Tze-Wei Goh, None; Sai Kiang Lim, None; Jodhbir Mehta, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5249. doi:https://doi.org/
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      Hon Shing Ong, Gary Hin-Fai Yam, Tze-Wei Goh, Sai Kiang Lim, Jodhbir S Mehta; Topical corneal application of mescenchymal stem cell-derived exosomes: an evaluation of feasibility, distribution, and safety of administration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5249. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Corneal scarring is a leading cause of worldwide blindness and an important indication for corneal transplantation. However, global shortage of donor corneas is a major concern. Corneal transplantations also have inherent limitations (e.g. graft rejection, need for surgical expertise, and prolonged rehabilitation). There is thus a need to explore alternative therapies for corneal scarring. We hypothesize that mesenchymal stem cell (MSC)-derived exosomes can be used to treat corneal scarring. In this study, we investigated the optimal dosing frequency, distribution and safety of corneal delivery of exosomes.

Methods : Conditioned media of human embryonic stem cells (H9)-derived MSC was collected, concentrated and fractionated by high performance liquid chromatography to obtain exosome-enriched fractions (size range 80-150nm). Exosomes (4mg total protein) were topically applied (epithelium on versus off models) or intrastromally injected to normal rat corneas. Time-lapse tracing of Alexa Fluor-488-labeled exosomes was imaged using a confocal scanning laser (Spectralis HRA-OCT, Heidelberg) for distribution and dosage-intensity studies. Corneal changes were assessed using slit-lamp imaging and optical coherent tomography. Histopathology of excised corneas was performed.

Results : Topical administration of labeled exosomes to epithelium-off corneas (n=3) showed signals retained for 24h and a time-dependent clearance (mean half-life of 4h). Exosomes applied every 4h maintained signals above 50% peak intensity. In contrast, a rapid signal disappearance (<1h) was observed in epithelium-on corneas and Alexa Fluor label-only controls. Exosome-treated corneas (topical or injection) had no detectable changes in clarity, thickness, and vascularization. Histopathology revealed that exosomes slowly permeated the anterior stromal collagen lamellae with time [2.1±0.4% corneal thickness at 1h;12.2±1.7% at 24h]; there was negligible expression of inflammatory and fibrosis markers.

Conclusions : This study established the safety and appropriate corneal dosing of topical exosomes, which serves as a basis for future therapeutic studies on scarring. As corneal epithelium impedes exosomes permeation, topical delivery should be to epithelium-off corneas (e.g. acute injury phase). Slow permeation of topical exosomes may mean stromal injections are more suitable for deep scars.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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