Name: ex vivo and in vivo animal models for mechanical and chemical injuries of corneal epithelium
Uploaded: 2022-04-06T13:00:00
Description: Watch this Scientific Journal Video about Ex Vivo and In Vivo Animal Models for Mechanical and Chemical Injuries of Corneal Epithelium at JoVE.com

The study was funded by the Atomic Energy Council of Taiwan (Grant No. A-IE-01-03-02-02), Ministry of Science and Technology (Grant No. NMRPG3E6202-3), and Chang Gung Medical Research Project (Grant No. CMRPG3H1281).

All of the experimental procedures in animal studies were approved by the Research Ethics Committee at the Chang Gung Memorial Hospital and adhered to the ARVO statement for use of animals in ophthalmic and vision research.
1. Ex vivo wound healing model of the mouse corneal epithelium
<ol>
	<li>Preparation of the mice
	<ol>
		<li>Administer general anesthesia to C57BL/6 mice by intraperitoneal delivery of ketamine hydrochloride (80-100&#160;mg/kg of body weight) an...

<ol>
	<li>Sridhar, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anatomy+of+cornea+and+ocular+surface.">Anatomy of cornea and ocular surface.</a> Indian Journal of Ophthalmology. 66 (2), 190-194 (2018).</li><li>Henriksson, J. T., McDermott, A. M., Bergmanson, J. P. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dimensions+and+morphology+of+the+cornea+in+three+strains+of+mice.">Dimensions and morphology of the cornea in three strains of mice.</a> Investigative Ophthalmology &amp; Visual Science. 50 (8), 3648-3654 (2009).</li><li>Wang, X., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MANF+promotes+diabetic+corneal+epithelial+wound+healing+and+nerve+regeneration+by+attenuating+hyperglycemia-induced+endoplasmic+reticulum+stress.">MANF promotes diabetic corneal epithelial wound healing and nerve regeneration by attenuating hyperglycemia-induced endoplasmic reticulum stress.</a> Diabetes. 69 (6), 1264-1278 (2020).</li><li>Ma, X., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Corneal+epithelial+injury-induced+norepinephrine+promotes+Pseudomonas+aeruginosa+keratitis.">Corneal epithelial injury-induced norepinephrine promotes Pseudomonas aeruginosa keratitis.</a> Experimental Eye Research. 195, 108048 (2020).</li><li>Chan, M. F., Werb, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+corneal+injury.">Animal models of corneal injury.</a> Bio Protocol. 5 (13), 1516 (2015).</li><li>Lan, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Kinetics+and+function+of+mesenchymal+stem+cells+in+corneal+injury.">Kinetics and function of mesenchymal stem cells in corneal injury.</a> Investigative Ophthalmology &amp; Visual Science. 53 (7), 3638-3644 (2012).</li><li>Watanabe, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Promotion+of+corneal+epithelial+wound+healing+in+vitro+and+in+vivo+by+annexin+A5.">Promotion of corneal epithelial wound healing in vitro and in vivo by annexin A5.</a> Investigative Ophthalmology &amp; Visual Science. 47 (5), 1862-1868 (2006).</li><li>Murataeva, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cannabinoid+CB2R+receptors+are+upregulated+with+corneal+injury+and+regulate+the+course+of+corneal+wound+healing.">Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.</a> Experimental Eye Research. 182, 74-84 (2019).</li><li>Carter, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterizing+the+impact+of+2D+and+3D+culture+conditions+on+the+therapeutic+effects+of+human+mesenchymal+stem+cell+secretome+on+corneal+wound+healing+in+vitro+and+ex+vivo.">Characterizing the impact of 2D and 3D culture conditions on the therapeutic effects of human mesenchymal stem cell secretome on corneal wound healing in vitro and ex vivo.</a> Acta Biomaterialia. 99, 247-257 (2019).</li><li>Sanie-Jahromi, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Propagation+of+limbal+stem+cells+on+polycaprolactone+and+polycaprolactone/gelatin+fibrous+scaffolds+and+transplantation+in+animal+model.">Propagation of limbal stem cells on polycaprolactone and polycaprolactone/gelatin fibrous scaffolds and transplantation in animal model.</a> Bioimpacts. 10 (1), 45-54 (2020).</li><li>Sun, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epithelial+membrane+protein+(EMP2)+antibody+blockade+reduces+corneal+neovascularization+in+an+In+vivo+model.">Epithelial membrane protein (EMP2) antibody blockade reduces corneal neovascularization in an In vivo model.</a> Investigative Ophthalmology &amp; Visual Science. 60 (1), 245-254 (2019).</li><li>Yang, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cannabinoid+receptor+1+suppresses+transient+receptor+potential+vanilloid+1-induced+inflammatory+responses+to+corneal+injury.">Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury.</a> Cell Signal. 25 (2), 501-511 (2013).</li><li>Bai, J. Q., Qin, H. F., Zhao, S. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Research+on+mouse+model+of+grade+II+corneal+alkali+burn.">Research on mouse model of grade II corneal alkali burn.</a> International Journal of Ophthalmology. 9 (4), 487-490 (2016).</li><li>Oh, J. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anti-inflammatory+protein+TSG-6+reduces+inflammatory+damage+to+the+cornea+following+chemical+and+mechanical+injury.">Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury.</a> Proceedings of the National Academy of Sciences of the United States of America. 107 (39), 16875 (2010).</li><li>Wang, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+the+effects+of+biohcly+in+an+in+vivo+model+of+mechanical+wounds+in+the+rabbit+cornea.">Evaluation of the effects of biohcly in an in vivo model of mechanical wounds in the rabbit cornea.</a> Journal of Ocular Pharmacology and Therapeutics. 35 (3), 189-199 (2019).</li><li>Gong, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+nintedanib+thermos-sensitive+hydrogel+on+neovascularization+in+alkali+burn+rat+model.">Effect of nintedanib thermos-sensitive hydrogel on neovascularization in alkali burn rat model.</a> International Journal of Ophthalmology. 13 (6), 879-885 (2020).</li><li>Yao, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Role+of+mesenchymal+stem+cells+on+cornea+wound+healing+induced+by+alkali+burn.">Role of mesenchymal stem cells on cornea wound healing induced by alkali burn.</a> PLoS One. 7 (2), 30842 (2012).</li></ol>

Mouse and rabbit models of corneal injury provide a useful ex vivo and in vivo platform for monitoring wound healing, testing new therapeutics, and studying underlying mechanisms of wound healing and treatment pathways. Different animal models can be used for a short-term or long-term experiment, depending on the purpose of the research. For instance, after creating an epithelial defect on mouse cornea in vivo, a confined epithelial defect could be used to monitor liquid therapeutic agents in a...

The human cornea consists of five major layers and plays a pivotal role in ocular refraction to maintain visual acuity and structural integrity for protecting intraocular tissues1. The outermost part of the cornea is the corneal epithelium, composed of five to six layers of cells that sequentially differentiate from the basal cells and move upward to shed from the ocular surface1. Compared to the cornea in humans and New Zealand rabbits, mouse cornea has a similar corneal structure, but thinner periphery than the central part due to a reduced thickness in the epithelium and the stroma2. Because of its unique position in the ocular optic system, many external insults such as mechanical injury, bacterial inoculation, and chemical agents may easily endanger epithelial integrity and further lead to vision-threatening epithelium defect, infectious keratitis, corneal melting, and even corneal perforation.
Although various therapeutic agents, such as lubricants, antibiotics, anti-inflammatory agents, auto-serum products, and amniotic membrane have already been used to improve re-epithelialization and reduce scarring, other potential treatment modalities that can enable wound healing, reduce inflammation, and suppress scar formation are still being developed and tested on different platforms. Various animal models for corneal epithelial wound healing have been proposed, including corneal epithelium removal with a corneal rust ring remover in diabetic mouse3, linear scratches over mouse corneal epithelium by a sterile 25 G needle for bacterial inoculation4, trephine-assisted removal of the corneal epithelium by corneal rust ring remover5, epithelial cautery over half of the cornea and limbus6, trephine-facilitated rabbit corneal abrasion by a dulled scalpel blade7, and bovine cornea injury by flash freezing in liquid nitrogen8.
Other than mechanical injury to the corneal epithelium, chemical agents are also common insults to the ocular surface, especially acidic and alkali agents. Sodium hydroxide (NaOH, 0.1-1 N for 30-60 s) is one of the commonly used chemicals in murine and rabbit models of corneal chemical burn9,10,11,12,13. 100% ethanol had also been applied to the cornea in the rat chemical burn model, followed by additional mechanical scrapping using a surgical blade14. Since maintenance of a healthy ocular surface relies on functional units, including the eyelids, Meibomian glands, lacrimal system, the conjunctiva, and the cornea, in vivo animal models have some merits over ex vivo cultured cornea epithelial cells or corneal tissues. In this article, the mouse model of corneal abrasion wound, and the rabbit model of corneal alkali burn are demonstrated.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>6/0 Ethicon vicryl suture</td>
			<td>Ethicon</td>
			<td>6/0VICRYL</td>
			<td>tarsorrhaphy</td>
		</tr>
		<tr>
			<td>Barraquer lid speculum</td>
			<td>katena</td>
			<td>K1-5355</td>
			<td>15 mm</td>
		</tr>
		<tr>
			<td>Barraquer needle holder</td>
			<td>Katena</td>
			<td>K6-3310</td>
			<td>without lock</td>
		</tr>
		<tr>
			<td>Barron Vacuum Punch 8.0 mm</td>
			<td>katena</td>
			<td>K20-2108</td>
			<td>for cutting filter paper</td>
		</tr>
		<tr>
			<td>C57BL/6 mice</td>
			<td>National Laboratory Animal Center</td>
			<td>RMRC11005</td>
			<td>mouse strain</td>
		</tr>
		<tr>
			<td>Castroviejo forceps 0.12 mm</td>
			<td>katena</td>
			<td>K5-2500</td>
			<td></td>
		</tr>
		<tr>
			<td>Corneal rust ring remover with 0.5 mm burr</td>
			<td>Algerbrush IITM; Alger Equipment Co., Inc. Lago Vista, TX</td>
			<td>CHI-675</td>
			<td>for debridement of the corneal epithelium</td>
		</tr>
		<tr>
			<td>Filter paper</td>
			<td>Toyo Roshi Kaisha,Ltd.</td>
			<td>1.11</td>
			<td></td>
		</tr>
		<tr>
			<td>Fluorescein sodum ophthalmic strips U.S.P</td>
			<td>OPTITECH</td>
			<td>OPTFL100</td>
			<td>staining for corneal epithelial defect</td>
		</tr>
		<tr>
			<td>Ketamine hydrochloride</td>
			<td>Sigma-Aldrich</td>
			<td>61763-23-3</td>
			<td>intraperitoneal or intramuscular anesthetics</td>
		</tr>
		<tr>
			<td>New Zealand White Rabbits</td>
			<td>Livestock Research Institute, Council of Agriculture,Executive Yuan</td>
			<td></td>
			<td>Rabbit models</td>
		</tr>
		<tr>
			<td>Normal saline</td>
			<td>TAIWAN BIOTECH CO., LTD.</td>
			<td>100-120-1101</td>
			<td></td>
		</tr>
		<tr>
			<td>Proparacaine</td>
			<td>Alcon</td>
			<td>ALC2UD09</td>
			<td>topical anesthetics</td>
		</tr>
		<tr>
			<td>Skin biopsy punch 2mm</td>
			<td>STIEFEL</td>
			<td>22650</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride (NaOH)</td>
			<td>Sigma-Aldrich</td>
			<td>1310-73-2</td>
			<td>a chemical agent for alkali burn</td>
		</tr>
		<tr>
			<td>Stereomicroscope</td>
			<td>Carl Zeiss Meditec, Dublin, CA</td>
			<td>SV11</td>
			<td>microscope for surgery</td>
		</tr>
		<tr>
			<td>Westcott Tenotomy Scissors Medium</td>
			<td>katena</td>
			<td>K4-3004</td>
			<td></td>
		</tr>
		<tr>
			<td>Xylazine hydrochloride 23.32 mg/10 mL</td>
			<td>Elanco animal health Korea Co., LTD.</td>
			<td>047-956</td>
			<td>intraperitoneal or intramuscular anesthetics</td>
		</tr>
	</tbody>
</table>

ex vivo and in vivo animal models for mechanical and chemical injuries of corneal epithelium

Corneal injury to the ocular surface, including chemical burn and trauma, may cause severe scarring, symblepharon, corneal limbal stem cells deficiency, and result in a large, persistent corneal epithelial defect. Epithelial defect with the following corneal opacity and peripheral neovascularization result in irreversible visual impairment and hinder future management, especially keratoplasty. Since the animal model can be used as an effective drug development platform, models of corneal injury to the mouse and alkali burn to rabbit corneal epithelium are developed here. New Zealand white rabbit is used in the alkali burn model. Different concentrations of sodium hydroxide can be applied onto the central circular area of the cornea for 30 s under intramuscular and topical anesthesia. After copious isotonic normal saline irrigation, residual loose corneal epithelium was removed with corneal burr deep down to the Bowman's layer within this circular area. Wound healing was documented by fluorescein staining under Cobalt blue light. C57BL/6 mice were used in the traumatic model of murine corneal epithelium. The murine central cornea was marked using a skin punch, 2 mm in diameter, and then debrided by a corneal rust ring remover with a 0.5 mm burr under a stereomicroscope. These models can be prospectively used to validate the therapeutic effect of eye drops or mixed agents such as stem cells, which potentially facilitate corneal epithelial regeneration. By observing corneal opacity, peripheral neovascularization, and conjunctival congestion with stereomicroscope and imaging software, therapeutic effects in these animal models can be monitored.

Ex vivo wound healing model of the mouse corneal epithelium: 
After in vivo debridement of mouse corneal epithelium with hand-held corneal rust ring remover, a mildly depressed central corneal area with positive fluorescein stain can be found in the central 2 mm area (Figure 3A-B). After harvesting the mouse eyeball, it was easily fixed onto a wax-coated 48-well culture plate without significant rotati...

Watch this Scientific Journal Video about Ex Vivo and In Vivo Animal Models for Mechanical and Chemical Injuries of Corneal Epithelium at JoVE.com

Ex Vivo and In Vivo Animal Models for Mechanical and Chemical Injuries of Corneal Epithelium

Here, animal models based on mouse and rabbit are developed for mechanical and chemical injury of corneal epithelium to screen new therapeutics and the underlying mechanism.

Ex Vivo and In Vivo Animal Models for Mechanical and Chemical Injuries of Corneal Epithelium

Corneal injury to the ocular surface, including chemical burn and trauma, may cause severe scarring, symblepharon, corneal limbal stem cells deficiency, ...

Ex vivo and in vivo animal models were set up for studying mechanical and chemical corneal injury. The technique provides an easily built-up platform for researchers to study mechanical and chemical injury of the cornea. To create a murine corneal epithelial wound, mark the central cornea of the anesthetized mouse using a skin biopsy punch to confirm a well-circumscribed and well-measurable area of the wound.Gently indent the punch over the central cornea to leave a circular mark Debride the corneal epithelial down to the Bowman's layer utilizing a hand-held corneal rust ring remover with a 0.5 millimeter burr ensuring not to damage the Bowman's layer. Remove the residual loose tissues in the wound margin with corneal forceps. Confirm the area of debridement with fluorescent staining by putting a drop of normal saline onto a fluorescein paper to dissolve fluorescein and then placing the fluorescein-containing drop onto murine epithelial defect to visualize it under cobalt blue light.Proceed with ex vivo culture of the murine corneal abrasion wound model by gently pressing at the superior and inferior orbital rims of euthanized mice to push the eyeball out. Introduce the tip of the closed corneal scissors into the retrobulbar space along the inferior orbital wall ensuring not to penetrate the eyeball. Hold the eyeball steady with 0.3-millimeter corneal forceps and then cut the optic nerve and periorbital soft tissue with corneal scissors to isolate the eyeball.For ex vivo culturing of murine eyeballs, prepare a 48-well plate with melted wax inside the well and wait for solidification, then with the tip of conjunctiva forceps, create a round hole on solidified wax's surface to accommodate the eyeballs. Place the harvested eyeballs directly onto the 48-well plate with wax-covered bottoms and sidewalls to establish stabilization. Culture the eyeballs with DMEM containing 1%fetal bovine serum with or without antibiotics depending on the purpose of the study.Immerse the ocular surface with the culture medium without causing the eyeball to float and document the course of wound healing by fluorescein staining and collecting photographs with a digital camera under cobalt blue light. To induce an alkaline burn injury, place a circular filter paper with a diameter of 8 millimeters in a Petri dish. Using a dropper, add 0.5 normal sodium hydroxide into the Petri dish to soak the filter papers and drain the excess solution from the filter paper before placing them onto the anesthetized rabbit cornea.After opening the eyelids with a lid speculum, ensure that the rabbit nictitating membrane is not interfering with the insertion of filter paper and place the alkali-soaked filter paper onto the central cornea for 30 seconds. Remove the filter paper and rinse the ocular surface with 10 milliliters of normal saline to wash out alkali material. To complete the corneal defect, debride the corneal epithelium within the opacified area down to the Bowman's membrane using a corneal rust ring remover.Confirm the debridement area with fluorescein staining under the cobalt blue light and remove residual corneal epithelium using corneal forceps. To secure wound condition with tarsorrhaphy, confirm that the nictitating membrane smoothly covers the ocular surface and corneal epithelial defect at the nasal side. Perform a temporary tarsorrhaphy with or without topical agents using a 6-0 suture to protect the ocular surface and to prevent the rabbit from scratching it, ensure that the suture for tarsorrhaphy is at 3 to 4 millimeters from the upper and lower lid margins with four to five ties and longer knots to prevent the rabbit from breaking the sutures.In the mouse corneal epithelium's ex vivo wound healing model, the mildly depressed central corneal area with positive fluorescein stain was observed in the central two millimeters after the in vivo debridement of the mouse corneal epithelium. The ex vivo culture of the murine eyeballs fixed onto a wax-coated 48-well culture plate was examined and documented daily within a 48-well culture plate under a stereo microscope. A day after debriding the murine corneal epithelium, one circular fluorescein-stained epithelial defect of 2 millimeters in diameter was revealed in digital photographs obtained under cobalt blue light.After creating an alkali injury to the rabbit corneal epithelium, positive fluorescein staining was observed with or without cobalt blue light over the central cornea with a clear and complete circular margin. The corneal epithelial wound re-epithelialization with pannus ingrowth was observed from the limbus. The most important steps are procedures to create smooth and even epithelial defects on mouse and rabbit corneal surfaces.New medical and surgical therapeutics can be tested on these platforms. The effect of re-epithelialization can be monitored after the procedures. Corneal neovascularization and opacity after injury in this protocol would be an unmet need for further research.

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