(33e) Engineering an Adhesive Hydrogel for Corneal Sealing and Regeneration

Authors: 
Shirzaei Sani, E., Northeastern University
Annabi, N., Northeastern University
Rana, D., Northeastern University
Khademhosseini, A., Massachusetts Institute of Technology
Kheirkhah, A., Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School
Foulsham, W., Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
Amouzgar, A., Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
Dana, R., Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
Sheikhi, A., Biomaterials Innovation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Engineering an Adhesive Hydrogel for Corneal Sealing and
Regeneration

Ehsan Shirzaei
Sani1,Ahmad kheirkhah2, Devyesh Rana1, William Foulsham2, Afsaneh Amouzegar2,
Amir Sheikhi3, Ali Khademhosseini3,4,5,
Reza Dana2, Nasim Annabi1,3,4

1Department of Chemical Engineering,
Northeastern University, Boston, MA, USA.

2Massachusetts Eye and Ear Infirmary, Department
of Ophthalmology, Harvard Medical School, Boston, MA, USA

3Biomaterials Innovation Research Center,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

4Harvard-MIT Division of Health Sciences
and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.

5Wyss Institute for Biologically
Inspired Engineering, Harvard University, Boston, MA, USA.

Introduction

Corneal stromal defects are one of the main corneal wounds which
cost the healthcare system over $2 billion per year [1]. Conventional standards of care for corneal stromal defects,
including the use of cyanoacrylate glue, tissue grafting, or corneal
transplantation, have significant drawbacks. For instance, cyanoacrylate glue
is associated with cytotoxicity, lack of transparency, rough and irregular
surface, difficult handling, and lack of biointegration with the corneal
stromal tissue. Tissue grafting and

Figure 1. (a, b) Representative slit lamp and (c) optical coherence tomography (OCT) images of GelMA-based bioadhesive after applying to deep corneal stromal defects in a rabbit model. Bioadhesive remained intact and stayed completely attached to the cornea over the 4-week follow up. The hydrogels were photocrosslinked in situ using 20 %(w/v) GelMA and 4 min light exposure time.

Figure 1. (a, b) Representative slit lamp and (c) optical coherence tomography (OCT) images of GelMA-based bioadhesive after applying to deep corneal stromal defects in a rabbit model. Bioadhesive remained intact and stayed completely attached to the cornea over the 4-week follow up. The hydrogels were photocrosslinked in situ using 20 %(w/v) GelMA and 4 min light exposure time.
" src="https://www.aiche.org/sites/default/files/aiche-proceedings/conferences/..." v:shapes="_x6587__x672c__x6846__x0020_2" height="445" class="documentimage">corneal transplantation
require donor tissue and advanced surgical skills and
equipment and suffers from a shortage of the donor cornea worldwide [2]. To
overcome these challenges, here we engineered a highly biocompatible and and
transparent adhesive hydrogel for corneal reconstruction using a naturally
derived polymer, gelatin which is a partially hydrolyzed form of collagen with
similar bioactivity.

Materials
and Methods

 All
chemicals were purchased at analytical grade and used without further
purification. GelCORE (gelatin for corneal regeneration) adhesive was
synthesized through the methacrylation of porcine
skin gelatin (Sigma) with methacrylic anhydride (Sigma), according to a
procedure described previously [3].
Hydrogels were photopolymerized using Eosin Y (0.1 mM)
as a photoinitiator, Triethanolamine (1.5
%(w/v)) as a co-initiator and N-vinylcaprolactam (1
%(w/v)) as a co-monomer. The hydrogel prepolymer solution containing 20 %(w/v) GelCORE
and photoinitiators, were mixed gently and photopolymerized for 4 min using a Food
and Drug Administration (FDA) approved visible light source, FocalSeal (Genzyme
Biosurgery, Inc., 450-550 nm).

Results
and Discussion

Our results demonstrated that physical properties and adhesion
strength of the engineered bioadhesives could be tuned by changing the total
polymer concentration, and visible light exposure time. Furthermore, following American
Society for Testing and Materials (ASTM) standard tests, the bioengineered
hydrogels showed superior adhesive properties (i.e. adhesion strength, burst
pressure, and lap shear) compared to commercial surgical adhesives, Evicel® and CoSEAL®.
In
vitro
cell studies also showed that engineered hydrogels were
cytocompatible with corneal keratocytes (corneal fibroblast cells) and promoted
cell integration after application. Finally, we applied the hydrogel precursor
to the half-thickness corneal stromal defects in a rabbit model and photopolymerized
it with visible light for 4 min to form a highly adhesive hydrogel (Figure 1).
In vivo experiments in rabbits showed that adhesive hydrogels could effectively
seal corneal defects and form a transparent adhesive gel with a smooth surface (Figure
1
). In situ photopolymerization of bioadhesives facilitated easy delivery
to the cornea, and allowed for curing of the bioadhesive exactly according to
the required geometry of the tissue to be sealed, which is an advantage over
pre-formed materials, as e.g., scaffolds or sheets.

Conclusion

In this study, we synthesized photocrosslinkable gelatin-based hydrogels
that possessed superior physical and adhesion properties compared to
commercially-available alternatives. In addition, the adhesive hydrogels showed
high cytocompatibility in vitro using keratocytes. In vivo
experiments in rabbits showed that the adhesive hydrogels could effectively
seal corneal defects. Overall, our results proved that the bioengineered GelCORE
hydrogels may constitute an effective strategy to be used for corneal sealing
and regeneration.

Acknowledgment

Authors acknowledge the support from National Institutes of Health
(NIH) (R01EB023052; R01HL140618)
and Northeastern University.

References

[1] A. V. Ljubimov, M. Saghizadeh, Progress in Retinal and Eye Research,
49, 17-45, 2015.

[2] P. Gain, R. Jullienne, Z. He, M. Aldossary, S. Acquart, F. Cognasse, G. Thuret. JAMA Ophthalmology,
134, 167-173,.4776, 2016.

[3] A. Assmann, A.Vegh, M. Ghasemi-Radab,
S. Bagherifard, G. Cheng, E. Shirzaei
Sani, G. U.Ruiz-Esparza, I. Noshadi,
A. D. Lassaletta, S. Gangadharan,
A. Tamayol, A. Khademhosseini,
N. Annabi, Biomaterials, 140, 115-127, 2017.

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