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Supramolecular host-guest hyaluronic acid hydrogels as a corneal endothelial cell delivery mechanism

Caitlin M Logan


Caitlin M Logan, Gabriella M Fernandes-Cunha, Sei Kwang Hahn, David Myung



1. Stanford Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA, United States

2. Department of Materials Science and Engineering, POSTECH, 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk, 37673, Republic of Korea

3. VA Palo Alto HealthCare System, Palo Alto, CA, United States


Purpose: Corneal blindness is a leading cause of vision impairment worldwide, with curative treatment being limited to corneal transplantation, which relies on donor tissue availability and advanced surgical techniques. Innovative approaches to overcome these limitations are needed for all corneal surgeries, including Descemet Membrane Endothelial Keratoplasty (DMEK). Supramolecular, non-covalent crosslinking modalities, including host-guest interactions, have evolved as ways to create biomaterial polymer networks with dynamic, reversible crosslinks that have widespread potential applications. Here, supramolecular HA (s-HA) hydrogels were formed by cyclodextrin (CD) and adamantine (Ad) host-guest interaction to serve as a potential vehicle for cell delivery to assess for improved delivery and adhesion of encapsulated endothelial corneal cells.

Methods : HA-CD and HA-Ad were synthesized by amide bonding and esterification, and confirmed by 1H-NMR. HA-Ad-FITC was formed by the coupling reaction between FITC-amine and HA-Ad. S-HA hydrogels were synthesized by host-guest interaction between HA-CD and HA-Ad or HA-Ad-FITC. Corneal endothelial cells (CECs) were encapsulated in s-HA hydrogel for cell delivery. Rabbit corneas were prepared by peeling of Descemet’s membrane from overlying stroma following clear corneal incision, followed by direct application of the endothelial cell containing hydrogel or control gel to the area and creation of a bubble to ensure retention of the cells at the stromal surface. These eyes were then fixed in paraformaledehyde at days 1, 2, 4 or 10, and stained with phalloidin for actin, DAPI for nuclei and analyzed by confocal microscopy for evidence of retention of both gel and endothelial cells.

Results: Corneal endothelial cells showed high viability after encapsulation in s-HA hydrogel and injection through a needle, confirming biocompatibility. The s-HA hydrogel with encapsulated CECs showed successful delivery to wounded rabbit corneas, with retention of both hydrogel and cells at the surface of wounded corneas on days following delivery and no evidence of gel degradation. With the application of a bubble, there was minimal dispersion of the hydrogel or encapsulated cells outside of the site of application.

Conclusions: Supramolecular HA hydrogels are a viable delivery mechanism for encapsulated corneal endothelial cells, with multiple potential clinical applications.


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