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First Vaegan Seminar for 2019

31/03/2019By Lewis Williams PhD
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The first of the Vaegan Seminars for 2019 examined current developments in corneal bioengineering. LEWIS WILLIAMS details Dr Jingjing You’s presentation and work in the field.

The Vaegan Seminars are a series of presentations to staff, graduate students, and other interested parties given at the School of Optometry and Vision Science (SOVS), University of New South Wales (UNSW). Dr Jingjing You, a postdoctoral research associate from Sydney’s Save Sight Institute (SSI) at the University of Sydney, presented the first seminar of 2019.

She leads a laboratory research team that is part of the SSI’s Corneal Bioengineering Group, and is also a visiting academic to SOVS, an external scientific advisor to the NSW Tissue Bank, and a working committee member of the ANZ Human Eye Cell Atlas Consortium.

Her current research is focused on corneal bioengineering and the development of biomaterials to optimise corneal repair and reconstruction. To date, her team’s highest profile achievement is the patented iFix system, the combination of a corneal adhesive and dispensing device for use in in vivo repairs to corneal defects, such as ulcers and corneal trauma. Although it at an advanced stage, the system is yet to be used on human patients.

The title of her presentation was: Tissue engineering – focusing on the eye (corneal applications).

Tissue Engineering

You gave the essential goal of tissue engineering (TE) as tissue creation and repair, which she also described as an opportunity to work across many clinical and laboratory-based disciplines. TE also overlaps with the discipline of regenerative medicine.

She focused her presentation on the use of TE in the treatment of corneal disease and injury. In so doing, she provided an overview of the scope of TE, recent developments and some of the common TE challenges faced by workers in the field.

One challenge is gaining an understanding of the relationship between structure and function in normal and pathological circumstances. TE investigates biological substitutes, tissue/function restoration, tissue maintenance and functional increases, and the induction of regeneration. The aim is for at least a partial recovery. Though it is the ideal, a full recovery is not always possible.

The first comprehensive definition of TE was produced after a workshop held in Granlibakken (Tahoe City, California, USA) which offered the following: “‘Tissue Engineering’ is the application of principles and methods of engineering and life sciences toward fundamental understanding of structure-function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore, maintain, or improve tissue function.”

Biomaterials are living substances or materials of natural origin that substitute for damaged or diseased body tissue. In some instances, support structures and scaffolds are employed to assist with substitution or repair by providing a physical, biocompatible resource that can be seeded with appropriate cells. These cells will invade, inhabit, and grow within the support structure offered. While not always possible, the best source of suitable cells is the patient themselves as compatibility is of the utmost importance.

A corneal focus

An example of a scaffold is a transplanted cornea, such as that used in a penetrating keratoplasty (PKP) procedure. A secondary aim is wound minimisation, and that takes the form of the corneal lamellar procedures such as Descemet’s Stripping Endothelial Keratoplasty (DSEK), Descemet Stripping Automated Endothelial Keratoplasty (DSAEK), Descemet’s Membrane Endothelial Keratoplasty (DMEK) and Deep Anterior Lamellar Keratoplasty (DALK) that have replaced PKPs in many instances.

A possible starting point for a cornea replacement scaffold is a decellularised donor cornea. Removing all cells and associated contents is a difficult and involved process that leaves just the structural matrix which, it is hoped, will be colonised by the patient’s own cells.

Synthetic polymers are also under active investigation, as well as known compatible materials used previously and successfully in contact lenses. These materials include Polymethyl Methacrylate (PMMA) in rigid lenses, and Poly-Hydroxyethyl Methacrylate (pHEMA) in soft contact lenses. These materials may yet see future applications long after their earlier uses ceased due to the arrival of superior, albeit more complex, materials.

Regardless, according to You, rejection of synthetics remains a problem. Where hydrogels are involved, a water content of greater than 10% w/w is usually required. Other materials being investigated include Polyethylene Glycol (PEG), cellulose, chitosan (a derivative of mollusc and crustacean exoskeletons), elastin, fibrin, and alginate.

Corneal stroma substitutes have been attempted using biosynthetic grafts based on type-1 and type-3 human collagen such as RHC III, a carbodiimide cross-linked recombinant human collagen type-3 material with good optical properties. However, clinical trials with RHC III at four years showed significant corneal flattening largely due to eyelid pressure.

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That led to cross-linking RHC III further with 2-methacryloyl phosphorylcholine (MPC) to enhance its bioperformance. Under artificial circumstances, natural collagen exhibits poor mechanical strength, which remains the biggest challenge to its use.

Work being undertaken at the University of Wollongong by Professor Gordon Wallace uses so-called electro-compacted collagen (ECC) to form transparent and clear membranes, as well as collagen fibrils, to which cells can attach. ECC fibrils are longer and better oriented. Another material called CLP-PEG (collagen-like peptides conjugated to PEG) has also been used, but vascularisation remains a problem.

If an implant approach is taken, sutures are still required and achieving adequate mechanical strength remains an issue. Once a hole is made in an implant, its initiated-tear strength is reduced significantly.

3D printing

Moving to the concept of 3D printing tissue, You spoke of the use of bioink, a relatively recent technology. As is still the case, the resolution of 3D printing is not ideal, and the much higher resolution of a laser-based system has resulted in attempts to laser bioprint tissue.

While very different, a laser-based approach still requires a suitable bioink. A bioink is firstly a liquid vehicle for the carriage of viable cells, and solidity of a tissue is achieved by stacking deposited layers. The final product must still be bio-integratable or if appropriate, biodegradable. Currently, bioinks can use laminin, Type I collagen with hyaluronic acid (for laser printing), alginate and collagen (3D print/extrusion). A recent development is so-called 4D printing; a process in which a 3D printed tissue starts a self-assembly process after being printed, to form a more desirable product.

An alternative method of printing is to use a Bio-Pen, a device with a duopen dispenser. The design is similar to the dispenser used to apply, while mixing, a two-part epoxy adhesive. It consists of a dual-chamber of a two-part biopolymer with a photo initiator, and a UV LED at the dispensing nozzle to polymerise the mix almost immediately after dispensing.

Other possible bioink components aside from a photoinitiator include gel methacrylic acid and a combination of hyaluronic and methacrylic acids. In a corneal context, collagen-based inks are preferred, and a cross-linking process usually follows their application to impart the desired physical properties to the biomaterial.

When collagen Type–I based bioink is used to form a flexible membrane for use in animal models, especially the rabbit, researchers monitor the animals’ behaviour as well as the physical/anatomical outcomes produced. In particular researches look for pain response, behavioural changes, and other observations that might indicate how the animal is faring after a course of treatment.

The hand-held, 3D printing, iFix corneal ulcer and corneal defects repair system, consisting of iFix bioink and the 2-chamber iFix pen, is a result of co-operation between SSI’s Prof Gerard Sutton, Dr Simon Cooper, Dr Li Wen, PhD candidate Ms Hannah Frazer, You, and the University of Wollongong’s Intelligent Polymer Institute team headed by Wallace. Initial pre-seed funding of $45,000 for the project came from the inaugural (2017) Sydney Research Innovation Challenge –The Big Idea. In mid-2018 the project received a $1.1 million grant from the NSW State’s NSW Medical Devices Fund to assist in the commercialisation of the system.

Currently, the system takes about 2 minutes to polymerise in situ, and research suggests that the epithelium tends to grow over the iFix ink over time. The ink tends to degrade where it grows into the bioink. Ultimately, the team is seeking the full integration of iFix ink, cornea, and colonising cells in an immuno-neutral scenario. The bioink’s degradation is a result of corneal cells consuming the all-natural materials of the ink.

The team’s next task is to use the system in a large animal study, probably using rabbits. No human trials have been undertaken, but it is hoped that Phase 1 human trials will commence sometime this year. The same team is hoping to create a 3D bioengineered whole cornea within 5 to 10 years. The ability to become less reliant on donor corneal tissue for corneal surgery constitutes a strong motivation for the SSI and its collaborators.

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