Developing eye models to improve eye treatments and contact/intraocular lens technologies

Cataract surgery is the most common surgery in the developed world with over 300,000 operations in the UK and 2 million operations in the USA each year. It is also a leading cause of visual impairment in the developing world. Optimum implantation of intraocular lenses can also correct refractive error, recognised as the developing world's leading cause of visual impairment. Presbyopia, the loss of eye focus due to a hardening of the crystalline lens, requires reading correction around 45 years of age. This is a universal eye problem in older people (with current treatments associated with side effects or lacking efficacy) which has great potential to be overcome by intraocular lens technology. Currently, the development of new intraocular lens designs and materials to replace the optical power of the surgically removed crystalline lens which has opacified, requires years of animal work and clinical trials and due to the cost, progress tend to be slow and incremental. Animal models are not that close to the human eye, so many human clinical trials do not result in acceptable safe and efficacious advances. Hence, what is required is a human-like eye in-vitro model with 'living' tissue.

Aims: Previous research has established the viability of maintaining both corneal (Zhao et al, 2006,2008) and crystalline lens (Cleary et al., 2010) tissue physiologically stable for a period of at least 10 days. This project will combine these structures in a complete anterior eye model by vacuum sealing the ring of tissue posterior to the lens in a transparent chamber to allow imaging of the anatomy from the posterior aspect. A porcine eye has been chosen due to its similar biometry to the human eye (Menduni et al., 2018). A series of precision motors will mimic the action of the ciliary muscle which would need a blood supply to maintain its patency, allowing natural eye focus to be simulated. The lens stretcher allows the lens to be stretched while in the microgravity fluidic environment providing a more accurate model than previous studies as the lens will be maintained at physiologically realistic temperatures and hydration levels. The pressure in the anterior chamber will be monitored by a sensor and adjusted by altering the height differential of the physiological solution (Zhao et al, 2006) passed through the anterior chamber to maintain its patency. A second pump will pass fluid over the anterior surface of the cornea every 8-20 seconds to mimic the action of the tear film and allow dry eye conditions to be investigated. The environmental control system will be closed loop and allow temperature, pressure, oxygen saturation, pH, and flow rates to be controlled and continuously monitored. An alert system linked to the researchers' phones will ensure any deviations can be rapidly rectified. The eye model will be modular and scalable, reducing waste and energy usage while migrating risk in the development phase. The system will be able to scale from 1 to 24 test cells, with the multiple cells controlled by the same system allowing incremental differences to be examined simultaneously or experimental reliability to be tested.


Performance will be evaluated by the eye model maintaining optical transparency measured with optical imaging and wound closure occurring (after intraocular lens insertion) assessed by fluorescein dye excited under blue light and observed through a yellow filter. Light and electron microscopy will be used to assess the cell morphology and ultrastructure. Cell viability will be assessed through the LDH and K+ release, ATP depletion, and TBARS levels. Finally evaluation of intraocular lens implantation and pharmacological evaluation will be conducted in conjunction with a consultant ophthalmologist.

Humanised, 3D tissue models are finding interest due to current overly-simplified immortal cell lines and non-human in vivo models providing poor prediction of drug safety, dosing and efficacy; 43% of drug fails are not predicted by traditional screening and move into phase I clinical trials1. Phase I sees a 48% success rate, phase II a 29% success rate and phase III a 67% success rate [1]. The drug development pipeline is pressurised due to adoption of high throughput screening / combinatorial libraries. However, while R&D spend has increased to meet this growing screening programme, success, measured by launched drugs, remains static [2]. This poor predictive power of the >1 million animals used in the UK each year drives the 12-15 year, £1.85B pipeline, for each new drug launch [3]. Contract research organisations (CROs) are also similarly hit by these problems.

Drive to reduce animal experimentation in toxicology and outright banning of animal testing for e.g. cosmetics in the UK has driven companies to outsource or to adopt the limited number of regulator approved NAT models for e.g. skin [4,5].

Another key area that uses 3D tissues is the field of advanced therapeutic medicinal products (ATMPs), i.e. tissue engineering/regenerative medicine. Regulation is a major ATMP bottleneck. It is thus noteworthy that regulators, such as the UKs Medicines and Healthcare Products Regulatory Agency (MHRA), are receptive to the inclusion of NAT-based data in investigative medicinal product dossiers [6].

The lifETIME CDT will directly address these issues through nurturing of a cohort training not only in the research skills required to conceive and design new NATs, but also in skills based on:

- GMP and manufacture.
- Commercialisation and entrepreneurship.
- Regulation.
- Drug discovery and toxicology - a focus on the end product.
- Policy.
- Public engagement.

Our NAT graduate community will impact on:

- Pharma - access to skills that develop tools to unlock their drug discovery and testing portfolios. By helping train graduates who can create and deploy NATs, they will increase efficiency of drug development pipelines.

- ATMP manufacturers - the same skills and tools used to deliver NAT innovation will help to deliver tissue engineered / combination product ATMPs.

- CROs - access to skills to create platform tools providing more sophisticated approaches to the diverse research challenges they face.

- Catapult Centres - access to skills that provide innovation that can be deployed across the broader healthcare sector.

- Regulatory agencies e.g. MHRA - better education for the next generation of scientists on development of investigational new drug / medicinal product dossiers to speedup approvals.

- Clinicians and NHS - access to more medicines more quickly through provision of highly skilled scientists, manufacturers and regulators. NATs will help drive the stratified/personalised medicine revolution and understand safety and efficacy parameters in human-relevant tissues. Clinicians will also benefit from development of ATMP-based regenerative medicine.

- Patients - benefit from skills for faster and more economically streamlined development of new medicines that will improve lifespan and healthspan.

- Public and Society - benefit from the economic growth of a thriving drug development industry. Benefits will be direct, via jobs creation and access to wider and more targeted healthcare products; and indirect, via increased economic benefit of patients returning to work and increased tax revenues, that in turn feed back into the healthcare systems.


[1]. Cook. Nat Rev Drug Discov 13, 419-431 (2014).
[2]. Pammolli. Nat Rev Drug Discov 10, 428-438 (2011).
[3]. DiMasi. Health Econ 47, 20-33 (2016).
[4]. Cotovio. Altern Lab Anim 33, 329-349 (2005).
[5]. Kandarova. Altern Lab Anim 33, 351-367 (2005).
[6]. https://goo.gl/i6xbmL