The future of materials innovations in ophthalmology: This article will explore developments in materials science on the design of new eye drops and discusses the potential impact of 3D printing on the future treatment of patients.
Therapeutic optometrists [??]
Dispensing opticians [??]
Materials have been used to help reconstruct parts of the body for thousands of years. Indeed, the earliest documented use of a material in medicine is from ancient Egypt and can be found in the Edwyn Smith papyrus (c. 1600BC), which describes the use of sutures, splints, bandages and poultices. (1) The oldest physical example of an implant is attributable to the Romans (60AD), who used iron dental devices, which were well tolerated following implantation in the jaw and alveolar ridge. (2) Up until the last century, the majority of materials that were used in medicine were used principally to fulfil a mechanical role. An increasing understanding of the composition and mechanical properties of tissues in the last century led to a more rational approach to the design of materials for replacing tissue function beyond simple bulk mechanical properties. The use of materials to restore ocular function has seen a similar revolution in approach, with constant innovation in contact lenses since their original use in 1801 leading to them being one of the most frequently used medical devices in the UK and Ireland with 4.2m wearers in 2014. (3) More invasive technologies were also pioneered in the 20th century, with the revolutionary work of Ridley resulting in the first intraocular lens, (4) which significantly enhanced the quality of life of individuals requiring interventions following the formation of cataracts. With our ever-improving understanding of how we can modify materials to provide very unusual properties and our capacity to control the structuring of materials using methods collectively described as 3D printing, we are entering an era where it is very possible that materials may once again provide a step-change in how we approach the treatment of many ocular diseases. This article will describe recent improvements in the use of materials to design new eye drops and will also discuss how 3D printing is primed to revolutionise the treatment of many patients.
Many people would not think of an eye drop as a material, but rather as a medicine or a means to deliver a medicine to a region of the eye. In the case of simple saline drops, they would be right. Saline drops are simple liquids in which a drug may be dispersed and then delivered directly onto the ocular surface. The limitation with this technology is the relatively short retention time for the drop on the eye's surfaces. When applied, saline drops typically reside on the ocular surface for as little as 90 seconds before being blinked away. Enhancing the retention of the eye drops on the surface of the eye is achieved through creating structure within the liquid; (5) this is most simply accomplished through the addition of polymer into the aqueous phase. Currently, a number of different polymeric materials are used to modify the structure of eye drops, including hydroxypropyl methylcellulose (HPMC) and hyaluronan. The polymer chains that are dispersed in the liquid interact with one another and the water (see Figure 1A) and it is this interaction that results in an increase in the thickness (or viscosity) of the drop. Increasing the viscosity of the eye drop achieves two goals: first, it reduces the capacity of the material to flow across the surface and this slows the rate at which the material may be cleared by blinking; second, the polymer chains may interact with the underlying mucosa, which then increases the amount of time that the polymer will be retained on the eye's surface.
Typically, 0.3% by volume of HPMC is used to modify eye drops and this increases the retention of the drop on the ocular surface to several minutes. Hypothetically, further increasing polymer loading should enhance retention, but there is a limitation on the viscosity of the drop that may be dispensed through a standard eye dropper. To try and counteract this, researchers have attempted to formulate eye droppers that form gels on the surface of the eye. A hydrogel is an interconnected network of polymer chains that is swollen by water (see Figure IB). The major limitation with this approach is that the gel must be formed as it hits the surface on which it should be retained. The lack of a reproducible stimulus for the cross-linking creates a major barrier to producing a product that gels in all patients in the same way. The stimulus that is used to create this network (from shorter chained molecules) typically requires the addition of another chemical or a significant change in temperature. Given variations in tear compositions and ambient temperature, this is a significant challenge, which has yet to be overcome. As a consequence, there are currently no eye drops on the market that match the scientific description of a 'true gel' (a dilute, cross-linked material that will exhibit no flow under steady-state). Even though some purport to be gels, they are most likely only gels in the same sense that shower gel is a gel--that is to say, they are a viscous polymer dispersion that will continue to flow under their own weight when deposited onto a surface.
In an attempt to address the limitations that are currently associated with eye drops, the authors have developed a method for processing true polymer gels so that they exhibit the desirable properties of gel material but may still be extruded onto the surface of the eye. The key innovation that the lab has made to the gel production process is that during manufacture of the material, a shearing (or twisting motion) is applied. (6) As the polymer chains begin to cross-link, the shear disturbs the longer-range ordering within the gel, and this stops the polymer network from ever being entirely continuous through the whole structure; this results in a structure that is formed from gel particles and ribbons that sit within a highly hydrated environment (see Figure 1C). Importantly, these individual particles form interactions with one another, and these so-called secondary interactions cause the material to form a loosely bonded network of particles in the absence of applied force. When this network of particles is sheared, the interactions between the particles are broken and the gel structure re-liquefies, which allows it to be ejected through an eye dropper or even to be sprayed onto a surface using an airbrush (see Figure 2). When the material strikes the surface and the shear force is removed, the network reforms and the gel solidifies. As a consequence, these 'structured' eye drops can be applied to the ocular surface and will be retained, slowly being removed by the application of a shear force from the eyelid. It has been demonstrated that these drops can be modified so that they can have residence times of up to 180 minutes following application in a blinking animal model. Clearly, such an improvement in retention time presents opportunities for the more effective delivery of expensive biotherapeutics which otherwise are quickly cleared from the ocular surface (as recently reported for the scar reducing molecule decorin (7)) or could provide a means to stabilise serum eye drops on the surface of the eye for the treatment of dry eye. They may even act as an occlusive ocular dressing/ lubricant when applied alone. The authors' team has now used this technology to develop several products, which will go into trial in late 2019, early 2020.
Additive layer manufacturing
The term additive layer manufacturing (ALM), or 3D printing as it is more frequently known in the popular media, describes any number of processes that are used to create an object by steadily building up layers, as opposed to the whittling away of material from a larger structure, which has formed the bedrock of manufacturing since humans first crafted and utilised tools. ALM has actually been used clinically since the early 1990s when it was used to create structures that could be exploited to plan surgical procedures. It has subsequently been used in dentistry to rapidly manufacture prosthetics with bespoke geometry. More recently, it has been used to manufacture bespoke prosthetic devices to restore quantities within the face and skull. ALM can be used as a strategy to print a number of different materials, employing different methods to consolidate the part that is being produced. Laser consolidation is frequently used for metallic materials, the spraying of liquid onto a surface for the creation of cement/ceramic structures and UV-light for hard/brittle polymeric structures. Each of these technologies is getting to the stage of maturity where they can be used to create robust and reproducible parts. An area of research which is still under rapid development and promises to have a huge clinical impact is the 3D printing of biological structures, a process which is more commonly known as 'bioprinting.'
Given the requirement of biological entities such as cells for nutrients, the materials that are most frequently employed for bioprinting are hydrogels; this is because they are formed principally from water, which means that nutrients are able to diffuse into these structures and metabolic waste products are able to diffuse back out. However, a major challenge with ALM of soft materials is that they are not sufficiently strong to support their own weight (unlike both ceramics and metals), which means that only simple structures and those that can self-support (normally pyramid-like or flat structures) are usually manufacturable. As a consequence, the cornea is the perfect candidate tissue for bioprinting. Recently, Che Connon from the University of Newcastle has developed a method for the printing of cornea-like structures. (8) In this method, a combination of alginate (a sugar-based polymer that is derived from seaweed) and collagen (the main structural protein in the human body) are combined and then extruded onto a pre-curved surface. Keratocytes can be combined with alginate/ collagen-based bio-ink and may be extruded onto this surface. The manufacturing method is extremely gentle and maintains high levels of cell viability. At present, the team at Newcastle is looking at how to combine this method into the patient pathway and it has the potential to replace costly transplant processes and lessen the burden on the NHS and other healthcare providers to deliver tissue for transplantation. This will of course enhance patient care and reduce the time patients must wait for these procedures.
The authors are working on printing much larger, anatomically realistic structures using a process they have termed 'suspended layer additive manufacturing' (SLAM). In this method, structural support is provided to the forming part using a bed of the fluid gel that is described in the section on eye drops. A bio-ink can then be formed from any hydrogel and a dispersion of live cells. The bio-ink can then be formed into this supporting matrix through a needle. When the bio-ink is extruded into place it is supported on all sides and can maintain the geometry in which it is deposited during the gelation process. This level of support from all sides enables printing of very complex structures which are large compared with the simple two-dimensional structures which have been widely reported in the literature (see Figure 3). SLAM also enables production of structures that are formed of several different materials and cell types and enables the modification of the local mechanical and chemical properties offering control over cell behaviour.
The authors have already reported on the use of this method to regenerate complex multi-tissue structures such as the osteochondral region. (9) The next aim is to apply the method to reconstruct some of the tissues that are found in the eye, and the lab has shown that it is possible to print structures that have a close structural resemblance to the optic disc and optic nerve (see Figure 4). Although work is clearly at an early stage in the transfer of this technology through to the clinic, the bioprinting of tissues is something that truly sits within view on the horizon and could very well be used to create models to enhance our understanding of biological processes or may even be used as a means to print tissues to reduce the demand for tissue transplants.
Balancing optimism for new technologies with their capacity to deliver is always a major challenge in the development of any area. Over-hyped technologies that fail to deliver are ultimately harmful since they can result in disillusionment among practitioners.
Now that researchers are becoming more sensitive to this and are encouraged by funders to think about how to create a pathway to impact, the authors believe that we are now in a position to transfer some of the technology described into clinical reality.
* Professor Liam Grover is a professor of biomaterials science at the University of Birmingham. He has been in post at the University of Birmingham since 2006, prior to which he was a CIHR skeletal health scholar at McGill University, Montreal. He has taken medical technologies from bench through to the clinic and heads up the newly established Healthcare Technologies Institute. He has written more than ISO scientific papers, filed more than 10 patents and has given over 50 invited talks internationally. Twitter:@>DWLiam
* Dr Lisa Hill is a recently appointed lecturer at the University of Birmingham. Dr Hill leads research in the fields of translational ophthalmology and ocular drug delivery and has a particular interest in developing new treatments for ocular fibrotic and degenerative diseases. Dr Hill holds current funding from Fight for Sight, MRC and Queen Elizabeth Hospitals Birmingham and has multiple national and international collaborative projects with groups from London, Bristol, Australia and the US. Twitter:@>Neuroscience_Dr
The authors would like to acknowledge Dr Megan Cooke, Jess Senior, Dr Richard Moakes and Prof Alan Smith for assistance with compiling the figures.
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Course code: C-71175 Deadline: 23 August 2019
* Be aware of emerging technologies for novel eye drop development and ocular tissue bioprinting (Group 2.5.3)
* Be aware of the latest evidence relating to pioneering research for developing novel eye drops and ocular tissue using bioprinting techniques (Group 7.1.6)
* Be aware of emerging technologies for novel eye drop development and ocular tissue bioprinting (Group 2.5.3)
Professor Liam M Grover BMedSc (Hons), PhD, FIMMM and Dr Lisa J Hill BMedSc (Hons), PhD
Caption: Figure 1 Simple schematic diagrams showing the structure of: 1A An entangled polymer network; IB A polymeric hydrogel where polymer chains interact strongly (junction zones marked with blue circles) and the structure is swollen with water; 1C Fluid-gel material formed of particles and ribbons of a disrupted gel network (wider field of view than the A or B). These particles interact with one another and yet flow when sheared strongly. This means that they can be retained effectively on the ocular surface but may still be extruded from an eye-dropper, a major challenge that limits the application of traditional hydrogel materials
Caption: Figure 2 The fluid-gel that we have developed as an eye drop is shear responsive, meaning that it can be ejected through an eyedropper (top left), before solidifying across a surface (top right) and being retained on a surface (bottom right). It may also be sprayed using an airbrush (bottom left) without affecting its resolidification
Caption: Figure 3 The process of suspended layer additive manufacturing (SLAM) utilises a supportive matrix into a which a bio-ink may be extruded (A); this bio-ink will gel within the supportive matrix to form a consolidated structure, which will solidify in-situ (B). Providing support on all sides means that it is possible to produce highly complex parts (C) within the supportive phase (D)
Caption: Figure 4 it is straightforward to create simple computer models of tissues I and structures and then manufacture them using the SLAM method. Here I we have a simplified model of an optic nerve and optic disc (left), which was H then printed into our supportive matrix (centre) and once hardened and I removed from the structure, retained its gross morphology (right)_I
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|Title Annotation:||Material innovation|
|Author:||Grover, Liam M.; Hill, Lisa J.|
|Date:||Jul 1, 2019|
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