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BCLA CLEAR – Contact lens technologies of the future

      Abstract

      Contact lenses in the future will likely have functions other than correction of refractive error. Lenses designed to control the development of myopia are already commercially available. Contact lenses as drug delivery devices and powered through advancements in nanotechnology will open up further opportunities for unique uses of contact lenses.
      This review examines the use, or potential use, of contact lenses aside from their role to correct refractive error. Contact lenses can be used to detect systemic and ocular surface diseases, treat and manage various ocular conditions and as devices that can correct presbyopia, control the development of myopia or be used for augmented vision. There is also discussion of new developments in contact lens packaging and storage cases.
      The use of contact lenses as devices to detect systemic disease has mostly focussed on detecting changes to glucose levels in tears for monitoring diabetic control. Glucose can be detected using changes in colour, fluorescence or generation of electric signals by embedded sensors such as boronic acid, concanavalin A or glucose oxidase. Contact lenses that have gained regulatory approval can measure changes in intraocular pressure to monitor glaucoma by measuring small changes in corneal shape. Challenges include integrating sensors into contact lenses and detecting the signals generated. Various techniques are used to optimise uptake and release of the drugs to the ocular surface to treat diseases such as dry eye, glaucoma, infection and allergy. Contact lenses that either mechanically or electronically change their shape are being investigated for the management of presbyopia. Contact lenses that slow the development of myopia are based upon incorporating concentric rings of plus power, peripheral optical zone(s) with add power or non-monotonic variations in power. Various forms of these lenses have shown a reduction in myopia in clinical trials and are available in various markets.

      Keywords

      Abbreviations

      CE
      Conformité Européenne
      ConA
      Concanavalin A
      DEAA
      N,N-diethylacrylamide
      DED
      dry eye disease
      Dk/t
      oxygen transmissibility
      ECP
      eye care professional
      EGDMA
      ethylene glycol dimethacrylate
      FDA
      Food and Drug Administration
      HEMA
      poly (2-hydroxyethyl methacrylate)
      HPMC
      hydroxypropyl methylcellulose
      IgE
      immunoglobulin E
      IgG
      immunoglobulin G
      IL
      interleukin
      IOP
      intraocular pressure
      LED
      light emitting diode
      MAA
      methacrylic acid
      MMP
      matrix Metalloproteinase
      PEG
      polyethylene glycol
      PLGA
      poly (lactic-co-glycolic acid)
      PMMA
      polymethylmethacrylate
      PoLTF
      post-lens tear film
      TFOS DEWS II
      Tear Film and Ocular Surface Society Dry eye workshop II
      TNF
      tumor necrosis factor

      1. Introduction

      Contact lenses were invented to correct refractive error and they have become a successful, convenient and widely used commodity for this purpose. However, looking forward into the not-so-distant future, the potential applications for these devices are proliferating to uses where vision correction per se is often not the main intention. Industries as far ranging as bio-sensors, pharmaceuticals, defence and the entertainment sector could all potentially apply contact lens-based technologies to achieve solutions to problems for their specific unmet needs. This review will explore some of these innovations and consider how these efforts will change the way contact lenses are used in the future.

      2. Diagnosis and screening for systemic disease

      Historically, the quantification of analytes in the tear film has primarily focused on the diagnosing and monitoring of ocular conditions. However, it is increasingly apparent that the tear film contains a wide range of biomarkers that may help diagnose systemic disease for a range of conditions [
      • Hagan S.
      • Martin E.
      • Enriquez-de-Salamanca A.
      Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine.
      ]. A contact lens-based diagnostic device would allow a biosensor to be placed in close proximity to the ocular tissue and be bathed in the tear fluid, which is known to reflect pathophysiological changes in several systemic and ocular diseases, as described in Table 1.
      Table 1Systemic disease biomarkers found within the tear film.
      DiseasePotential tear biomarkers
      Alzheimer’s diseaseIncreased levels of dermcidin, lacritin, lipocalin-1 and lysozyme-C [
      • Kallo G.
      • Emri M.
      • Varga Z.
      • Ujhelyi B.
      • Tozser J.
      • Csutak A.
      • et al.
      Changes in the chemical barrier composition of tears in Alzheimer’s disease reveal potential tear diagnostic biomarkers.
      ]
      CancerIncreased levels of lacryglobin [
      • Evans V.
      • Vockler C.
      • Friedlander M.
      • Walsh B.
      • Willcox M.D.
      Lacryglobin in human tears, a potential marker for cancer.
      ,
      • de Freitas Campos C.
      • Cole N.
      • Van Dyk D.
      • Walsh B.J.
      • Diakos P.
      • Almeida D.
      • et al.
      Proteomic analysis of dog tears for potential cancer markers.
      ], changes in combination of specific proteins [
      • You J.
      • Willcox M.D.
      • Madigan M.C.
      • Wasinger V.
      • Schiller B.
      • Walsh B.J.
      • et al.
      Tear fluid protein biomarkers.
      ]
      Cystic fibrosisIL-8 and IFN-γ [
      • Mrugacz M.
      • Kaczmarski M.
      • Bakunowicz-Lazarczyk A.
      • Zelazowska B.
      • Wysocka J.
      • Minarowska A.
      IL-8 and IFN-gamma in tear fluid of patients with cystic fibrosis.
      ], MIP-1α [
      • Mrugacz M.
      • Zelazowska B.
      • Bakunowicz-Lazarczyk A.
      • Kaczmarski M.
      • Wysocka J.
      Elevated tear fluid levels of MIP-1alpha in patients with cystic fibrosis.
      ] and MIP-1β [
      • Mrugacz M.
      CCL4/MIP-1beta levels in tear fluid and serum of patients with cystic fibrosis.
      ]
      DiabetesIncreased levels of glucose [
      • Aihara M.
      • Kubota N.
      • Kadowaki T.
      Study of the correlation between tear glucose concentrations and blood glucose concentrations.
      ], advanced glycation end products [
      • Zhao Z.
      • Liu J.
      • Shi B.
      • He S.
      • Yao X.
      • Willcox M.D.
      Advanced glycation end product (age) modified proteins in tears of diabetic patients.
      ], cytokine changes [
      • Liu J.
      • Shi B.
      • He S.
      • Yao X.
      • Willcox M.D.
      • Zhao Z.
      Changes to tear cytokines of type 2 diabetic patients with or without retinopathy.
      ]
      Multiple sclerosisOligoclonal bands of IgG [
      • Coyle P.K.
      • Sibony P.
      • Johnson C.
      Oligoclonal IgG in tears.
      ,
      • Devos D.
      • Forzy G.
      • de Seze J.
      • Caillez S.
      • Louchart P.
      • Gallois P.
      • et al.
      Silver stained isoelectrophoresis of tears and cerebrospinal fluid in multiple sclerosis.
      ] and α-1-antichymotrypsin [
      • Salvisberg C.
      • Tajouri N.
      • Hainard A.
      • Burkhard P.R.
      • Lalive P.H.
      • Turck N.
      Exploring the human tear fluid: discovery of new biomarkers in multiple sclerosis.
      ]
      Parkinson’s diseaseTNF-α [
      • Comoglu S.S.
      • Guven H.
      • Acar M.
      • Ozturk G.
      • Kocer B.
      Tear levels of tumor necrosis factor-alpha in patients with Parkinson’s disease.
      ] and oligomeric alpha-synuclein [
      • Hamm-Alvarez S.F.
      • Janga S.R.
      • Edman M.C.
      • Feigenbaum D.
      • Freire D.
      • Mack W.J.
      • et al.
      Levels of oligomeric alpha-synuclein in reflex tears distinguish Parkinson’s disease patients from healthy controls.
      ]
      Thyroid diseaseIL-1β, IL-6, IL-17, TNF-α [
      • Huang D.
      • Luo Q.
      • Yang H.
      • Mao Y.
      Changes of lacrimal gland and tear inflammatory cytokines in thyroid-associated ophthalmopathy.
      ] and IL-7 [
      • Cai K.
      • Wei R.
      Interleukin-7 expression in tears and orbital tissues of patients with graves’ ophthalmopathy.
      ]
      IL – Interleukin; IFN – Interferon; MIP – Macrophage inflammatory protein; TNF – tumor necrosis factor; IgG – Immunoglobulin G.
      Biochemical tear film sensing technology is rapidly evolving, allowing the incorporation of either electrochemical or optical sensing technologies into future diagnostic contact lenses [
      • Tseng R.C.
      • Chen C.C.
      • Hsu S.M.
      • Chuang H.S.
      Contact-lens biosensors.
      ]. This approach offers distinct advantages over direct tear sampling, as a contact lens enables the cumulative detection of biomarkers during the wearing period, potentially increasing assay sensitivity [
      • Kim Y.S.
      Functionalized eyewear device for detecting biomarker in tears.
      ]. In addition, a range of sensing technologies is now available which could be incorporated into future diagnostic contact lenses to monitor clinical ophthalmic biomarkers, including blink tracking [
      • Pugh R.B.
      • Toner A.
      • Humphreys S.R.
      • Otts D.B.
      • Neeley W.C.
      Blink detection system for electronic ophthalmic lens.
      ], eye movement tracking [
      • Chen R.
      • Kalinli O.
      Interface using eye tracking contact lenses.
      ], pupillary responses [

      A. Shtukater. Smart contact lens. Google Patents. US10845620B2. USA; 2015.

      ] and retinal vessel pulsation/imaging [

      RB. Pugh. Ophthalmic lens with retinal vascularization monitoring system. Google Patents. US10159461B2. USA: Johnson & Johnson Vision Inc.; 2018.

      ]. In addition, due to the relatively large surface area of the contact lens, there is potential for multiplexing to monitor various biomarkers at the same time via a single device [
      • Badugu R.
      • Jeng B.H.
      • Reece E.A.
      • Lakowicz J.R.
      Contact lens to measure individual ion concentrations in tears and applications to dry eye disease.
      ,
      • Yetisen A.K.
      • Jiang N.
      • Castaneda Gonzalez C.M.
      • Erenoglu Z.I.
      • Dong J.
      • Dong X.
      • et al.
      Scleral lens sensor for ocular electrolyte analysis.
      ]. Future research will likely focus on identifying and refining the key biomarkers for these conditions, establishing the specificity and sensitivity of the biomarkers for the particular diseases, and developing tear film capturing and sensing technologies to allow such analysis to be truly diagnostic. This will allow the potential for simple contact lens-based technologies that could diagnose systemic disease at an earlier stage, allowing prompt management and improved clinical outcomes.
      Two specific examples of research in this area relate to diabetes monitoring via tear film glucose detection and detection of cancer-markers within the tear film.

      2.1 Diabetes monitoring via tear-film glucose detection

      Diabetes, a chronic condition characterised by high levels of blood sugar, affects more than 463 million people worldwide and is on the rise [
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • Malanda B.
      • Karuranga S.
      • Unwin N.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9(th) edition.
      ]. As there is currently no cure, effective monitoring and control of blood glucose levels are critical in managing the condition and its complications. The gold standard for blood glucose monitoring is the finger-prick method, where a lancet is used to pierce the skin of a finger or another site to obtain a blood sample that is read by a glucose meter. This procedure can cause discomfort and is inconvenient, while also raising the risk of loss of sensation and secondary infection in repeatedly sampled areas [
      • Heinemann L.
      Finger pricking and pain: a never ending story.
      ]. Non-invasive methods for glucose detection have thus been proposed to alleviate these complications and improve patient quality of life.
      The tear fluid is a potential site for non-invasive glucose monitoring due to its relative accessibility. The concentration of tear glucose is higher in diabetics than healthy individuals [
      • Aihara M.
      • Kubota N.
      • Kadowaki T.
      Study of the correlation between tear glucose concentrations and blood glucose concentrations.
      ] and several groups have proposed contact lens-based biosensors to measure tear glucose levels [
      • Liao Y.-T.
      • Yao H.
      • Lingley A.
      • Parviz B.
      • Otis B.P.
      A 3-μw cmos glucose sensor for wireless contact-lens tear glucose monitoring.
      ,
      • Otis B.
      • Liao Y.
      • Amirparviz B.
      • Yao H.
      Wireless powered contact lens with biosensor.
      ,
      • Elsherif M.
      • Hassan M.U.
      • Yetisen A.K.
      • Butt H.
      Wearable contact lens biosensors for continuous glucose monitoring using smartphones.
      ,
      • Cummins B.M.
      • Garza J.T.
      • Cote G.L.
      Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy.
      ,

      M. Lamrani. Glucose sensing contact lens. Google Patents. US10478104B2. USA: Menicon Co Ltd; 2019.

      ,
      • Senior M.
      Novartis signs up for Google smart lens.
      ,
      • Park S.
      • Boo H.
      • Chung T.D.
      Electrochemical non-enzymatic glucose sensors.
      ,
      • Liu M.
      • Liu R.
      • Chen W.
      Graphene wrapped Cu2O nanocubes: non-enzymatic electrochemical sensors for the detection of glucose and hydrogen peroxide with enhanced stability.
      ,
      • Feng D.
      • Wang F.
      • Chen Z.
      Electrochemical glucose sensor based on one-step construction of gold nanoparticle–chitosan composite film.
      ,
      • Park J.
      • Kim J.
      • Kim S.Y.
      • Cheong W.H.
      • Jang J.
      • Park Y.G.
      • et al.
      Soft, smart contact lenses with integrations of wireless circuits, glucose sensors, and displays.
      ,
      • Shende P.
      • Sahu P.
      • Gaud R.
      A technology roadmap of smart biosensors from conventional glucose monitoring systems.
      ,

      Y. Yang, Y.S. Rim, j. Yang High performance chemical and bio sensors using metal oxide semiconductors. US 20180059051 A1. 2019.

      ,
      • Sei K.H.
      • Young C.S.
      • Beom H.M.
      • Keon J.L.
      • Dohee K.
      Smart contact lenses and smart glasses.
      ]. This concept would open up the possibility of continuous tear glucose monitoring rather than the “snapshots” which are provided by monitoring through finger prick testing.

      2.1.1 Mode of detection

      Glucose detection using a biosensor can be broadly categorised into either optical or electrochemical methods (see Table 2 for examples).
      Table 2Examples of glucose biosensors developed for contact lenses.
      Mode of detectionGlucose sensorReader
      Fluorescence [

      W.F. March, M.F. Mowery-McKee. Ocular analyte sensor. Google Patents. US6980842B2. USA: Eyesense AG; 2002.

      ]
      Boronic acid,

      Concanavalin A
      External detector
      Colourimetric [
      • Alexeev V.L.
      • Das S.
      • Finegold D.N.
      • Asher S.A.
      Photonic crystal glucose-sensing material for noninvasive monitoring of glucose in tear fluid.
      ]
      Boronic acidColour chart
      Fluorescence [
      • Geddes C.D.
      • Badugu R.
      • Lakowiccz J.R.
      Quaternary nitrogen heterocyclic compounds for detecting aqueous monosaccharides in physiological fluids.
      ]
      Boronic acidPhotodetector
      Fluorescence, colourimetric [
      • Morris C.A.
      • Carney F.P.
      • Lane J.D.
      Kits for assays of rapid screening of diabetes.
      ]
      Boronic acid, Concanavalin AExternal detector
      Fluorescence, colourimetric [

      J. Zhang, W.G. Hodge. Contact lens integrated with a biosensor for the detection of glucose and other components in tears. Google Patents. US8385998B2. USA; 2009.

      ]
      Boronic acid, Concanavalin APhotodetector
      Fluorescence [
      • Ibey B.L.
      • Yadavalli V.K.
      • Rounds R.M.
      • Beier H.T.
      • Cote G.L.
      • Pishko M.V.
      Method for glucose monitoring using fluorescence quenching.
      ]
      Boronic acid,

      Concanavalin A
      External detector
      Light emitted [

      W.F.A. Besling. Flexible eye insert and glucose measuring system. Google Patents. US9737245B2. USA: NXP BV; 2012.

      ]
      Boronic acidPhotodetector
      Electrochemical [
      • Kajisa T.
      • Sakata T.
      Glucose-responsive hydrogel electrode for biocompatible glucose transistor.
      ]
      Boronic acidElectrode
      Fluorescence, luminescence [

      C.A. Yildirim. A contact lens design sensing tear glucose level. Google Patents. WO2017116350A1. 2017.

      ]
      Boronic acidExternal reader
      Light emitted [
      • Elsherif M.
      • Hassan M.U.
      • Yetisen A.K.
      • Butt H.
      Wearable contact lens biosensors for continuous glucose monitoring using smartphones.
      ]
      Boronic acidSmart phone
      Optical [

      M. Lamrani. Glucose sensing contact lens. Google Patents. US10478104B2. USA: Menicon Co Ltd; 2019.

      ]
      Boronic acidExternal reader
      Absorbance [
      • Aslan K.
      • Lakowicz J.R.
      • Geddes C.D.
      Tunable plasmonic glucose sensing based on the dissociation of con a-aggregated dextran-coated gold colloids.
      ]
      Concanavalin ASpectrophotomer
      Fluorescence [
      • March W.
      • Lazzaro D.
      • Rastogi S.
      Fluorescent measurement in the non-invasive contact lens glucose sensor.
      ]
      Concanavalin AHandheld photofluorometer
      Fluorescence [
      • Cummins B.M.
      • Garza J.T.
      • Cote G.L.
      Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy.
      ]
      Concanavalin AHandheld photofluorometer
      Electrochemical [
      • Yao H.
      • Liao Y.
      • Lingley A.R.
      • Afanasiev A.
      • Lähdesmäki I.
      • Otis B.P.
      • et al.
      A contact lens with integrated telecommunication circuit and sensors for wireless and continuous tear glucose monitoring.
      ]
      Glucose oxidaseElectrode
      Electrochemical [
      • Liao Y.-T.
      • Yao H.
      • Lingley A.
      • Parviz B.
      • Otis B.P.
      A 3-μw cmos glucose sensor for wireless contact-lens tear glucose monitoring.
      ]
      Glucose oxidaseSmart phone
      Electrochemical [
      • Otis B.
      • Liao Y.
      • Amirparviz B.
      • Yao H.
      Wireless powered contact lens with biosensor.
      ]
      Glucose oxidaseHandheld reader or smart phone
      Electrochemical [

      Z. Liu Contact lenses having two-electrode electrochemical sensors. Google Patents. US20140194713A1. USA: Verily Life Sciences LLC; 2014.

      ]
      Glucose oxidaseExternal receiver
      Electrochemical [
      • Park J.
      • Kim J.
      • Kim S.Y.
      • Cheong W.H.
      • Jang J.
      • Park Y.G.
      • et al.
      Soft, smart contact lenses with integrations of wireless circuits, glucose sensors, and displays.
      ]
      Glucose oxidaseOn lens display
      Electrochemical [
      • Gandhi H.
      • Gao H.
      • Baig M.
      • Chen R.
      Functional contact lens and related systems and methods.
      ]
      Metal oxidesExternal receiver

      2.1.1.1 Optical detection methods

      For optical detection, the binding of glucose to the sensors typically results in a colourimetric or fluorescence change which is measured using an external reader such as a photodetector or a smartphone. Optical sensors are relatively inexpensive and simple to fabricate since they do not require any additional embedded circuits for power or communication. However, optical detection can be somewhat subjective and prone to errors influenced by elements such as lighting conditions and detector distance.

      2.1.1.2 Electrochemical detection methods

      Electrochemical sensors are more complex, requiring additional micro-components such as a power source, microprocessor and an antenna for external communication. The underlying mechanism of glucose detection in these systems is a redox reaction of glucose by a catalyst into hydrogen peroxide, which is then oxidised at an electrode to release free electrons [
      • Miyashita M.
      • Ito N.
      • Ikeda S.
      • Murayama T.
      • Oguma K.
      • Kimura J.
      Development of urine glucose meter based on micro-planer amperometric biosensor and its clinical application for self-monitoring of urine glucose.
      ,
      • Koudelka M.
      • Gernet S.
      • De Rooij N.F.
      Planar amperometric enzyme-based glucose microelectrode.
      ,
      • Clark Jr., L.C.
      • Lyons C.
      Electrode systems for continuous monitoring in cardiovascular surgery.
      ]. The free electrons produce an electric current that is proportional to the amount of glucose present in the system. The catalyst can be an enzyme [
      • Miyashita M.
      • Ito N.
      • Ikeda S.
      • Murayama T.
      • Oguma K.
      • Kimura J.
      Development of urine glucose meter based on micro-planer amperometric biosensor and its clinical application for self-monitoring of urine glucose.
      ,
      • Koudelka M.
      • Gernet S.
      • De Rooij N.F.
      Planar amperometric enzyme-based glucose microelectrode.
      ,
      • Clark Jr., L.C.
      • Lyons C.
      Electrode systems for continuous monitoring in cardiovascular surgery.
      ], a metal [
      • Park S.
      • Boo H.
      • Chung T.D.
      Electrochemical non-enzymatic glucose sensors.
      ,
      • Liu M.
      • Liu R.
      • Chen W.
      Graphene wrapped Cu2O nanocubes: non-enzymatic electrochemical sensors for the detection of glucose and hydrogen peroxide with enhanced stability.
      ,
      • Feng D.
      • Wang F.
      • Chen Z.
      Electrochemical glucose sensor based on one-step construction of gold nanoparticle–chitosan composite film.
      ] or another glucose-binding molecule [
      • Kajisa T.
      • Sakata T.
      Glucose-responsive hydrogel electrode for biocompatible glucose transistor.
      ].
      The advantages of the electrochemical approach is that these systems are highly accurate and can provide continuous and seamless real-time monitoring of tear glucose. The challenge of such a system lies in methods harnessing the electric current, translating it into a quantifiable signal and creating the accessory micro-components to an electrochemical sensor. Previous work has discussed the development of a contact lens platform that coupled the current from the glucose sensor with an antenna and microprocessor [
      • Liao Y.-T.
      • Yao H.
      • Lingley A.
      • Parviz B.
      • Otis B.P.
      A 3-μw cmos glucose sensor for wireless contact-lens tear glucose monitoring.
      ,
      • Otis B.
      • Liao Y.
      • Amirparviz B.
      • Yao H.
      Wireless powered contact lens with biosensor.
      ,
      • Yao H.
      • Liao Y.
      • Lingley A.R.
      • Afanasiev A.
      • Lähdesmäki I.
      • Otis B.P.
      • et al.
      A contact lens with integrated telecommunication circuit and sensors for wireless and continuous tear glucose monitoring.
      ]. This system was powered entirely wirelessly using radio frequencies, solving the difficulties involved with powering the individual micro-components [
      • Liao Y.-T.
      • Yao H.
      • Lingley A.
      • Parviz B.
      • Otis B.P.
      A 3-μw cmos glucose sensor for wireless contact-lens tear glucose monitoring.
      ,
      • Otis B.
      • Liao Y.
      • Amirparviz B.
      • Yao H.
      Wireless powered contact lens with biosensor.
      ,
      • Yao H.
      • Liao Y.
      • Lingley A.R.
      • Afanasiev A.
      • Lähdesmäki I.
      • Otis B.P.
      • et al.
      A contact lens with integrated telecommunication circuit and sensors for wireless and continuous tear glucose monitoring.
      ]. This concept spurred several startup companies that have tried to develop a so-called “smart” glucose contact lens, the most prominent example being led by the tech giant Google (Mountain View, CA, USA) in 2014, followed later by a collaboration between Google and Novartis (Basel, Switzerland) [
      • Senior M.
      Novartis signs up for Google smart lens.
      ].

      2.1.2 Glucose sensor types

      Several forms of glucose-sensors exist in the contact lens-based glucose sensors proposed (see Table 2 for examples).

      2.1.2.1 Boronic acid-based glucose sensors

      Boronic acids reversibly bind to carbohydrates, particularly diol-containing molecules such as glucose. These acids have unique optical properties when bound to glucose, resulting in a colourimetric or fluorescence change, depending on the specific boronic acid derivative used [
      • Alexeev V.L.
      • Das S.
      • Finegold D.N.
      • Asher S.A.
      Photonic crystal glucose-sensing material for noninvasive monitoring of glucose in tear fluid.
      ,
      • Sun X.
      • Zhai W.
      • Fossey J.S.
      • James T.D.
      Boronic acids for fluorescence imaging of carbohydrates.
      ].

      2.1.2.2 Concanavalin A-based glucose sensors

      Concanavalin A (ConA) is a lectin or carbohydrate binding protein. A ConA competitive binding assay biosensor has been applied to a contact lens system [
      • Cummins B.M.
      • Garza J.T.
      • Cote G.L.
      Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy.
      ,
      • March W.
      • Lazzaro D.
      • Rastogi S.
      Fluorescent measurement in the non-invasive contact lens glucose sensor.
      ]. In the absence of glucose, ConA is bound to a ligand, such as fluorescein-labelled dextran and produces minimal fluorescence [
      • Cummins B.M.
      • Garza J.T.
      • Cote G.L.
      Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy.
      ,
      • March W.
      • Lazzaro D.
      • Rastogi S.
      Fluorescent measurement in the non-invasive contact lens glucose sensor.
      ]. In the presence of glucose, the ligand is displaced and glucose instead binds to ConA, resulting in an increase in fluorescence related to the amount of glucose present, with the change in fluorescence measured using a handheld fluorometer [
      • Cummins B.M.
      • Garza J.T.
      • Cote G.L.
      Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy.
      ,
      • March W.
      • Lazzaro D.
      • Rastogi S.
      Fluorescent measurement in the non-invasive contact lens glucose sensor.
      ,
      • Aslan K.
      • Lakowicz J.R.
      • Geddes C.D.
      Tunable plasmonic glucose sensing based on the dissociation of con a-aggregated dextran-coated gold colloids.
      ].

      2.1.2.3 Enzymatic glucose sensors

      Enzymatic detection of glucose by glucose oxidase, which specifically targets glucose, has both high sensitivity and selectivity [
      • Park S.
      • Boo H.
      • Chung T.D.
      Electrochemical non-enzymatic glucose sensors.
      ,
      • Villena Gonzales W.
      • Mobashsher A.T.
      • Abbosh A.
      The progress of glucose monitoring-a review of invasive to minimally and non-invasive techniques, devices and sensors.
      ]. In the presence of water and oxygen, the enzyme converts glucose to gluconic acid and hydrogen peroxide. The hydrogen peroxide is then oxidised at the anode of an electrochemical probe to produce a current corresponding to the amount of glucose in solution [
      • Villena Gonzales W.
      • Mobashsher A.T.
      • Abbosh A.
      The progress of glucose monitoring-a review of invasive to minimally and non-invasive techniques, devices and sensors.
      ].
      The significant advantage of enzymatic sensors lies in their specificity for the molecule in question, but a challenge lies in the integration of the microelectronic components into a contact lens platform. Other drawbacks relate to stability, especially for long term storage [
      • Park S.
      • Boo H.
      • Chung T.D.
      Electrochemical non-enzymatic glucose sensors.
      ,
      • Koudelka M.
      • Gernet S.
      • De Rooij N.F.
      Planar amperometric enzyme-based glucose microelectrode.
      ] and that the sterilisation methods typically used by the contact lens industry (such as autoclaving) will generally denature the enzymes.

      2.1.2.4 Metal-based glucose sensors

      The stability problems associated with enzymatic sensors can be overcome by using metals such as platinum [
      • Park S.
      • Boo H.
      • Chung T.D.
      Electrochemical non-enzymatic glucose sensors.
      ], gold [
      • Feng D.
      • Wang F.
      • Chen Z.
      Electrochemical glucose sensor based on one-step construction of gold nanoparticle–chitosan composite film.
      ], copper oxide [
      • Liu M.
      • Liu R.
      • Chen W.
      Graphene wrapped Cu2O nanocubes: non-enzymatic electrochemical sensors for the detection of glucose and hydrogen peroxide with enhanced stability.
      ], zinc or nickel oxide [
      • Zhu H.
      • Li L.
      • Zhou W.
      • Shao Z.
      • Chen X.
      Advances in non-enzymatic glucose sensors based on metal oxides.
      ] and molybdenum disulfide [
      • Guo S.
      • Wu K.
      • Li C.
      • Wang H.
      • Sun Z.
      • Xi D.
      • et al.
      Integrated contact lens sensor system based on multifunctional ultrathin mos2 transistors.
      ]. However, these sensors are less specific and sensitive to glucose than enzymes such as glucose oxidase.

      2.1.3 Challenges to contact lens-based glucose sensors

      Aside from the technical challenges associated with integrating a glucose sensor (whether optical or electrochemical) into a contact lens, other issues also challenge the viability of these devices. There is approximately 20 min lag time between changes in blood glucose and tear glucose levels [
      • Zhang J.
      • Hodge W.
      • Hutnick C.
      • Wang X.
      Noninvasive diagnostic devices for diabetes through measuring tear glucose.
      ,
      • Badugu R.
      • Lakowicz J.R.
      • Geddes C.D.
      A glucose-sensing contact lens: from bench top to patient.
      ,
      • Vaddiraju S.
      • Burgess D.J.
      • Tomazos I.
      • Jain F.C.
      • Papadimitrakopoulos F.
      Technologies for continuous glucose monitoring: current problems and future promises.
      ]. For patients with insulin-dependent diabetes that require real-time information to accurately calculate and administer insulin to avoid hyper- and hypo-glycemia, the discordance between tear and blood glucose levels [
      • McQueen R.B.
      • Ellis S.L.
      • Campbell J.D.
      • Nair K.V.
      • Sullivan P.W.
      Cost-effectiveness of continuous glucose monitoring and intensive insulin therapy for type 1 diabetes.
      ,
      • Diabetes C.
      • Complications Trial Research G.
      • Nathan D.M.
      • Genuth S.
      • Lachin J.
      • Cleary P.
      • et al.
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
      ] may be fatal. Thus, for severe diabetics, a contact lens-based glucose sensor which only measures levels of glucose in the tears may not be relied upon as the only glucose monitoring device. There will also be market challenges related to the adoption of these smart contact lenses, due to their cost and practicality, in addition to regulatory hurdles to obtain approval for the use of such diagnostic devices. The initial hype towards the commercialisation of a contact lens-based glucose sensor has waned since Google and Novartis put aside their joint venture in 2018, citing a variety of technical challenges [
      • Comstock J.
      Alphabet’s verily shelves glucose-sensing contact lens project with novartis.
      ]. However, the outlook remains positive as the fields of biosensors, microelectronics and nanotechnology continually advance and converge.

      2.2 Cancer detection

      The tear film is well suited to the detection of cancer biomarkers as it is less biologically complex than blood [
      • Zhou L.
      • Beuerman R.W.
      The power of tears: how tear proteomics research could revolutionize the clinic.
      ,
      • Zhou L.
      • Zhao S.Z.
      • Koh S.K.
      • Chen L.
      • Vaz C.
      • Tanavde V.
      • et al.
      In-depth analysis of the human tear proteome.
      ] and tear sampling is also relatively non-invasive compared with collecting blood samples.
      Early work in tear film cancer detection highlighted the presence of a tear film protein called lacryglobin [
      • Molloy M.P.
      • Bolis S.
      • Herbert B.R.
      • Ou K.
      • Tyler M.I.
      • van Dyk D.D.
      • et al.
      Establishment of the human reflex tear two-dimensional polyacrylamide gel electrophoresis reference map: new proteins of potential diagnostic value.
      ] that has similarities to mammaglobins upregulated in breast cancer [
      • Goedegebuure P.S.
      • Watson M.A.
      • Viehl C.T.
      • Fleming T.P.
      Mammaglobin-based strategies for treatment of breast cancer.
      ]. Lacryglobin is present in the tear film of patients with colon, lung, breast and prostate cancer, as well as patients with a family history of cancer [
      • Evans V.
      • Vockler C.
      • Friedlander M.
      • Walsh B.
      • Willcox M.D.
      Lacryglobin in human tears, a potential marker for cancer.
      ]. A protein analogous to lacryglobin is also present in the tear film of dogs suffering from a range of cancers [
      • de Freitas Campos C.
      • Cole N.
      • Van Dyk D.
      • Walsh B.J.
      • Diakos P.
      • Almeida D.
      • et al.
      Proteomic analysis of dog tears for potential cancer markers.
      ]. Lebrecht and colleagues used time-of-flight mass spectroscopy to compare the tear film of cancer patients and healthy controls, identifying differences in 20 tear film biomarkers [
      • Bohm D.
      • Keller K.
      • Pieter J.
      • Boehm N.
      • Wolters D.
      • Siggelkow W.
      • et al.
      Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.
      ,
      • Lebrecht A.
      • Boehm D.
      • Schmidt M.
      • Koelbl H.
      • Grus F.H.
      Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry to detect breast cancer markers in tears and serum.
      ,
      • Lebrecht A.
      • Boehm D.
      • Schmidt M.
      • Koelbl H.
      • Schwirz R.L.
      • Grus F.H.
      Diagnosis of breast cancer by tear proteomic pattern.
      ].
      Contact lens technology may play a key role in offering a platform for sensing these cancer biomarkers, either via a direct measurement using an electronically-active biosensor mounted on a contact lens [
      • Herman G.
      Glucose-monitoring contact lens would feature transparent sensor.
      ] or by the natural accumulation of tear components within a contact lens material during wear, which could then be analysed following contact lens removal. Such contact lens-based technology would allow early diagnosis, improved monitoring and gauge susceptibility to a range of cancers, aiding the clinician in providing improved patient care.

      3. Diagnosis and screening for ocular disease

      3.1 Intraocular pressure monitoring for glaucoma

      Glaucoma is a leading cause of blindness globally and thus developments in improving intraocular pressure (IOP) monitoring are of great interest to clinicians. However, methods of measuring IOP in clinical practice are suboptimal and do not reflect its dynamic nature, including its circadian variation and short-term fluctuations [
      • Sit A.J.
      Continuous monitoring of intraocular pressure: rationale and progress toward a clinical device.
      ]. Current gold standard tonometry techniques provide an estimate of the IOP only over a matter of seconds, are generally only available during typical clinic hours and take the reading in an upright, seated position. However, studies have suggested that large IOP fluctuations, in particular nocturnal pressure spikes not captured with conventional tonometry, could have a direct impact on glaucoma progression [
      • Matlach J.
      • Bender S.
      • Konig J.
      • Binder H.
      • Pfeiffer N.
      • Hoffmann E.M.
      Investigation of intraocular pressure fluctuation as a risk factor of glaucoma progression.
      ,
      • Asrani S.
      • Zeimer R.
      • Wilensky J.
      • Gieser D.
      • Vitale S.
      • Lindenmuth K.
      Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma.
      ]. The use of continuous monitoring over a 24 -h period would therefore provide a more holistic description of the patient’s IOP profile and contact lens sensors have been suggested as a suitable vehicle for this purpose [
      • Gillmann K.
      • Bravetti G.E.
      • Niegowski L.J.
      • Mansouri K.
      Using sensors to estimate intraocular pressure: a review of intraocular pressure telemetry in clinical practice.
      ].

      3.1.1 Contact lens-based devices to monitor IOP

      The Triggerfish contact lens sensor (Sensimed, Switzerland) (Fig. 1) is a commercially available contact lens device that permits extended monitoring of IOP. This flexible silicone-based contact lens was first described in 2004 [
      • Leonardi M.
      • Leuenberger P.
      • Bertrand D.
      • Bertsch A.
      • Renaud P.
      First steps toward noninvasive intraocular pressure monitoring with a sensing contact lens.
      ] and has received both CE marking and FDA approval for 24 -h measurement of IOP. Rather than measuring IOP directly, the device measures minute dimensional changes in corneal shape, which correspond to changes in ocular biomechanical properties and volume, as well as IOP [
      • Mansouri K.
      • Medeiros F.A.
      • Tafreshi A.
      • Weinreb R.N.
      Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma.
      ]. This is based on the principle that a change in IOP of 1 mmHg elicits a change in corneal curvature of 3 μm, for an average corneal radius of 7.8 mm [
      • Mansouri K.
      • Medeiros F.A.
      • Tafreshi A.
      • Weinreb R.N.
      Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma.
      ,
      • Leonardi M.
      • Pitchon E.M.
      • Bertsch A.
      • Renaud P.
      • Mermoud A.
      Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes.
      ]. Initial results demonstrated good reliability of the device during ocular pulsation and against known induced IOP changes in porcine eyes [
      • Leonardi M.
      • Pitchon E.M.
      • Bertsch A.
      • Renaud P.
      • Mermoud A.
      Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes.
      ].
      Fig. 1
      Fig. 1(a) Contact lens sensor (SENSIMED Triggerfish) on the eye; (b) The sensor transmits the information gathered when in situ to an antenna, which is connected to a portable recorder. (Sensimed AG).
      The Triggerfish device has an embedded circumferential sensor consisting of two strain gauges that measure dimensional change. The gauges sit in a circular arc of 11.5 mm diameter, which is the typical position of the corneo-scleral junction, where maximal corneal deformation due to IOP change is assumed to occur [
      • Gillmann K.
      • Bravetti G.E.
      • Niegowski L.J.
      • Mansouri K.
      Using sensors to estimate intraocular pressure: a review of intraocular pressure telemetry in clinical practice.
      ]. Measurements are recorded for 30 s periods every 5 min during wear, providing 288 datapoints over a 24 -h period [
      • Mansouri K.
      • Medeiros F.A.
      • Tafreshi A.
      • Weinreb R.N.
      Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma.
      ]. The readings are transmitted wirelessly to an adhesive antenna patch placed around the eye and then through a wired connection to the portable receiver worn by the patient. Since the device is wearable, the patient can perform their daily activities as normal with minimal interruption, although device instructions suggest avoiding driving and contact with water. The device is available in three base curves to aid in achieving an appropriate fit and has an oxygen transmissibility (Dk/t) of 119 units to facilitate overnight wear.
      Many clinical studies have demonstrated that the Triggerfish device has good safety and tolerability in both healthy and glaucomatous eyes [
      • Mansouri K.
      • Medeiros F.A.
      • Tafreshi A.
      • Weinreb R.N.
      Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma.
      ,
      • De Smedt S.
      • Mermoud A.
      • Schnyder C.
      24-hour intraocular pressure fluctuation monitoring using an ocular telemetry sensor: tolerability and functionality in healthy subjects.
      ,
      • Lorenz K.
      • Korb C.
      • Herzog N.
      • Vetter J.M.
      • Elflein H.
      • Keilani M.M.
      • et al.
      Tolerability of 24-hour intraocular pressure monitoring of a pressure-sensitive contact lens.
      ,
      • Hollo G.
      • Kothy P.
      • Vargha P.
      Evaluation of continuous 24-hour intraocular pressure monitoring for assessment of prostaglandin-induced pressure reduction in glaucoma.
      ,
      • Marando C.M.
      • Mansouri K.
      • Kahook M.Y.
      • Seibold L.K.
      Tolerability and functionality of a wireless 24-hour ocular telemetry sensor in african american glaucoma patients.
      ]. The most common adverse effects seen in clinical trials include transient blurred vision, conjunctival hyperaemia and superficial punctate keratitis. These mild effects are common, being present in up to 95 % of wearers [
      • Mansouri K.
      • Medeiros F.A.
      • Tafreshi A.
      • Weinreb R.N.
      Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma.
      ,
      • Lorenz K.
      • Korb C.
      • Herzog N.
      • Vetter J.M.
      • Elflein H.
      • Keilani M.M.
      • et al.
      Tolerability of 24-hour intraocular pressure monitoring of a pressure-sensitive contact lens.
      ], but typically resolve within 24−48 hours. A reduction in best corrected visual acuity during and after wear has been noted, possibly due to orthokeratologic effects of intentionally tight-fitting lenses (to minimise lens mobility) [
      • Morales-Fernandez L.
      • Garcia-Bella J.
      • Martinez-de-la-Casa J.M.
      • Sanchez-Jean R.
      • Saenz-Frances F.
      • Arriola-Villalobos P.
      • et al.
      Changes in corneal biomechanical properties after 24 hours of continuous intraocular pressure monitoring using a contact lens sensor.
      ,
      • Tojo N.
      • Hayashi A.
      Influence of ocular dimensional change on 24-hour intraocular pressure measurement with contact lens sensor.
      ]. Studies report that the device captures reproducible 24 -h IOP profiles [
      • Mottet B.
      • Aptel F.
      • Romanet J.P.
      • Hubanova R.
      • Pepin J.L.
      • Chiquet C.
      24-hour intraocular pressure rhythm in young healthy subjects evaluated with continuous monitoring using a contact lens sensor.
      ,
      • Agnifili L.
      • Mastropasqua R.
      • Frezzotti P.
      • Fasanella V.
      • Motolese I.
      • Pedrotti E.
      • et al.
      Circadian intraocular pressure patterns in healthy subjects, primary open angle and normal tension glaucoma patients with a contact lens sensor.
      ,
      • Cutolo C.A.
      • De Moraes C.G.
      • Liebmann J.M.
      • Mansouri K.
      • Traverso C.E.
      • Ritch R.
      • et al.
      The effect of therapeutic IOP-lowering interventions on the 24-hour ocular dimensional profile recorded with a sensing contact lens.
      ], although its validity in estimating IOP remains unknown [
      • Dunbar Ge
      • Shen By
      • Aref Aa.
      The Sensimed Triggerfish contact lens sensor: efficacy, safety, and patient perspectives.
      ]. The device outputs measurement in ‘mV equivalent’ units, which are relative to its initial baseline measurement. These outputs are not comparable to tonometric measurements in mmHg, making direct evaluation of accuracy difficult [
      • Mottet B.
      • Aptel F.
      • Romanet J.P.
      • Hubanova R.
      • Pepin J.L.
      • Chiquet C.
      24-hour intraocular pressure rhythm in young healthy subjects evaluated with continuous monitoring using a contact lens sensor.
      ] and further work is warranted to explore the accuracy of the device and its relationship with conventional IOP measurement. Continuous IOP monitoring has enabled further investigation of several factors beyond what is possible with conventional measurement techniques, including the effects of topical medication and surgical interventions, certain activities and body position (e.g. supine versus seated), and circadian rhythm [
      • Gillmann K.
      • Bravetti G.E.
      • Niegowski L.J.
      • Mansouri K.
      Using sensors to estimate intraocular pressure: a review of intraocular pressure telemetry in clinical practice.
      ].
      The Triggerfish is likely to be the first in a generation of commercially available contact lens-based devices to monitor ocular biomarkers of disease. However, there are a number of limitations with the current device, principally driven by the bulky microprocessor and strain gauge assembly, which when encapsulated within the contact lens results in a 325 μm centre thickness, which is 2–3 times thicker than a typical contact lens. Consequently, to ensure sufficient oxygen is able to pass through the lens, particularly during overnight wear, the lens is manufactured from a highly oxygen permeable silicone elastomer material. This combination of a thick lens and relatively stiff material may potentially negatively impact the sensitivity of the strain gauge system and comfort during wear [
      • Chen G.Z.
      • Chan I.S.
      • Leung L.K.
      • Lam D.C.
      Soft wearable contact lens sensor for continuous intraocular pressure monitoring.
      ]. The need for an external adhesive patch to power and monitor the system would also ideally be addressed in a less obtrusive manner, either by integration into a spectacle frame or by on-lens power systems.
      These limitations have led to a range of different technologies being studied in order to develop future systems that are less invasive and more effective at monitoring IOP. A metal strain gauge electrode with an integrated Wheatstone bridge circuit has been developed allowing a thinner lens design and improved sensitivity, although it lacks integration of the control electronics or aerial and evaluation was limited to laboratory testing only [
      • Pang Y.
      • Li Y.
      • Wang X.
      • Qi C.
      • Yang Y.
      • Ren T.-L.
      A contact lens promising for non-invasive continuous intraocular pressure monitoring.
      ]. The use of a flexible, highly piezoresistive organic bilayer film sensor has been proposed, which was reported to improve sensitivity to the subtle changes in ocular surface curvature (3–10 times greater sensitivity in comparison with metal strain gauges) [
      • Sanchez I.
      • Laukhin V.
      • Moya A.
      • Martin R.
      • Ussa F.
      • Laukhina E.
      • et al.
      Prototype of a nanostructured sensing contact lens for noninvasive intraocular pressure monitoring.
      ]. The prototype film sensor was mounted on a rigid contact lens annulus with a wired connection to the external monitoring equipment. Evaluation in a laboratory and clinical setting (single participant) highlighted the ability of the system to monitor change in IOP. The incorporation of a graphene woven fabric into a contact lens has been described [
      • Zhang Y.
      • Chen Y.
      • Man T.
      • Huang D.
      • Li X.
      • Zhu H.
      • et al.
      High resolution non-invasive intraocular pressure monitoring by use of graphene woven fabrics on contact lens.
      ], demonstrating excellent sensitivity to ocular surface deformation due to large changes in resistivity in the stretchable fabric when IOP changes altered corneal curvature. The graphene woven fabric material was also reported to have reasonable transparency and biocompatibility, although evaluation was limited to laboratory testing with tethered resistance measurements.
      An alternative to monitoring IOP with resistive strain sensors is the use of capacitive sensors, which are generally thought to have a higher sensitivity and lower power consumption [
      • Puers R.
      Capacitive sensors: when and how to use them.
      ]. These sensors monitor subtle changes in corneal curvature by measuring the resulting change in capacitance due to altered capacitive gap spacing. When combined with an inductor, this change in capacitance influences its resonant frequency allowing this passive device to be read wirelessly [
      • Kim J.
      • Kim M.
      • Lee M.S.
      • Kim K.
      • Ji S.
      • Kim Y.T.
      • et al.
      Wearable smart sensor systems integrated on soft contact lenses for wireless ocular diagnostics.
      ]. In addition, capacitive sensors are more compact, with a lens thickness of around 100 μm achievable [
      • Huang Y.-C.
      • Yeh G.-T.
      • Yang T.-S.
      • Chiou J.-C.
      A contact lens sensor system with a micro-capacitor for wireless intraocular pressure monitoring.
      ]. Graphene-silver nanowire technology has been sued to form a capacitance sensor within a silicone elastomer contact lens [
      • Kim J.
      • Kim M.
      • Lee M.S.
      • Kim K.
      • Ji S.
      • Kim Y.T.
      • et al.
      Wearable smart sensor systems integrated on soft contact lenses for wireless ocular diagnostics.
      ]. Recently, a passive doughnut-shaped IOP sensor has been developed which consists of a microfabricated capacitor and variable inductor (in the form of a stretchable serpentine wire) that serves as both the sensor and antenna [
      • Kouhani M.
      • Wu J.
      • Tavakoli A.
      • Weber A.J.
      • Li W.
      Wireless, passive strain sensor in a doughnut-shaped contact lens for continuous non-invasive self-monitoring of intraocular pressure.
      ]. Near field electromagnetic coupling is used to wirelessly monitor the resonant frequency of the sensor, enabling continuous monitoring of change in corneal curvature induced by IOP variation. This relatively simple passive device avoids the need for lens-mounted electronic chips, with laboratory testing suggesting good sensitivity, although the authors are yet to report on any clinical evaluation.
      With many of these IOP monitoring systems, an obvious limitation is that the sensor measures changes in corneal curvature as a proxy for IOP. This means that the measurements are dependent on the biomechanical properties of the human eye and their output is not a direct measure of pressure. In an attempt to address this, a novel IOP sensing contact lens has been developed which operates on the basis of applanation rather than topographical change [
      • Elsheikh A.
      • Clamp J.
      Device for monitoring intraocular pressure.
      ]. This silicone hydrogel lens contains a capacitive pressure sensor mounted into an annular recess in the mid-periphery of the lens. This annular recess causes the underlying portion of the lens to protrude and experience a reactive deformation when pressed into the cornea by the blinking action of the lids or during sleep. The deformation is detected by the capacitive sensor and wirelessly monitored by a portable external controller. This system is claimed to provide profiles of IOP change in actual pressure values (mmHg) and is reportedly less influenced by the mechanical behaviour of the cornea and the sclera [
      • Steer R.
      Feeling the pressure.
      ]. The system has undergone pilot clinical testing, with the device reported to be able to track IOP changes whilst causing only low levels of discomfort [
      • Elsheikh A.
      Clinical study success for novel contact lens device to improve glaucoma treatment.
      ].
      Due to the complexity of integrating electronics within a contact lens, microfluidic and optical technologies have also been considered. Microfluidic contact lenses typically contain a network of enclosed microchannels, with a fluid level indicator that tracks changes in internal volume due to variations in corneal curvature or IOP. It is envisaged that these microfluidic IOP sensors could be read directly by the clinician or imaged using a mobile phone camera [
      • Campigotto A.
      • Leahy S.
      • Zhao G.
      • Campbell R.J.
      • Lai Y.
      Non-invasive intraocular pressure monitoring with contact lens.
      ,
      • An H.
      • Chen L.
      • Liu X.
      • Zhao B.
      • Zhang H.
      • Wu Z.
      Microfluidic contact lenses for unpowered, continuous and non-invasive intraocular pressure monitoring.
      ]. An alternative approach is based on the generation of optical nanostructures using laser processing on a commercial contact lens, which forms a holographic optical sensor [
      • AlQattan B.
      • Yetisen A.K.
      • Butt H.
      Direct laser writing of nanophotonic structures on contact lenses.
      ]. This type of sensor would be read by observing the spectral shift of reflected light due to changes in corneal curvature or IOP [
      • Campigotto A.
      • Leahy S.
      • Zhao G.
      • Campbell R.J.
      • Lai Y.
      Non-invasive intraocular pressure monitoring with contact lens.
      ,
      • An H.
      • Chen L.
      • Liu X.
      • Zhao B.
      • Zhang H.
      • Wu Z.
      Microfluidic contact lenses for unpowered, continuous and non-invasive intraocular pressure monitoring.
      ]. Although these optical and microfluidic sensors lack the ability to track IOP during sleep or on a continuous basis, their relative simplicity may allow for more rapid sensor development and a lower cost device than electronically active systems [
      • Campigotto A.
      • Leahy S.
      • Zhao G.
      • Campbell R.J.
      • Lai Y.
      Non-invasive intraocular pressure monitoring with contact lens.
      ].
      Rapid progress is being made in developing a broad range of biosensing technologies to support the development of biocompatible minimally invasive contact lens for IOP monitoring. However, with the exception of the Sensimed Triggerfish lens, many of the proposed sensors have had limited, if any, clinical evaluation. This likely relates to (i) the complexity of integrating electronics within a contact lens, (ii) the early stage of development of many of these new sensors and (iii) the costs associated with medical device development and clinical evaluation. However, the latest IOP sensor technology from Sensimed AG (known as “Goldfish” (Clinicaltrials.gov number: NCT03689088)), highlights continuous monitoring of IOP in humans over a 24 -h period [
      • Wasilewicz R.
      • Varidel T.
      • Simon-Zoula S.
      • Schlund M.
      • Cerboni S.
      • Mansouri K.
      First-in-human continuous 24-hour measurement of intraocular pressure and ocular pulsation using a novel contact lens sensor.
      ] using a micro-electro-mechanical system pressure sensor technology, offering an exciting glimpse into the potential impact contact lens-based technology could have on the future of glaucoma diagnosis and management.

      3.2 Dry eye disease diagnosis and monitoring

      The diagnostic approach proposed for confirmation of dry eye disease (DED) in the TFOS DEWS II report involves a screening questionnaire and measurement of various homeostasis markers, including non-invasive tear break-up time, tear film osmolarity and ocular surface staining [
      • Wolffsohn J.S.
      • Arita R.
      • Chalmers R.
      • Djalilian A.
      • Dogru M.
      • Dumbleton K.
      • et al.
      TFOS DEWS II diagnostic methodology report.
      ]. Due to the placement of contact lenses on the ocular surface, contact lens-related technology has the potential to provide additional clinical information to aid in the diagnosis and monitoring of DED. A full description of the ocular surface anatomy, which may be useful to refer to, is given in the CLEAR Anatomy and Physiology of the Anterior Eye report [
      • Downie L.E.
      • Bandlitz S.
      • Bergmanson J.P.G.
      • Craig J.P.
      • Dutta D.
      • Maldonado-Codina C.
      • et al.
      CLEAR - anatomy and physiology of the anterior eye.
      ].

      3.2.1 Osmolarity

      Tear film osmolarity is an important tool in the diagnosis and management of DED [
      • Wolffsohn J.S.
      • Arita R.
      • Chalmers R.
      • Djalilian A.
      • Dogru M.
      • Dumbleton K.
      • et al.
      TFOS DEWS II diagnostic methodology report.
      ,
      • Potvin R.
      • Makari S.
      • Rapuano C.J.
      Tear film osmolarity and dry eye disease: a review of the literature.
      ]. Point-of-care osmometers, based on lab-on-a-chip technology, are now available that measure the osmolarity of microscopic tear film samples using electrical impedance [
      • Lemp M.A.
      • Bron A.J.
      • Baudouin C.
      • Benitez Del Castillo J.M.
      • Geffen D.
      • Tauber J.
      • et al.
      Tear osmolarity in the diagnosis and management of dry eye disease.
      ]. Given the importance of osmolarity to the development of DED, a number of research groups have studied the feasibility of measuring this via contact lens technology. Researchers have developed a prototype contact lens which can evaluate tear osmolarity, tear evaporation rate and ocular surface temperature [
      • Chiou J.C.
      The development of smart contact lens system: taking dry eye syndrome diagnosis as an example.
      ]. The authors aim to apply this technology in a clinical setting to assist in DED diagnosis, evaluate the effectiveness of clinical treatments and monitor clinical performance. This approach has the advantage of providing a continuous assessment of these clinical metrics. However, it is relatively complex, requiring external power induction and the integration of complex electronics within the contact lens.
      An alternative approach to determining the electrolyte composition of the tear film uses coloured or fluorescent dyes that are integrated within the contact lens material. A microfluidics system has been developed [
      • Yetisen A.K.
      • Jiang N.
      • Castaneda Gonzalez C.M.
      • Erenoglu Z.I.
      • Dong J.
      • Dong X.
      • et al.
      Scleral lens sensor for ocular electrolyte analysis.
      ], where a number of fluorescent chemical sensors were multiplexed in cavities engraved into a scleral lens. A handheld fluorescence imaging device was also developed to read the sensors and provide quantitative measurements. A similar approach has been used [
      • Badugu R.
      • Jeng B.H.
      • Reece E.A.
      • Lakowicz J.R.
      Contact lens to measure individual ion concentrations in tears and applications to dry eye disease.
      ], where a hydrophobic ion-sensitive fluorophore was bound into commercial silicone hydrogel lenses, allowing individual ion concentrations in tears to be quantified. These fluorophore-based systems appear to avoid much of the complexity of an electronic sensor approach and are more specific about the concentration of each ionic species in tears than conventional osmometers. However, significant clinical work is required to better understand how these sensors would work in the chemically complex tear film environment, to review the safety of these dyes in a clinical setting and to understand how these dyes might otherwise influence clinical performance.
      Finally, holographic grating sensors, which have previously been used to monitor analytes such as metal ions, glucose, water content and pH, have also been proposed as contact lens osmolarity sensors [
      • Alexeev V.L.
      • Das S.
      • Finegold D.N.
      • Asher S.A.
      Photonic crystal glucose-sensing material for noninvasive monitoring of glucose in tear fluid.
      ,
      • Tsangarides C.P.
      • Yetisen A.K.
      • da Cruz Vasconcellos F.
      • Montelongo Y.
      • Qasim M.M.
      • Wilkinson T.D.
      • et al.
      Computational modelling and characterisation of nanoparticle-based tuneable photonic crystal sensors.
      ,
      • Yetisen A.K.
      • Montelongo Y.
      • da Cruz Vasconcellos F.
      • Martinez-Hurtado J.L.
      • Neupane S.
      • Butt H.
      • et al.
      Reusable, robust, and accurate laser-generated photonic nanosensor.
      ,
      • Yetisen A.K.
      • Butt H.
      • Volpatti L.R.
      • Pavlichenko I.
      • Humar M.
      • Kwok S.J.
      • et al.
      Photonic hydrogel sensors.
      ,
      • Hu Y.
      • Jiang X.
      • Zhang L.
      • Fan J.
      • Wu W.
      Construction of near-infrared photonic crystal glucose-sensing materials for ratiometric sensing of glucose in tears.
      ]. When a holographic sensor comes into contact with its analyte, the polymer within the sensor grows or shrinks, resulting in a change in the colour of the hologram (with the wavelength of the reflected light proportional to the analyte concentration). Holographic sensors can be produced on a commercial contact lens by direct laser processing for the sensing of sodium ion concentrations [
      • AlQattan B.
      • Yetisen A.K.
      • Butt H.
      Direct laser writing of nanophotonic structures on contact lenses.
      ]. This approach is appealing as these sensors are purely optical, relatively low cost, compatible with hydrogel lens materials and require no complex electronics. However, they are yet to undergo any significant clinical evaluation and it is not fully understood how they are likely to perform in the biologically complex tear film environment.

      3.2.2 Inflammatory cytokines and other biomarkers

      In DED, a range of cytokines/chemokines are elevated in the tears, including TNF-α, IL-6, IL-17a and IL-8 [
      • Roy N.S.
      • Wei Y.
      • Kuklinski E.
      • Asbell P.A.
      The growing need for validated biomarkers and endpoints for dry eye clinical research.
      ]. Although no contact lens-integrated cytokine sensor currently exists, the feasibility of integrating antibody functionalised sensors into thin flexible polymer membranes for continuous studying of analytes (in this case monitoring IL-6 using a wearable diagnostic sweat biosensor) has been described [
      • Munje R.D.
      • Muthukumar S.
      • Jagannath B.
      • Prasad S.
      A new paradigm in sweat based wearable diagnostics biosensors using room temperature ionic liquids (RTILs).
      ]. This type of technology, integrated into a contact lens, would allow the development of a continuous monitoring system for tear film cytokines, in addition to point-of-care diagnostics, both potentially useful tools in the diagnosis and monitoring of DED, contact lens discomfort and other ocular surface diseases.
      Immunoglobulin proteins found in the tears are also known to vary in concentration in a range of ocular surface diseases [
      • Borderie V.M.
      • Gineys R.
      • Goldschmidt P.
      • Batellier L.
      • Laroche L.
      • Chaumeil C.
      Association of anti-herpes simplex virus IgG in tears and serum with clinical presentation in patients with presumed herpetic simplex keratitis.
      ,
      • Grus F.H.
      • Dick B.
      • Augustin A.J.
      • Pfeiffer N.
      Analysis of the antibody repertoire in tears of dry-eye patients.
      ,
      • Kwon J.
      • Surenkhuu B.
      • Raju I.
      • Atassi N.
      • Mun J.
      • Chen Y.F.
      • et al.
      Pathological consequences of anti-citrullinated protein antibodies in tear fluid and therapeutic potential of pooled human immune globulin-eye drops in dry eye disease.
      ,
      • Zandbelt M.
      • te Boome L.
      • Klasen I.
      • van de Putte L.
      • van den Hoogen F.
      Tear fluid measurement of anti-SS-a and anti-SS-b antibody in anti-SS-a and anti-SS-b seronegative Sjogren’s syndrome patients.
      ]. Optical biosensing, using a photonic nonporous crystal structure within a hydrogel, has been described for use in the detection of IgG antibodies [
      • Choi E.
      • Choi Y.
      • Nejad Y.H.P.
      • Shin K.
      • Park J.
      Label-free specific detection of immunoglobulin g antibody using nanoporous hydrogel photonic crystals.
      ]. The binding of IgG to these photonic sensors results in a refractive index change, with a change in colour from green to red with increasing IgG concentration. This type of photonic crystal sensor is simple, low-cost, label-free and requires a simple imaging system for the detection of immunoglobulin proteins, meaning that it is well suited to point-of-care testing. This technology could also potentially be integrated into contact lenses to form wearable biosensors [
      • Choi E.
      • Choi Y.
      • Nejad Y.H.P.
      • Shin K.
      • Park J.
      Label-free specific detection of immunoglobulin g antibody using nanoporous hydrogel photonic crystals.
      ], although improvements in sensor sensitivity may be required to detect trace amounts of biomarkers within tears [
      • Tseng R.C.
      • Chen C.C.
      • Hsu S.M.
      • Chuang H.S.
      Contact-lens biosensors.
      ], unless changes in the concentration of sIgA are diagnostic, as this is in relatively high concentration in tears [
      • Craig J.P.
      • Willcox M.D.
      • Argueso P.
      • Maissa C.
      • Stahl U.
      • Tomlinson A.
      • et al.
      The TFOS international workshop on contact lens discomfort: report of the contact lens interactions with the tear film subcommittee.
      ].
      An alternative approach for tear film biosensing is the use of contact lenses to collect biomarkers for point-of-care diagnostics. An example of this approach is the development of a portable reader to quantify lysozyme, using a contact lens as the sample collector [
      • Ballard Z.
      • Bazargan S.
      • Jung D.
      • Sathianathan S.
      • Clemens A.
      • Shir D.
      • et al.
      Contact lens-based lysozyme detection in tear using a mobile sensor.
      ]. An example of this system has been described in the literature, where a balafilcon A lens was worn for 15 min and then washed in a microtube containing a reaction buffer. The lens was then discarded and the solution mixed with a fluorophore, with the fluorescence monitored over time using a mobile phone-based well-plate reader. The presence of lysozyme in this assay reduces the degree of fluorophore quenching, with the degree of fluorescence proportional to the activity of lysozyme. This type of point-of-care technology could enable the clinician to diagnose and monitor diseases such as dry eye or Sjögren's syndrome, where reduced concentrations of tear film proteins such as lactoferrin and lysozyme occur [
      • von Thun Und Hohenstein-Blaul N.
      • Funke S.
      • Grus F.H.
      Tears as a source of biomarkers for ocular and systemic diseases.
      ]. In addition, this technique could be adapted to detect the presence of pathogens such as Staphylococcus aureus, viruses that cause conjunctivitis or Acanthamoeba [
      • Ballard Z.
      • Bazargan S.
      • Jung D.
      • Sathianathan S.
      • Clemens A.
      • Shir D.
      • et al.
      Contact lens-based lysozyme detection in tear using a mobile sensor.
      ]. Indeed, it may be that the material and/or design of a contact lens could specifically be developed to extract analytes of interest from the tear film, particularly where they are present in only trace quantities. This point-of-care approach has the potential for advanced health diagnosis and monitoring and for personalised medicine-related applications.

      3.2.3 Blink monitoring, material dehydration and ocular surface temperature

      Blinking frequency and completeness are known change during contact lens wear [
      • Morgan P.
      • Murphy P.J.
      • Gifford K.
      • Gifford P.
      • Golebiowski B.
      • Johnson L.
      • et al.
      CLEAR - effect of contact lens materials and designs on the anatomy and physiology of the eye.
      ] but are also important clinical metrics in the diagnosis and management of both DED and contact lens discomfort [
      • Tsubota K.
      Tear dynamics and dry eye.
      ,
      • Su Y.
      • Liang Q.
      • Su G.
      • Wang N.
      • Baudouin C.
      • Labbe A.
      Spontaneous eye blink patterns in dry eye: clinical correlations.
      ,
      • Jansen M.E.
      • Begley C.G.
      • Himebaugh N.H.
      • Port N.L.
      Effect of contact lens wear and a near task on tear film break-up.
      ]. Although blinking can be studied in a clinical setting, the integration of a blink sensor within a contact lens would allow continuous monitoring of blink dynamics whilst undertaking real-world activities. In addition to IOP monitoring, the commercially available Sensimed Triggerfish lens has been reported to be capable of tracking basic blinking characteristics during lens wear, due to a spike in resistance associated with blinking [
      • Gisler C.
      • Ridi A.
      • Hennebert J.
      • Weinreb R.N.
      • Mansouri K.
      Automated detection and quantification of circadian eye blinks using a contact lens sensor.
      ]. However, the increased thickness and modulus, and the invasive nature of the external antennae are likely to interfere with natural blinking dynamics. A contact lens-based blink monitoring system has been described [
      • Pugh R.B.
      • Toner A.
      • Humphreys S.R.
      • Otts D.B.
      • Neeley W.C.
      Blink detection system for electronic ophthalmic lens.
      ], where transient reductions in light falling on an integrated photo-sensor would allow the frequency and completeness of eyelid blinking to be monitored, although this idea currently appears to be only conceptual in nature.
      Another technology with potential application in diagnosing and monitoring DED is a structurally coloured contact lens sensor to detect changes in moisture and pressure by altering its colour [
      • Wang Y.
      • Zhao Q.
      • Du X.
      Structurally coloured contact lens sensor for point-of-care ophthalmic health monitoring.
      ]. These lenses were manufactured by dispensing silica particles onto the concave section of the contact lens mould, forming a highly ordered ring-like crystalline template, which was then polymerised into a hydrogel contact lens material. The contact lens was then placed in acid to etch the silica particles and subsequently washed with deionised water. The resulting contact lens had an inverse opal structure and displayed brilliant colour in the lens periphery. During material dehydration, polymer shrinkage reduces the spacing of the inverse opal structures, with the lens periphery displaying a visible shift in colour, which can be quantified using a spectrophotometer. In addition, the material is sensitive to pressure, due to the associated decrease in structure spacing, leading to a decrease in the reflectance wavelength. This may have diagnostic value in highlighting surface desiccation and/or increased pressure applied to the contact lens due to inadequate lubrication in DED (in addition to the potential of monitoring IOP). Although these devices have yet to undergo clinical testing, their simple approach to measuring the variation in hydration and pressure, suggests that this type of sensor holds promise for point-of-care diagnosis and monitoring of conditions such as DED and contact lens discomfort.
      Ocular surface temperature has also been studied in relation to DED, as an unstable tear film is thought to increase tear film evaporation, resulting in a relative cooling of the ocular surface [
      • Braun R.J.
      • King-Smith P.E.
      • Begley C.G.
      • Li L.
      • Gewecke N.R.
      Dynamics and function of the tear film in relation to the blink cycle.
      ,
      • Li W.
      • Graham A.D.
      • Selvin S.
      • Lin M.C.
      Ocular surface cooling corresponds to tear film thinning and breakup.
      ,
      • Su T.Y.
      • Chang S.W.
      • Yang C.J.
      • Chiang H.K.
      Direct observation and validation of fluorescein tear film break-up patterns by using a dual thermal-fluorescent imaging system.
      ,
      • Tan L.L.
      • Sanjay S.
      • Morgan P.B.
      Static and dynamic measurement of ocular surface temperature in dry eyes.
      ]. An optical temperature sensor has been developed, where temperature-sensitive liquid crystals incorporated into a contact lens exhibited a fully reversible temperature-dependent colour change [
      • Moreddu R.
      • Elsherif M.
      • Butt H.
      • Vigolo D.
      • Yetisen A.K.
      Contact lenses for continuous corneal temperature monitoring.
      ]. An alternative approach [

      H.J. Lai. System for measuring and analyzing ocular temperature, receiving analyzer and methods for using the same. Google Patents. US9642533B2. USA: Ubiquity Biomedical Corp; 2017.

      ] relates to the incorporation of an electronic temperature sensor into a contact lens, with the change in temperature over the interblink period reported to be useful in diagnosing DED. Depending on the placement of these sensors, it may be possible to independently sample the temperature of the underlying ocular surface (which is potentially raised in DED due to inflammation) and the temperature at the contact lens/pre-lens tear film interface (which is potentially reduced in DED due to evaporative cooling).

      3.3 Monitoring of ocular vasculature

      Monitoring of the vascular system is critically important in the medical management of a wide range of health conditions. Historically, devices to measure characteristics such as heart rate, oxygen saturation and the hyperaemic response of tissue were medical instruments, but this technology is increasingly being found in consumer technology, such as mobile phones and wearable technology. The eye is an ideal site to monitor the vascular system, as it allows an unobstructed view of the blood vessels in both the retina and conjunctiva.

      3.3.1 Retinal vasculature

      Typically, retinal imaging is performed using ophthalmic instrumentation in a clinical setting, but a recent patent [
      • Pugh R.B.
      • Toner A.
      • Humphreys S.R.
      • Otts D.B.
      • Neeley W.C.
      Ophthalmic lens with retinal vascularization monitoring system.
      ] has proposed the incorporation of an ultrasonic transducer within a contact lens to allow retinal vascular imaging during wear. This patent describes the incorporation of an annular ring within a contact lens, which would contain the power system, control electronics and a piezoelectric element, whilst allowing the central portion of the lens to be transparent. The device would emit an ultrasonic pulse that would travel through the ocular media towards the retina. The returned ultrasonic signal would then detect pulsation of the retinal vessels and generate an image of these vessels. It is primarily envisaged that this technology would be applied to monitor general vascular health, with warnings provided to the wearer if the device detected a cardiac rhythm and/or rate of blood vessel displacement outside of a normal range. The patent also discusses its potential for monitoring ocular disease by analysing specific regions of the retinal vasculature, such as the macula or optic nerve head. Such data could either be continuously logged for later review by the clinician, provide live alerts to the wearer (either wirelessly or via an audio/visual alert via micro-acoustic/micro-photonic elements) or communicate directly with a concurrent drug delivery apparatus. Although there are numerous technical challenges in developing such a system and the patent seems to report on a concept rather than a working model, it does highlight the potential for an electronically active contact lens to monitor retinal vasculature.

      3.3.2 Conjunctival response to contact lens wear

      Conjunctival blood vessels are typically evaluated during an ophthalmic examination, with hyperaemia associated with ocular disease, inflammation and irritation [
      • Murphy P.J.
      • Lau J.S.
      • Sim M.M.
      • Woods R.L.
      How red is a white eye? Clinical grading of normal conjunctival hyperaemia.
      ]. A patent describes the incorporation of an optical sensor within a contact lens, which emits light onto the conjunctiva to allow detection of characteristics such as pulse rate and blood oxygen levels [

      H. Ho, B. Amirparviz. Contact lens with integrated pulse oximeter. In: Office UP, ed. Google Patents. US8971978B2. USA: Verily Life Sciences LLC; 2012:25.

      ]. Although the proposed device is primarily intended for monitoring systemic vascular characteristics, this type of device has a range of potential uses in monitoring ocular health, including detecting hyperaemia of the bulbar and/or tarsal conjunctiva. Monitoring hyperaemia in a continuous fashion would allow a clinician to review changes in vasculature over a prolonged period of time to more appropriately manage a range of clinical conditions, including allergic conjunctivitis, DED, uveitis and contact lens complications. In addition, the device could either highlight to the lens wearer if hyperaemia was detected (via a visual or auditory stimulus [

      H. Ho, B. Amirparviz. Contact lens with integrated pulse oximeter. In: Office UP, ed. Google Patents. US8971978B2. USA: Verily Life Sciences LLC; 2012:25.

      ]), could prompt a consultation with their eyecare practitioner (ECP), or act as a trigger to dispense a therapeutic agent from a drug-delivering contact lens.
      The range of approaches and technologies currently being studied as potential contact lens and point-of-care biosensors highlights the huge interest in the area. These biosensors, however, should not necessarily be viewed as independent technologies, as it is likely that many of these sensors provide complementary information and, in the future, these differing technologies may be brought together into a single diagnostic lens, with the capability to monitor a wide range of characteristics. Alternatively, key biosensors may be incorporated into standard contact lenses as a routine feature of the lens, such as is now the case with ultraviolet blockers or lens inversion indicators.

      4. Treatment and management of ocular conditions

      The use of contact lenses in the treatment and management of ocular diseases is a relatively routine part of clinical practice. From providing pain relief in cases of corneal abrasion, corneal protection for trichiasis, to promotion of wound healing in neurotrophic keratitis, contact lenses are employed by clinicians for a broad variety of anterior segment conditions. However, the application of contact lenses for disease indications beyond what is currently undertaken in clinical practice has been a subject of significant research. The CLEAR Medical Use of Contact Lenses report provides a detailed review of the use of other aspects related to this section [
      • Jacobs D.S.
      • Carrasquillo K.G.
      • Cottrell P.D.
      • Fernández-Velázquez F.J.
      • Gil-Cazorla R.
      • Jalbert I.
      • et al.
      CLEAR - medical use of contact lenses.
      ].

      4.1 Dry eye disease

      Dry eye disease is one of the most common conditions managed by ECPs and some novel contact lens options offer alternatives to the use of traditional therapies such as ocular lubricants. However, to date all of the options described have little, if any, clinical data to support their use in the management of DED and further clinical studies are required.

      4.1.1 Dehydration resistant materials

      A novel approach to avoiding ocular surface desiccation is the use of electro-osmotic flow [
      • Kusama S.
      • Sato K.
      • Yoshida S.
      • Nishizawa M.
      Self‐moisturizing smart contact lens employing electroosmosis.
      ]. This involves using an ionic contact lens material (such as a HEMA/methacrylic acid (MAA) copolymer), which serves as the fluid conduit for electro-osmotic flow generation. The placement of an arcuate anode and cathode in the lens surface allows an upward electro-osmotic flow of tear fluid within the contact lens when an electrical current is applied. This electrical current could be applied either by wireless induction or using biocompatible battery technology. The laboratory prototype described appears able to compensate for evaporative water loss and maintain post-lens tear film thickness by driving fluid flow through the lens material.
      Another potential method to minimise dehydration is based around the use of an ultra-thin graphene layer on the anterior lens surface [
      • Lee S.
      • Jo I.
      • Kang S.
      • Jang B.
      • Moon J.
      • Park J.B.
      • et al.
      Smart contact lenses with graphene coating for electromagnetic interference shielding and dehydration protection.
      ]. Graphene has long been hailed as a ‘wonder material’ and its possible uses in the field of contact lenses include its potential to act as an electromagnetic interference shield [
      • Lee S.
      • Jo I.
      • Kang S.
      • Jang B.
      • Moon J.
      • Park J.B.
      • et al.
      Smart contact lenses with graphene coating for electromagnetic interference shielding and dehydration protection.
      ], as a clear flexible electrical conductor [
      • Kaur S.
      • Kim Y.J.
      • Milton H.
      • Mistry D.
      • Syed I.M.
      • Bailey J.
      • et al.
      Graphene electrodes for adaptive liquid crystal contact lenses.
      ,
      • Moser T.
      • Celma C.
      • Lebert A.
      • Charrault E.
      • Brooke R.
      • Murphy P.J.
      • et al.
      Hydrophilic organic electrodes on flexible hydrogels.
      ], as a means to enhance contact lens night vision [
      • Liu C.H.
      • Chang Y.C.
      • Norris T.B.
      • Zhong Z.
      Graphene photodetectors with ultra-broadband and high responsivity at room temperature.
      ] and as an antimicrobial material [
      • Huang J.F.
      • Zhong J.
      • Chen G.P.
      • Lin Z.T.
      • Deng Y.
      • Liu Y.L.
      • et al.
      A hydrogel-based hybrid theranostic contact lens for fungal keratitis.
      ]. In its application to combat desiccation, the applied graphene layer is proposed to act as a barrier to water loss from the contact lens material. In DED, the ocular surface typically shows signs of desiccation due to an unstable tear film, infrequent or incomplete blinking and subsequent air exposure [
      • Alex A.
      • Edwards A.
      • Hays J.D.
      • Kerkstra M.
      • Shih A.
      • de Paiva C.S.
      • et al.
      Factors predicting the ocular surface response to desiccating environmental stress.
      ]. Therefore, an engineered material that is resistant to dehydration does offer a potential solution.

      4.1.2 Lacrimal gland stimulation

      An alternative approach to the treatment of DED focuses on increasing tear production by incorporation of an electrical stimulator into a contact lens. This concept is based on a similar intranasal stimulator technology (TrueTear, Allergan, CA, USA) which delivers an intranasal electrical stimulus to stimulate tearing [
      • Friedman N.J.
      • Butron K.
      • Robledo N.
      • Loudin J.
      • Baba S.N.
      • Chayet A.
      A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease.
      ] and promote goblet cell secretion [
      • Gumus K.
      • Schuetzle K.L.
      • Pflugfelder S.C.
      Randomized controlled crossover trial comparing the impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation.
      ]. A recent patent highlighted the potential for this type of technology to be manufactured in the form of a contact lens [
      • Loudin J.D.
      • Franke M.
      • HAMILTON D.N.
      • Doraiswamy A.
      • Ackermann D.M.
      Contact lens for increasing tear production.
      ]. The patent details the incorporation of a stimulator chip, which would generate an electric waveform to stimulate the cornea, conjunctiva and/or sub-conjunctiva, resulting in activation of reflex pathways and an associated increase in tear production [
      • Loudin J.D.
      • Franke M.
      • HAMILTON D.N.
      • Doraiswamy A.
      • Ackermann D.M.
      Contact lens for increasing tear production.
      ]. The proposed design is envisaged to receive energy wirelessly from an external power source, potentially in the form of an external infrared light source and a contact lens mounted photodiode. To date, this appears to be conceptual, with no publicly available clinical studies. It is unclear whether such technology would produce a sub-threshold stimulus or whether the stimulus would be felt by the wearer, as is the case with the TrueTear stimulator, and whether the stimulus would be continuous or intermittent. Clinical evidence does support this neurostimulation approach to enhancing tear secretions [
      • Friedman N.J.
      • Butron K.
      • Robledo N.
      • Loudin J.
      • Baba S.N.
      • Chayet A.
      A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease.
      ,
      • Gumus K.
      • Schuetzle K.L.
      • Pflugfelder S.C.
      Randomized controlled crossover trial comparing the impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation.
      ] and therefore if a compact and comfortable contact lens-based treatment could be developed this would be exciting technology, offering an alternative option to new and existing contact lens wearers struggling with dryness symptoms.

      4.1.3 Scavenging of reactive oxygen species and matrix metalloproteinases

      Oxidative stress and the presence of reactive oxygen species at the ocular surface have been proposed to play an important role in the development of DED [
      • Dogru M.
      • Kojima T.
      • Simsek C.
      • Tsubota K.
      Potential role of oxidative stress in ocular surface inflammation and dry eye disease.
      ,
      • Seen S.
      • Tong L.
      Dry eye disease and oxidative stress.
      ] and studies have indicated that decreasing reactive oxygen species at the ocular surface is a potential treatment strategy [
      • Stoddard A.R.
      • Koetje L.R.
      • Mitchell A.K.
      • Schotanus M.P.
      • Ubels J.L.
      Bioavailability of antioxidants applied to stratified human corneal epithelial cells.
      ,
      • Brzheskiy V.V.
      • Efimova E.L.
      • Vorontsova T.N.
      • Alekseev V.N.
      • Gusarevich O.G.
      • Shaidurova K.N.
      • et al.
      Results of a multicenter, randomized, double-masked, placebo-controlled clinical study of the efficacy and safety of visomitin eye drops in patients with dry eye syndrome.
      ]. However, eye drop-based reactive oxygen species-scavenging/antioxidant therapeutics are likely to be rapidly eliminated from the ocular surface [
      • Janagam D.R.
      • Wu L.
      • Lowe T.L.
      Nanoparticles for drug delivery to the anterior segment of the eye.
      ] and require frequent reapplication [
      • Brzheskiy V.V.
      • Efimova E.L.
      • Vorontsova T.N.
      • Alekseev V.N.
      • Gusarevich O.G.
      • Shaidurova K.N.
      • et al.
      Results of a multicenter, randomized, double-masked, placebo-controlled clinical study of the efficacy and safety of visomitin eye drops in patients with dry eye syndrome.
      ]. A soft contact lens which incorporates Ceria nanoparticles [
      • Choi S.W.
      • Cha B.G.
      • Kim J.
      Therapeutic contact lens for scavenging excessive reactive oxygen species on the ocular surface.
      ], which are used for their known reactive oxygen species-scavenging properties [
      • Walkey C.
      • Das S.
      • Seal S.
      • Erlichman J.
      • Heckman K.
      • Ghibelli L.
      • et al.
      Catalytic properties and biomedical applications of cerium oxide nanoparticles.
      ], has recently been described. Unlike antioxidant therapeutic drops that can potentially act on intracellular reactive oxygen species, these antioxidant nanoparticles are tightly embedded within the lens matrix, exhibiting their effects through the reduction of extracellular reactive oxygen species levels. These lenses exhibited good transparency, biocompatibility and effective extracellular reactive oxygen species-scavenging properties in an ocular surface animal model [
      • Choi S.W.
      • Cha B.G.
      • Kim J.
      Therapeutic contact lens for scavenging excessive reactive oxygen species on the ocular surface.
      ].
      Another group of biomarkers commonly observed in ocular surface disease are the Matrix Metalloproteinases (MMPs) and a potential treatment in these conditions is the topical application of MMP inhibitors [
      • Bian F.
      • Pelegrino F.S.
      • Henriksson J.T.
      • Pflugfelder S.C.
      • Volpe E.A.
      • Li D.Q.
      • et al.
      Differential effects of dexamethasone and doxycycline on inflammation and MMP production in murine alkali-burned corneas associated with dry eye.
      ]. A hydrogel material containing dipicolylamine, which has a high affinity for zinc ions has been developed [
      • Lopez C.
      • Park S.
      • Edwards S.
      • Vong S.
      • Hou S.
      • Lee M.
      • et al.
      Matrix metalloproteinase-deactivating contact lens for corneal melting.
      ]. Sequestering of zinc results in a loss of essential ions from MMPs, resulting in their deactivation and this technology has the potential to treat conditions associated with excessive MMP activation, such as that found with increased amounts of MMP-9 in DED [
      • Jamerson E.C.
      • Elhusseiny A.M.
      • ElSheikh R.H.
      • Eleiwa T.K.
      • El Sayed Y.M.
      Role of matrix metalloproteinase 9 in ocular surface disorders.
      ,
      • Lanza N.L.
      • Valenzuela F.
      • Perez V.L.
      • Galor A.
      The matrix metalloproteinase 9 point-of-care test in dry eye.
      ,
      • Dohlman T.H.
      • Ciralsky J.B.
      • Lai E.C.
      Tear film assessments for the diagnosis of dry eye.
      ].

      4.2 Limbal stem cell deficiency

      An intact and healthy corneal epithelium is required to achieve an effective barrier against infection and maintain the transparency required for clear vision. To achieve this, the epithelium is continuously regenerated by the limbal epithelial stem cells. Destruction of the stem cell niche in conjunction with dysfunction or depletion of the limbal epithelial stem cells, through trauma or conditions such as aniridia, leads to limbal stem cell deficiency, a debilitating condition characterised by painful chronic ulceration, inflammation and vascularisation of the cornea. Limbal stem cell deficiency may be managed by using scleral lenses, as outlined in the CLEAR Scleral lenses and CLEAR Medical use of Contact Lenses reports [
      • Jacobs D.S.
      • Carrasquillo K.G.
      • Cottrell P.D.
      • Fernández-Velázquez F.J.
      • Gil-Cazorla R.
      • Jalbert I.
      • et al.
      CLEAR - medical use of contact lenses.
      ,
      • Barnett M.
      • Courey C.
      • Fadel D.
      • Lee K.
      • Michaud L.
      • Montani G.
      • et al.
      CLEAR - scleral lenses.
      ]. Conventional corneal grafts are typically ineffective for managing limbal stem cell deficiency and the therapeutic aim is to boost the limbal epithelial stem cell population through transplantation of donor tissue [
      • Bains K.K.
      • Fukuoka H.
      • Hammond G.M.
      • Sotozono C.
      • Quantock A.J.
      Recovering vision in corneal epithelial stem cell deficient eyes.
      ]. However, this method risks damaging the limbal epithelial stem cell population in the donor eye if the fellow eye of the recipient is used in unilateral cases of limbal stem cell deficiency, or graft rejection and the need for immunosuppression if a non-self donor is used [
      • Bobba S.
      Contact lens delivery of stem cells for restoring the ocular surface.
      ].
      Human amniotic membranes are the substrate commonly used for culturing and delivering limbal epithelial stem cells to the ocular surface [
      • Levis H.J.
      • Kureshi A.K.
      • Massie I.
      • Morgan L.
      • Vernon A.J.
      • Daniels J.T.
      Tissue engineering the cornea: the evolution of RAFT.
      ]. However, this process requires expensive donor screening and manipulating and securing the substrate can prove difficult [
      • Bobba S.
      Contact lens delivery of stem cells for restoring the ocular surface.
      ]. The use of contact lenses as a stem cell delivery device has been demonstrated, with the contact lens vehicle doubling as a protective bandage following grafting [
      • Pellegrini G.
      • Traverso C.E.
      • Franzi A.T.
      • Zingirian M.
      • Cancedda R.
      • De Luca M.
      Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium.
      ]. limbal epithelial stem cells have been shown to reliably transfer from the contact lens to the ocular surface [
      • Deshpande P.
      • Notara M.
      • Bullett N.
      • Daniels J.T.
      • Haddow D.B.
      • MacNeil S.
      Development of a surface-modified contact lens for the transfer of cultured limbal epithelial cells to the cornea for ocular surface diseases.
      ,
      • Brown K.D.
      • Low S.
      • Mariappan I.
      • Abberton K.M.
      • Short R.
      • Zhang H.
      • et al.
      Plasma polymer-coated contact lenses for the culture and transfer of corneal epithelial cells in the treatment of limbal stem cell deficiency.
      ] and an initial study of three patients with limbal stem cell deficiency reported a 100 % success rate at a 12-month follow-up [
      • Di Girolamo N.
      • Bosch M.
      • Zamora K.
      • Coroneo M.T.
      • Wakefield D.
      • Watson S.L.
      A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction.
      ].
      Contact lenses are beneficial in that they are synthetic and non-immunogenic, eliminating the xenobiotic infection risk from donor tissue. However, the risk of infection resulting from overnight contact lens wear should be considered and to date, no clinical trials have compared the delivery of stem cells via contact lenses and amniotic membrane, and this is warranted before large-scale implementation can take place.

      4.3 Pupil or iris defects

      Liquid crystal cells have been recently combined with miniaturized electronic circuits forming smart platforms in order to replicate the functionality of the pupil and iris arrangement [
      • Vasquez Quintero A.
      • Perez-Merino P.
      • De Smet H.
      Artificial iris performance for smart contact lens vision correction applications.
      ,
      • Raducanu B.C.
      • Zaliasl S.
      • Stanzione S.
      • van Liempd C.
      • Quintero A.V.
      • De Smet H.
      • et al.
      An artificial iris ASIC with high voltage liquid crystal driver, 10-nA light range detector and 40-nA blink detector for LCD flicker removal.
      ]. This may be useful for iris defects (aniridia and coloboma), transillumination of the iris (ocular albinism), high order aberrations (keratoconus) and high sensitivity to light (dry eye syndrome and chronic migraine). Such devices are intended to enhance the iris functionality by filtering incoming light autonomously controlled by application specific integrated circuits and on-lens light sensors and power directly by near magnetic fields and rechargeable micro-batteries [
      • Raducanu B.C.
      • Zaliasl S.
      • Stanzione S.
      • van Liempd C.
      • Quintero A.V.
      • De Smet H.
      • et al.
      An artificial iris ASIC with high voltage liquid crystal driver, 10-nA light range detector and 40-nA blink detector for LCD flicker removal.
      ].
      The smart platforms are build-up by means of microsystems technology (photolithography, sputtering, etc.), flip-chip of discrete components and thermoforming into a spherical shape fitting the contact lens body [
      • Vásquez Quintero A.
      • Verplancke R.
      • De Smet H.
      • Vanfleteren J.
      Stretchable electronic platform for soft and smart contact lens applications.
      ]. The platforms can be embedded inside soft contact lenses, thus avoiding contact with the surface of the eye and maintaining the conventional refractive correction of the ophthalmic device [
      • Vásquez Quintero A.
      • Arai R.
      • Yamazaki Y.
      • Sato T.
      • De Smet H.
      Near‐field communication powered hydrogel‐based smart contact lens.
      ]. The device was also protected against saline solution (at least for 25 weeks) and withstood mechanical bending forces [
      • Vásquez Quintero A.
      • Arai R.
      • Yamazaki Y.
      • Sato T.
      • De Smet H.
      Near‐field communication powered hydrogel‐based smart contact lens.
      ]. Contrasts of 1:2 between ON/OFF (effectively blocking 50 % of the light at least between wavelengths of 500 nm and 600 nm) were able to be achieved, producing a pin-hole effect, and simulated results of the light filter with a 2 mm pupil diameter embedded inside a scleral contact lens with data from patients with aniridia gave maximum depth-of-focus values of 3D, 2D and 0.75D for light levels of 1000 cd/m2, 10 cd/m2and 1 cd/m2 [
      • Vasquez Quintero A.
      • Perez-Merino P.
      • De Smet H.
      Artificial iris performance for smart contact lens vision correction applications.
      ]. Contrast values higher than 1:2 will be required in order to protect eyes with big pupils from excessive light.

      4.4 Diabetic retinopathy

      Diabetic retinopathy is the leading cause of blindness in the working age population and is a disease of ischemia leading to microvascular retinal damage. Oxygen consumption of the rod photoreceptors is greatest during dark adaptation [
      • Birol G.
      • Wang S.
      • Budzynski E.
      • Wangsa-Wirawan N.D.
      • Linsenmeier R.A.
      Oxygen distribution and consumption in the macaque retina.
      ], potentially causing hypoxia in the diabetic retina and driving further disease progression [
      • Arden G.B.
      • Jyothi S.
      • Hogg C.H.
      • Lee Y.F.
      • Sivaprasad S.
      Regression of early diabetic macular oedema is associated with prevention of dark adaptation.
      ]. To minimise hypoxia during sleep, researchers have considered various methods of delivering light to the retina during eye closure [
      • Sahni J.N.
      • Czanner G.
      • Gutu T.
      • Taylor S.A.
      • Bennett K.M.
      • Wuerger S.M.
      • et al.
      Safety and acceptability of an organic light-emitting diode sleep mask as a potential therapy for retinal disease.
      ] and the development of a phosphorescent contact lens for treatment of diabetic retinopathy has been described [
      • Cook C.A.
      • Martinez-Camarillo J.C.
      • Yang Q.
      • Scianmarello N.E.
      • Humayun M.S.
      • Tai Y.
      Phototherapeutic contact lens for diabetic retinopathy.
      ]. This novel silicone elastomer contact lens incorporates 24 radioluminescent gaseous tritium light sources arranged in a radial pattern, with a clear central 3 mm aperture. This design allows unobstructed vision under photopic conditions, whilst under scotopic conditions the enlarged pupil allows the retina to receive the phototherapeutic dose.
      The tritium light source is well suited to use in a contact lens, due to its compact size (300 μm by 2000 μm), safety profile (it emits no ionising radiation) and long life (12-year half-life). The therapeutic benefit of this concept is debatable, with electroretinogram testing in an animal model highlighting suppressed rod dark adaptation with this contact lens technology, whilst a large multi-centre randomised clinical trial, evaluating a similar mask-based technology, found no therapeutic benefit [
      • Sivaprasad S.
      • Vasconcelos J.C.
      • Prevost A.T.
      • Holmes H.
      • Hykin P.
      • George S.
      • et al.
      Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial.
      ]. This contact lens approach, however, has several advantages over the mask-based system, as the lens moves with the eye, avoiding issues associated with Bell’s phenomena, the light does not pass through the lid (thus the light intensity reaching the retina is more consistent), the presence of light is less bothersome (due to Troxler neural adaptation) and the wavelength better controlled [
      • Cook C.A.
      • Martinez-Camarillo J.C.
      • Yang Q.
      • Scianmarello N.E.
      • Humayun M.S.
      • Tai Y.
      Phototherapeutic contact lens for diabetic retinopathy.
      ]. Future clinical trials are clearly required to investigate whether this contact lens-based approach is able to reduce the long-term risk of diabetic retinopathy and diabetic macular oedema.

      4.5 Colour vision deficiency

      Colour vision deficiency is the result of an abnormality or absence of one or more of the three classes of cone photoreceptors in the normal human retina that are responsible for the perception of colour. Having abnormal colour vision may impact virtually all facets of modern life from childhood to adulthood, with implications extending across sports, driving, education, occupation and health and safety issues. For these reasons, exploring and understanding technologies that remove some of these limitations are of keen interest.
      Enhancement of colour perception in patients with colour vision deficiency has been mostly limited to using colour filters, which enhance colour discrimination by tuning the brightness, saturation and hue through selective absorption of certain wavelengths. The first contact lens example to use this concept was the X-Chrom lens, a red contact lens placed over one eye [

      H.I. Zeltzer. Method of improving color discrimination. Google Patents. US3586423A. USA; 1970.

      ]. This long-pass filter works by darkening yellow-green objects and making orange objects appear more red and slightly darker and appears more effective for anomalous trichomats than dichromats [
      • Hovis J.K.
      • Sirkka D.
      Color discrimination of deutan and protan observers through tinted soft contact lenses.
      ]. The X-Chrom concept was modified by Harris to develop the ChromaGen lens, a soft lens system with seven hues and light, medium and dark densities [
      • Harris D.A.
      • Lane G.
      • Green E.
      Color discrimination.
      ]. Tint selection is based on patient subjective response and their use significantly reduced error rates on Ishihara plates, the D-15 test, and an improvement in subjective colour perception, though it did suffer from reports of poor vision in dim light [
      • Swarbrick H.A.
      • Nguyen P.
      • Nguyen T.
      • Pham P.
      The ChromaGen contact lens system: colour vision test results and subjective responses.
      ].
      The most recent contact lens development concerns a metasurface-based approach [
      • Karepov S.
      • Ellenbogen T.
      Metasurface-based contact lenses for color vision deficiency.
      ]. A large-scale plasmonic metasurface was embedded on a rigid corneal contact lens to address deuteranomaly, the most common class of colour vision deficiency. These metasurfaces are engineered surfaces made of subwavelength building blocks that enable a tuneable control over their optical response, in this case, utilising the wavelength-selective features to overcome colour vision deficiency. The fabrication process utilises an electron beam lithography technique to fabricate a 40 nm thick metasurface of gold building blocks on an indium-tin-oxide-coated glass. A thin (∼350 nm) layer of polymethylmethacrylate (PMMA) is then spin-coated and subsequently baked onto the metasurface and hot, deionised water is used to separate the PMMA matrix (with the embedded metasurface) from the glass substrate. This membrane is then thermally fused to a plasma-treated rigid corneal lens. Using a variety of matrices, researchers were able to demonstrate a shift in the perception of a test pigment in the case of deuteranomaly closer to the pigment viewed in cases of normal vision, as was contrast restoration using a simulated Ishihara plate perception test [
      • Karepov S.
      • Ellenbogen T.
      Metasurface-based contact lenses for color vision deficiency.
      ].
      Clinical evaluation of commercial filters designed to enhance colour discrimination or “correct” colour vision deficiency indicates either no enhancement or substantial performance trade-offs. As a result, the potential benefits of the application of spectral filtering to mitigate colour vision deficiency are uncertain. Moreover, subjective anecdotes indicate that some colour vision deficiency subjects appreciate certain spectral filters, but the mechanism is not well understood. The metasurface contact lens technology holds some promise in that it may allow “tuneable” spectral filtering functionality into contact lenses to achieve an improved success rate over a range of patients with colour vision deficiency.

      5. Drug delivery to the ocular surface

      Drug releasing soft contact lenses have been widely studied and continue to show promise, primarily by overcoming the current limitations associated with delivering ophthalmic medications via an eye drop.
      The primary disadvantage with eye drops is their low bioavailability of less than 5% [
      • Urtti A.
      Challenges and obstacles of ocular pharmacokinetics and drug delivery.
      ], which is attributed to high tear turnover rates, blinking, nasolacrimal drainage, non-productive absorption by the conjunctiva, and low permeability of the cornea [
      • Zhang X.
      • Cao X.
      • Qi P.
      Therapeutic contact lenses for ophthalmic drug delivery: major challenges.
      ,
      • Alvarez-Lorenzo C.
      • Anguiano-Igea S.
      • Varela-Garcia A.
      • Vivero-Lopez M.
      • Concheiro A.
      Bioinspired hydrogels for drug-eluting contact lenses.
      ]. Thus, improving bioavailability by increasing the residence time of the drug on the ocular surface remains an important area of research. When placed on the eye, a contact lens splits the tear film into the pre-lens tear film overlying the lens and post-lens tear film (PoLTF) between the back surface of the lens and the ocular surface. This compartmentalisation is beneficial to drug releasing contact lens as the PoLTF is very thin with a relatively low turnover rate [
      • Muntz A.
      • Subbaraman L.N.
      • Sorbara L.
      • Jones L.
      Tear exchange and contact lenses: a review.
      ]. When a drug releasing lens elutes its medication into the PoLTF the low tear turnover rate promotes an increased concentration of the drug behind the lens, in addition to an increased residence time, leading to potentially greater bioavailability of the drug and increased ocular penetration [
      • Alvarez-Lorenzo C.
      • Anguiano-Igea S.
      • Varela-Garcia A.
      • Vivero-Lopez M.
      • Concheiro A.
      Bioinspired hydrogels for drug-eluting contact lenses.
      ,
      • Li C.-C.
      • Chauhan A.
      Modeling ophthalmic drug delivery by soaked contact lenses.
      ]. Additional benefits include decreased frequency of drug administration, minimised systemic absorption and a more controlled drug release profile [
      • Alvarez-Lorenzo C.
      • Anguiano-Igea S.
      • Varela-Garcia A.
      • Vivero-Lopez M.
      • Concheiro A.
      Bioinspired hydrogels for drug-eluting contact lenses.
      ].
      Drug delivering contact lenses may offer more accurate dosing over eye drops [
      • Davis S.A.
      • Sleath B.
      • Carpenter D.M.
      • Blalock S.J.
      • Muir K.W.
      • Budenz D.L.
      Drop instillation and glaucoma.
      ], provided the drug volume and release profile is consistent from lens to lens. Once the lens is placed on the eye, the medication will elute from the lens with few external factors influencing the release profile. Contrary to this, there are multiple factors that can affect the variability of dosing via eye drops. With conventional eye drop bottles, patients are required to tilt their head back and keep their eye open while simultaneously positioning the inverted bottle directly over their eye and squeezing the dropper bottle with the precise amount of force and with accurate aim in an attempt to deliver the prescribed amount of medication. Not only is there variability in how successful patients are in their aim but also in the drop size itself based on the bottle tip, amount of drug in the bottle and angle at which the bottle is held [
      • Sklubalova Z.
      • Zatloukal Z.
      Study of eye drops dispensing and dose variability by using plastic dropper tips.
      ].
      Incorporating drug-releasing technology into a soft contact lens may also significantly improve treatment compliance over eye drops. The compliance rate with the routine administration of eye drops is low [
      • Winfield A.J.
      • Jessiman D.
      • Williams A.
      • Esakowitz L.
      A study of the causes of non-compliance by patients prescribed eyedrops.
      ] and while the reasons are likely multifactorial, patients may simply have difficulty incorporating their eye drop therapy into their daily routine. However, assuming a contact lens technology can provide a sustained release over multiple days, a patient can wear the lens (or have it applied for them) and have their medication continually delivered over a predetermined period of time. If a drug releasing contact lens is loaded with a daily dose of medication, the vision correction function of the contact lens may improve compliance, particularly in habitual contact lens wearers, as inserting contact lenses are already part of their daily routine.
      Many topical ophthalmic drops require preservatives such as benzalkonium chloride to provide antimicrobial protection and maintain drug stability. However, even at low concentrations they can result in corneal and conjunctival epithelial cell toxicity [
      • Walsh K.
      • Jones L.
      The use of preservatives in dry eye drops.
      ,
      • Epstein S.P.
      • Ahdoot M.
      • Marcus E.
      • Asbell P.A.
      Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells.
      ]. Contact lenses are terminally sterilised and so the use of preservatives with drug-releasing contact lens technology is not required.

      5.1 Challenges to contact lens drug delivery

      While there are potential benefits to delivering ophthalmic medications via a contact lens, there are many challenges that must be overcome for this technology to become a commercial reality.

      5.1.1 Choosing a lens/drug combination to optimise the uptake and release profile

      The first consideration is in selecting the specific drug and contact lens material that will allow for a therapeutically meaningful uptake and release profile. A key attribute of the drug under consideration is its chemical nature. A more hydrophilic molecule will be more easily incorporated in a more hydrophilic hydrogel lens material, while a more lipophilic molecule will be more easily absorbed by a relatively hydrophobic silicone hydrogel material. However, if a drug molecule has an exceptionally high affinity for the lens material, then it could result in an unacceptably prolonged drug release profile once the lens is placed on the eye [
      • Zhang X.
      • Cao X.
      • Qi P.
      Therapeutic contact lenses for ophthalmic drug delivery: major challenges.
      ]. The molecular weight of the drug may also impact the ultimate uptake and release of the drug [
      • Maulvi F.A.
      • Soni T.G.
      • Shah D.O.
      A review on therapeutic contact lenses for ocular drug delivery.
      ].
      The efforts to identify various technologies to influence drug uptake and release from a contact lens have led to some compelling results from in vitro experiments. However, it is important to note that the correlations between in vitro models and in vivo results are not always strong, due to the difficulty in simulating continuous tear flow, eyelid blinking mechanics, and the morphology of the ocular surface. Thus, the drug release kinetics demonstrated in the laboratory may not be replicated when the drug releasing lens is placed on the eye [
      • Minami T.
      • Ishida W.
      • Kishimoto T.
      • Nakajima I.
      • Hino S.
      • Arai R.
      • et al.
      In vitro and in vivo performance of epinastine hydrochloride-releasing contact lenses.
      ].

      5.1.2 Drug viability during manufacturing

      On the path to commercialisation, once the specific drug and contact lens material has been selected and an optimal method for incorporating the drug into the lens matrix obtained, the combination must remain viable throughout the lens manufacturing process. The drug can be incorporated into the lens monomer mix, facilitating a relatively homogenous distribution throughout the manufactured lens. However, this requires that the drug withstand the lens curing steps (typically via a light or thermal curing process). Once cured, the lens then typically goes through a series of monomer extraction and lens hydration steps using aqueous and/or solvent solutions. Depending on the chemical nature and stability of the drug, these curing and extraction steps could have a significant impact on the final loaded drug concentration or may even accelerate drug degradation. To protect the drug from the lens manufacturing environment, the drug could be added after the lens has been fully polymerised and hydrated. In this scenario, the challenge is then to find the optimal method of drug incorporation, resulting in the desired drug uptake and release profile, in addition to incorporating a consistent amount of drug within the lenses. Finally, since most contact lenses are terminally sterilised via an autoclaving process, the selected drug would ultimately need to be able to withstand a period of intense heat (over 120 degrees Celsius).

      5.1.3 Impact of lens design on drug uptake

      While the consistent release of the drug is a key benefit of a drug releasing contact lens, a prerequisite of this is that a consistent amount of drug is taken up by the lens. The challenge in this comes from the multiple lens designs and range of lens powers that are required to provide this vision-correcting technology to a broad patient base. The different lens powers require subtle differences in lens shape, resulting in a change in lens volume. For example, a hyperopic lens has a greater centre thickness than a myopic contact lens. Similarly, the designs for toric contact lenses often have an increased thickness profile across specific regions (due to the stabilisation zones) as compared to a spherical power lens. Thus, to maintain a consistent and efficacious dose being released to the eye, the drug uptake must be tailored to each lens power and lens design during the manufacturing process, which is complex and likely to add cost and time to the production process.

      5.1.4 Impact on contact lens properties

      The incorporation of a drug into a contact lens cannot significantly alter the contact lens properties and parameters or have a detrimental impact on comfort, vision and handling. The tear film uptake profile is also an important consideration, as the chemical nature of the drug could result in tear film lipids and proteins to have a greater affinity to the lens. The lens also needs to maintain an acceptable base curve radius and diameter to ensure an optimal fit, as well as sufficient oxygen permeability based on the intended wear modality.

      5.1.5 Regulatory issues

      Another substantial hurdle relates to the clinical trials required to demonstrate the safety and efficacy of the drug releasing lens. The scope and timing associated with these trials can be influenced by multiple factors, including the disease state being evaluated, the endpoints required to demonstrate efficacy, the intended lens wear modality (such as daily wear or overnight wear), the existing safety profile of the drug and contact lens material, as well as the regulatory pathway for product approval, as combination products require both pharmaceutical and device review [
      • Zaki M.
      • Pardo J.
      • Carracedo G.
      A review of international medical device regulations: contact lenses and lens care solutions.
      ].
      The lens wear modality of a drug releasing contact lens is obviously an important factor as it will dictate the required release profile necessary to provide a therapeutic benefit. For chronic disease states or patients who may otherwise not wear contact lenses, an overnight wear or monthly replacement daily wear modality may seem logical. In these cases, the drug release profile would be tailored to elute the medication over multiple days or weeks. However, if intended to be worn on an overnight wear modality, the drug releasing lens would likely require extensive clinical testing to support an acceptable safety profile [
      • Zaki M.
      • Pardo J.
      • Carracedo G.
      A review of international medical device regulations: contact lenses and lens care solutions.
      ]. If the lens is designed for a frequent replacement, daily wear modality, then the drug-lens combination would need to be able to withstand the daily rubbing, rinsing, and overnight soaking steps associated with the use of multipurpose cleaning and disinfecting solutions. A daily disposable lens wear modality may provide some advantages by avoiding the interactions with lens care solutions, but to be commercially viable, the manufacturing process would need to be scaled up to allow for a sufficient quantity of lenses to be produced.

      5.1.6 Long-term stability

      A packaged drug-releasing contact lens is required to demonstrate long term stability with minimal drug degradation and with a consistent amount of drug in the lens over time [
      • Maulvi F.A.
      • Choksi H.H.
      • Desai A.R.
      • Patel A.S.
      • Ranch K.M.
      • Vyas B.A.
      • et al.
      pH triggered controlled drug delivery from contact lenses: addressing the challenges of drug leaching during sterilization and storage.
      ]. This can be challenging, as soft contact lenses need to remain hydrated and are usually immersed in solution in their primary packaging container. Once manufacturing and packaging are complete, the lenses are then shipped and stored in distribution centres, ECP offices, or in patient’s medicine cabinets for many months prior to use. During this time, the medicated lenses can be exposed to a wide range of temperatures, which can impact the stability of the product. Therefore the packaging solution and primary packaging must be compatible with the drug-lens combination to protect it from degradation over time [
      • Maulvi F.A.
      • Choksi H.H.
      • Desai A.R.
      • Patel A.S.
      • Ranch K.M.
      • Vyas B.A.
      • et al.
      pH triggered controlled drug delivery from contact lenses: addressing the challenges of drug leaching during sterilization and storage.
      ].

      5.2 Ocular drug delivering technologies

      A wide variety of technologies have been established in an attempt to develop commercially viable methods to deliver drugs to the ocular surface from contact lenses.

      5.2.1 Contemporary contact lens materials

      Contemporary contact lens materials are commonly used as part of the therapeutic management of conditions such as corneal abrasions and recurrent corneal erosions via their so-called use as “bandage lenses” [
      • Baenninger P.B.
      Survey on bandage contact lens practice in the united kingdom.
      ,
      • Miller D.D.
      • Hasan S.A.
      • Simmons N.L.
      • Stewart M.W.
      Recurrent corneal erosion: a comprehensive review.
      ], often in conjunction with concurrent use of topical pharmaceutical management agents such as antibiotics and steroids [
      • Jacobs D.S.
      • Carrasquillo K.G.
      • Cottrell P.D.
      • Fernández-Velázquez F.J.
      • Gil-Cazorla R.
      • Jalbert I.
      • et al.
      CLEAR - medical use of contact lenses.
      ,
      • Karlgard C.C.S.
      • Jones L.W.
      • Moresoli C.
      Survey of bandage lens use in North America, october-december 2002.
      ]. Despite this common clinical practice, few studies have investigated the impact of concurrent pharmaceutical and contact lens use on clinical outcomes or safety, or of the degree to which topical drugs are delivered to the eye when combined with commercially available contact lens materials.
      Almost every major class of ophthalmic medications in use has been investigated in vitro for their uptake and release into commercially available contact lenses, from anti-allergy [
      • Soluri A.
      • Hui A.
      • Jones L.
      Delivery of ketotifen fumarate by commercial contact lens materials.
      ,
      • Karlgard C.C.
      • Wong N.S.
      • Jones L.W.
      • Moresoli C.
      In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials.
      ], antibacterials [
      • Hui A.
      • Boone A.
      • Jones L.
      Uptake and release of ciprofloxacin-HCl from conventional and silicone hydrogel contact lens materials.
      ,
      • Karlgard C.C.
      • Jones L.W.
      • Moresoli C.
      Ciprofloxacin interaction with silicon-based and conventional hydrogel contact lenses.
      ,
      • Karlgard C.
      • Jones L.
      • Moresoli C.
      Uptake and release of ciloxan from silicone-hydrogel and conventional hydrogel contact lens materials.
      ,
      • Bajgrowicz M.
      • Phan C.M.
      • Subbaraman L.N.
      • Jones L.
      Release of ciprofloxacin and moxifloxacin from daily disposable contact lenses from an in vitro eye model.
      ,
      • Dixon P.
      • Chauhan A.
      Effect of the surface layer on drug release from delefilcon-A (Dailies Total1((r))) contact lenses.
      ,
      • Tian X.
      • Iwatsu M.
      • Sado K.
      • Kanai A.
      Studies on the uptake and release of fluoroquinolones by disposable contact lenses.
      ,