Ocular Surface Temperature Research Articles

Improving the topical ocular pharmacokinetics of an immunosuppressant agent with mucoadhesive nanoemulsions: Formulation development, in-vitro and in-vivo studies

Topical ocular conditions such as cornea transplant rejection and keratoconjunctivitis sicca (so called dry eye disease) require therapeutic concentration of immunosuppressant onto the ocular surface for prolonged period. Based on this rational, we optimized cyclosporine A (Cy-A) loaded polymeric mucoadhesive nanoemulsion (Cy-A-mN) with higher Cy-A payload, improved ocular retention, corneal and conjunctival bioavailability. The concentrations of oil, surfactant and co-surfactant needed for the stable nanoemulsion were screened followed by phase behavior study of the formulations components by the construction of pseudo-ternary phase diagrams. The concentration of chitosan was optimized according to the blinking force of eyelids. The size distribution, surface charge, mucoadhesiveness and Cy-A release were studied for Cy-A-mN along with other formulations. The corneal retention of Cy-A-mN was evaluated by gamma scintigraphy, revealing that the clearance was slowest in the case of Cy-A-mN. Biodistribution performed in rabbits showed that Cy-A-mN was able to maintain the therapeutic concentrations (≥50–300ng/g) of Cy-A in the cornea and conjunctiva over the period of 24h. The safety of formulation was confirmed by Draize’s test and by measuring the ocular surface temperature.

Ocular-surface temperature modification by cataract surgery

To analyze ocular-surface temperature changes after microincision cataract surgery and to correlate them with surgical, clinical, and laboratory parameters. Ophthalmology Unit, Saint Orsola-Malpighi Hospital, Bologna, Italy. Prospective case series. Patients affected by monolateral senile cataract were examined preoperatively and 7days and 28days postoperatively. Infrared thermography was used to measure the temperature soon after eye opening, the temperature after 10seconds of sustained eye opening, and the difference between these 2 values in the central cornea, nasal limbus, and temporal limbus. The Ocular Surface Disease Index (OSDI), Schirmer test, vital staining, tear breakup time (TBUT), conjunctival scraping cytology, exudated tear-serum albumin, and laser flare-cell meter examinations were performed. The study comprised 26 patients (10 men, 16 women). The temperature changed significantly after surgery. The temperature soon after eye opening showed cooling in the central cornea and nasal limbus and heating in the temporal limbus. The temperature after 10seconds of sustained eye opening minus the temperature soon after eye opening increased in all regions. The temperature after 10seconds of sustained eye opening minus the temperature soon after eye opening in the central cornea was inversely related to the OSDI and directly related to TBUT. The temperature soon after eye opening increased in the temporal limbus and was directly related to inflammatory indices. The ocular-surface temperature changed after cataract surgery depending on the region analyzed. The cooling in the central cornea could be related to the increased tear-film instability. The heating in the temporal limbus could be related to postoperative inflammation. None of the authors has a financial or proprietary interest in any material or method mentioned.

Development of mucoadhesive and thermosensitive eyedrops to improve the ophthalmic bioavailability of ibuprofen

Topical ophthalmic formulations prepared with nanostructured lipid carriers (NLC) exhibit low bioavailability. Specific physicochemical properties of the ocular tissues, namely, temperature, pH and electrolyte composition of the pre-corneal region, can be exploited to enhance the bioavailability of colloidal nanocarriers using in situ gelling systems. The aim of this study was to enhance the ophthalmic bioavailability of NLC dispersions through the addition of a thermoresponsive polymer (Pluronic® F-127) and a mucoadhesive polymer (chitosan). Simulating the physiological conditions, the addition of Pluronic® F 127 (PF 127) caused the sol-gel transition of the colloidal dispersion upon contact with the ocular surface temperature, while the addition of chitosan (CS) led to the establishment of electrostatic interactions with the mucin present in the ocular tissues. The results also suggested that NLC–based hydrogels were biocompatible with no significant cytotoxicity observed in the Y-79 human retinoblastoma cell line. The addition of PF 127 and CS to NLC dispersions can enhance the bioavailability and the therapeutic efficacy of topical ophthalmic formulations.

Relationship between Corneal Sensation, Blinking, and Tear Film Quality.

To examine the possible role of corneal sensitivity and tear film quality in triggering a blink by investigating the relationship between blink rate, central corneal sensitivity threshold (CST), ocular surface temperature (OST), tear meniscus height (TMH), tear film quality (noninvasive tear break-up time [NIBUT]), and tear film lipid pattern under normal conditions. Forty-two volunteers (average age, 27.76 ± 5.36 years; 11 males) with good ocular health (Ocular Surface Disease Index, <15.0) were recruited for this cross-sectional cohort study. Blink rate, CST (noncontact corneal air gas aesthesiometry, NCCA), minimum and maximum OST in the central and inferior cornea between blinks (thermal infrared camera), TMH, NIBUT, and lipid pattern of the tear film (Keeler Tearscope Plus) were recorded on the right eye only. Median blink rate was 11 blinks/min (interquartile range [IR], 6.95 to 17.05), CST was 0.35 mbars (IR, 0.30 to 0.40), minimum OST in the central cornea was 35.15°C (IR, 34.58 to 35.50), and NIBUT was 34.55 s (IR, 12.45 to 53.80). Moderate but statistically significant correlations were observed between CST and NIBUT (r = 0.535, p < 0.001), CST and blink rate (r = -0.398, p < 0.001), lipid pattern and OST (r = 0.556, p < 0.001), and between CST and OST (r = 0.371, p = 0.008). The correlations between blink rate and NIBUT (r = -0.696, p < 0.001) and between OST and NIBUT (r = 0.639, p < 0.001; Spearman test) achieved higher significance; this was highlighted by the linear regression model where NIBUT and minimum central and inferior OST were identified as significant predictor variables. There is strong evidence for significant interactions between corneal sensitivity, NIBUT, OST, and blink frequency, emphasizing that ocular surface conditions represent a possible important trigger for the initiation of a blink. However, the mechanisms involved in the initiation of a blink are complex, with local ocular sensory input as only one trigger, along with other external influences and internal factors under cortical control.

A thermographic study on eyes affected by Age-related Macular Degeneration: Comparison among various forms of the pathology and analysis of risk factors

The aims of this study are to investigate (1) the ocular thermographic profiles in eyes affected by Age related Macular Degeneration (AMD) and age-matched controls to detect possible hemodynamic abnormalities that could be involved in the pathogenesis of the disease, (2) whether any risk factors associated with the disease could affect the development of a form of AMD rather than another. Thirty-four eyes with Age-Related Maculopathy (ARM), 41 eyes with dry AMD, 60 eyes affected by wet AMD, and 74 eyes with fibrotic AMD were included in the study. The control group consisted of 48 healthy eyes. Exclusion criteria were represented by any other ocular diseases other than AMD, tear film abnormalities, systemic cardiovascular abnormalities, systemic diseases and a body temperature higher than 37.5°C. A total of 210 eyes without pupil dilation were investigated by infrared thermography (FLIR A320). The Ocular Surface Temperature (OST) of five ocular areas was calculated by means of an image processing technique from the infrared images. Two-sample t-test, one-way ANOVA test and multivariate analysis were used for statistical analyses. ANOVA analyses showed no significant differences among AMD groups (P-value>0.05), however, OST in AMD patients was significantly lower than in controls (P-value<0.0001). Smokers showed higher possibility (P-value=0.012) of developing wet AMD instead of dry AMD. Infrared thermography may be a helpful, non-invasive and not time-consuming method to be used in the management of patients with this common degenerative maculopathy.

Repeatability of infrared ocular thermography in assessing healthy and dry eyes.

To investigate the inter-image, inter-occasion and inter-examiner repeatability of NEC infrared thermo-tracer TH 9260 in assessing healthy and dry eyes. Ocular surface temperature (OST) was recorded using NEC infrared thermo-tracer TH 9260 on 21 healthy and 15 dry eyes. Data from the right eyes were analyzed. Marking of the ocular surface and OST acquisition was performed using a new 'diamond' demarcation method. Twelve OST indices were obtained at three different time points following a blink: 0s, 5s and 10s. Inter-image, inter-occasion and inter-examiner repeatability of the infrared ocular thermography was evaluated by calculating coefficients of repeatability (COR). Ten out of the twelve tested OST indices had good repeatability with small inter-image variability (%COR: 0.2-0.9), inter-occasion variability (%COR: 2.1-3.7) and inter-examiner variability (%COR: 1.5-3.7) for the three studied time points. Two of the OST indices (temperature standard deviation of the region of interest and radial temperature difference) had poor repeatability with much larger inter-image variability (%COR: 8.9-140.7), inter-occasion variability (%COR: 47.5-153.5) and inter-examiner variability (%COR: 54.7-142.0) for the three studied time points. Most of the metrics adopted in this assessment can be considered to be highly repeatable.

Static and Dynamic Measurement of Ocular Surface Temperature in Dry Eyes.

Purpose. To study ocular surface temperature (OST) in dry eyes by static and dynamic measures. Methods. OST was recorded on 62 dry eyes and 63 age- and sex-matched controls. Static measures were study of absolute OST at t = 0, 5, and 10 s after eye opening. Dynamic measures were study of mean change and net change in OST over 10 s of sustained eye opening. Ten OST indices studied were temperatures of the geometric center of the cornea (GCC), extreme temporal (T1) and nasal conjunctiva (T4), midtemporal (CT) and nasal conjunctiva (CN), temporal (LT) and nasal (LN) limbus, and mean (MOST), maximum (Max T), and minimum (Min T) temperatures of the region of interest. Results. For static measures, dry eyes recorded significantly lower GCC, MOST, Min T, Max T, T4, CT, LT, LN, and CN. For dynamic measures, dry eyes had significantly steeper regression line of mean change (corresponding to greater net change) for Max T 5 s onward and T4 at 3 s onward. Conclusions. Both static and dynamic measures of the OST were valuable and can be used as clinical tool to assess dry eye.

Diagnostic Ability of Conventional Dry Eye Tests and their Correlation with Ocular Surface Temperature

Objective: To study the diagnostic ability of conventional dry eye tests and their correlation with ocular surface temperature (OST) and derive the best combined objective tests for dry eye. Methods: This was a single visit study included a few conventional dry eye tests on 62 dry eye and 82 control subjects: symptom evaluation, fluorescein break-up time (FBUT), corneal epithelial staining (CES), non-invasive break-up time (NIBUT) and tear meniscus height (TMH). OST was recorded using NEC TH9260 thermo tracer and six temperature metrics of the extreme nasal conjunctiva was studied including the temperature 10 seconds after eye opening (T4-10). Diagnostic ability was assessed by calculating sensitivity and specificity and area under the receiver operating characteristics curve (AUC). Results: No correlation (Pearson's coefficient, -0.203 to 0.209; p>0.05) was found between Mscore, Scount, FBUT and CES with any of the temperature metrics. However, CES correlated significantly with TMH (r=0.276; p=0.030) and inversely correlated significantly with FBUT (r=- 0.258; p=0.043). Values of Mscore at 8 were found to give sensitivity of 87.1% (95% CI: 76.2 to 94.3%) and specificity of 92.7% (84.8 to 97.3%). Values of Scount at 1 were found to give sensitivity of 93.6% (84.3 to 98.2%) and specificity of 65.9% (54.6 to 76.0%). Values of FBUT at 2 s were found to give sensitivity of 58.1% (44.9 to 70.5%) and specificity of 87.8% (78.7 to 94.0%). Values of CES at grade 2 were found to give sensitivity of 71% (58.1 to 81.8%) and specificity of 59.8% (48.3 to 70.4%). Combining CES with T4-10 (series) had increased the AUC to 78% with sensitivity and specificity of 92.3% and 42.7% respectively. Conclusion: This work validated the ability of Mscore, Scount, FBUT and CES in diagnosing dry eye and further confirmed the discordance between its signs and symptoms. Combining CES with T4-10 (series) can be future objective tests for dry eye.

Ocular Surface Temperature and Tear Film Matrix Metalloproteinase-9 Concentration in Sjögren Syndrome Patients

Purpose: To evaluate the ocular surface temperature (OST) using an infrared thermography camera in Sjogren Syndrome (SS) patients compared with healthy subjects and correlate these results with the dry eye symptomatology, tear volume, stability and matrix metalloproteinase 9 (MMP-9) concentrations. Methods: Twelve patients of primary SS (46.64 ± 13.34 years), and twenty volunteers (41.38 ± 9.67 years) without dry eye, participated in this study. OSDI questionnaire, Schirmer test, tear break up time (TFBUT), matrix metalloproteinase 9 (MMP-9) concentrations and OST were evaluated. Results: Central cornea temperature was statistically higher in SS than in control group (p = 0.014), being 34.81 ± 0.37oC and 34.25 ± 0.65oC respectively. In the control group, the temperature increased in the periphery compared with central cornea, limbus and conjunctiva (p 0.05). The SS patients showed a significant lower Schirmer test and TFBUT compared with control group (p<0.005). Also, the OSDI score and MMP-9 concentration were statistically higher in SS patients compared with the control group (p<0.05). No correlation between central cornea temperature and TFBUT, OSDI and Schirmer test was found. However we found a strong positive correlation between central cornea temperature and MMP-9 concentration been 0.628 (p=0.029). Conclusion: Central cornea temperature is higher in SS compared with healthy subjects. The strong positive correlation between MMP-9 concentration and central cornea temperature suggests that the high temperature in SS could be due to ocular surface inflammation

Touch-free measurement of body temperature using close-up thermography of the ocular surface

In experimental animal research body temperature (BT) is measured for the objective determination of an animals’ physiological condition. Invasive, probe-based measurements are stressful and can influence experimental outcome. Alternatively BT can be determined touch-free from the emitted heat of the organism at a single spot using infrared thermometers [1]. To get visual confirmation and find more appropriate surfaces for measurement a hand-held thermal imager was equipped with a self-made, cheap, 3D-printable close-up lens system that reproducibly creates eight-time magnified thermal images and improves sensitivity. This setup was used to establish ocular surface temperature (OST), representing the temperature of the brain-heart axis, as a touch-free alternative for measurement of BT in mice, rats, rabbits and humans.OST measurement after isoflurane exposure and myocardial infarction (MI) experiments in mice revealed high physiological relevance and sensitivity, the possibility to discriminate between MI and sham operations in one hour and even long-term outcome-predictive capabilities of OST after MI. Summarized here we present:•Self-made close-up lens for thermal imaging cameras for eight-time magnification•Establishment of OST for touch-free determination of BT in rodents and humans•Short- and long-term predictive capabilities of OST in experimental MI in mice.

Editorial Retraction

This article refers to:Measurement of Dynamic Ocular Surface Temperature in Healthy Subjects Using a New Thermography Device

Corneal surface temperature and tear secretion in young and adult aqueous tear deficient guinea pigs

PurposeTo evaluate changes in ocular surface temperature and tear secretion in young and adult control and tear‐deficient (DE) guinea‐pigs.MethodsTearing rate (TR) was measured using phenol red threads (30s). Tear break‐up time (TBUT) was measured after fluorescein instillation. Corneal surface temperature (CST) was recorded continuously in the full open eye during 30s after the eye opening using an infrared thermal camera (InfRec R300SR, Nippon Avionics). Images were analyzed using dedicated software.ResultsTearing rate was significantly higher and TBUT was significantly lower (p &lt; 0.05) in adult (12‐18 months) compared with young (2‐4 months) animals (p &lt; 0.001). CST immediately after the eye opening had a value around 36.5°C in control eyes in young and adult animals. Most tear deficient eyes had initial CST over 37°C. The slope of temperature decrease during the interblink period was similar for all ages. As expected, DE animals had significantly lower TR (p &lt; 0.001) and TBUT (p &lt; 0.01) than intact animals, although their initial CST and the slope of interblink temperature decrease were similar to age‐matched control eyes.ConclusionsTear‐deficient eyes show higher CST values immediately after blink suggesting the presence of inflammation. Temperature reduction during the interblink period was not modified in DE, despite the reduced stability of tear film.

Ocular Surface Cooling Corresponds to Tear Film Thinning and Breakup.

To investigate the relationship between ocular surface temperature (OST) and tear film thinning and breakup. Simultaneous imaging of OST and fluorescein tear thinning and breakup (FTBU) was performed on 20 subjects. Subjects were asked to open their eyes and refrain from blinking for as long as they could during testing. Ocular surface temperature was measured using an infrared thermographic camera (FLIR A655sc) and rates of ocular surface cooling (OSC) were analyzed using commercially available software. A method was developed to quantify the rate of FTBU formation using image-processing software. Areas of FTBU and regions of OSC were observed to be colocalized, with localized cooling preceding the formation of FTBU. The rates of OSC and FTBU formation were positively correlated (r = 0.74). A second-order polynomial model accurately describes the physiological relationship between the area of FTBU and OST (p < 0.001). A linear approximation provides a more clinically interpretable rate of FTBU formation with decreasing OST (p < 0.001), while still retaining high R. The results suggest a direct relationship between FTBU formation and OSC. That cooling of the ocular surface precedes FTBU formation implies a process of evaporation contributing to tear film thinning and breakup. Our study suggests that measuring the OSC rate could be an indirect assessment of tear evaporation and could contribute to the management of evaporative dry eye.

Difference in ocular surface temperature by infrared thermography in phakic and pseudophakic patients.

PurposeTo assess the change in ocular surface temperature between healthy phakic and pseudophakic patients.MethodsWe included patients with no history of ocular disease other than cataract. Patients were divided into three groups: clear lens, cataract, and pseudophakic. All patients had two ocular surface digital thermal scans. An average of five surface points was used as the mean ocular surface temperature. Results were analyzed with a one-way analysis of variance and a Tukey’s least significance difference test. The patients were further divided into phakic and pseudophakic groups. Correlation coefficients between several variables were done in order to assess dependencies.ResultsFifty-six eyes (28 cataracts, 12 clear lenses, 16 pseudophakic) were enrolled. The mean ocular surface temperature in the cataract group was 34.14°C±1.51°C; clear lens: 34.43°C±2.27°C; and pseudophakic: 34.97°C±1.57°C. There were no statistical differences among the study groups (P=0.3). There was a nonsignificant negative correlation trend between age and surface temperature in the phakic group. The trend inverted in the pseudophakic group but without statistical significance.ConclusionAlthough cataract extraction and intraocular lens implantation seem to induce a mild increase in ocular surface temperature, the effect is not clear and not significant.

Correlations among ocular surface temperature difference value, the tear meniscus height, Schirmer's test and fluorescein tear film break up time

PurposeTo report the use of a thermographer for measuring ocular surface temperature, and to evaluate the correlation among the obtained temperature difference values (TDVs) and dry eye parameters (tear meniscus...

Correlation of corneal thickness, endothelial cell density and anterior chamber depth with ocular surface temperature in normal subjects

PurposeTo analyze corneal surface temperature profile in a young and healthy study population and to determine the impact of corneal thickness (CT), anterior chamber depth (ACD), and endothelial cell density (ECD) on surface temperature. MethodsIn this prospective, single-center study 61 healthy right eyes of 61 subjects without tear film pathologies (mean age 24.9±6.7years) were recruited. Ocular surface temperature (OST) was measured with the Ocular Surface Thermographer TG-1000. From Pentacam HR CT and ACD, and from specular microscopy ECD and central corneal thickness (CCT) were acquired. From the raw measurement data (OST, CT and ACD) we extracted a) local OST the corneal center and 3mm away from the center at the 3, 6, and 9 o‘clock positions, and b) Zernike parameters Z1, Z2 and Z3 to evaluate the general temperature profile within a 6mm circular area around the center. ResultsOverall, there was no correlation between OST and CT, ACD or ECD. Local OST did not correlate with CT at any measurement position. On average local OST was highest at measurement positions where CT was lowest, but without reaching statistical significance. Baseline OST was highest at thin corneal regions and temperature decay over time was smallest in those regions. Z1, Z2 and Z3 correlated well with CT. ConclusionsIn healthy subjects corneal thickness, endothelial cell density and anterior chamber depth have no effect on corneal surface temperature. The general temperature profile seems to be influenced by the corneal thickness profile effecting a higher temperature and lower decay at thinner corneal regions.

Heat transfer and tear film dynamics over multiple blink cycles

We consider model problems for the tear film over multiple blink cycles with heat transfer from the posterior side of the tear film. A nonlinear partial differential equation governs the film thickness on a moving domain in one space dimension and time. One end of the tear film moves in order to mimic blinking in the eye. The film thickness is coupled with the diffusion of heat from the posterior of the film, where the underlying cornea and aqueous humor are modeled as a rectangular domain. The domain of the tear film is located on one edge of the rectangle. The resulting problem is solved using the method of lines with a Chebyshev spectral method in space. Evaporation is included in the model, with end fluxes specified to compensate for the evaporation from the film. The numerical results reveal a similarity to quantitative in vivo observations of the film dynamics and measured ocular surface temperature. Periodicity in the film and temperature dynamics is explored with different flux conditions and end motions, and a transition between periodic and non-periodic solutions is analyzed.

Ocular Thermography: Investigation on some Pathologies

The focus of this research is the investigation of the Ocular Surface Temperature (OST) in both healthy and pathological (e.g. age-related macular degeneration, eye dry syndrome and choroidal lesions) eyes by using Infrared Thermography (IR). Specifically, the temperature of different anatomical areas (or points) of the eye is measured by applying image processing procedures on the infrared images recorded. It is known that the pathogenesis of some ocular pathology is related to the variation of ocular blood perfusion, and thus to the temperatures of the anterior segment of the eye. Results demonstrated that thermography can provide quantitative documentation of these temperature measurements. Furthermore, thermography is a non-invasive, cheap, harmless and portable technique. The challenge is to make ocular thermography part of the daily diagnostic procedure by providing more and more reliable experimental data.

Relationship between ocular surface temperature and peripheral vasoconstriction in healthy subjects: A thermographic study

An impairment of ocular blood flow regulation is commonly considered one of the main pathogenetic mechanisms involved in the development of several eye diseases, like glaucoma. The aim of this study was to investigate whether an alteration of ocular blood supply induced by peripheral vasoconstriction might be detected by measuring the ocular surface temperature. The ocular surface temperature was evaluated in a group of 38 healthy young subjects (28 males and 10 females; mean age: 25.4 ± 4.1 years) by infrared thermography. For each subject, the experimental procedure consisted of two thermographic acquisitions both lasting 10 s, recorded before and during the immersion of both hands in a mixture of ice and water (1.6 °C ± 0.4 °C). Specifically, the second acquisition began 20 s after the hand immersion. Analysis of variance was used to compare the ocular surface temperature of the two profiles. The analysis of infrared images was carried out every 2 s: at the eye opening (t(0)) until 10 s (t(5)), for both profiles. Data showed that ocular surface temperature increased significantly (p-value < 0.05), especially near the sources of ocular blood supply, that is, temporal and nasal areas (mean increasing temperature at t(0) for P(1) = 0.12 °C ± 0.13 °C). Therefore, these results suggest a response of the ocular hemodynamic to the peripheral vasoconstriction. The ocular surface temperature may represent a cheap, non-invasive and non-time-consuming test to evaluate ocular vaso-regulation.

Thermal fluctuation based study of aqueous deficient dry eyes by non-invasive thermal imaging

In this paper we have studied the thermal fluctuation patterns occurring at the ocular surface of the left and right eyes for aqueous deficient dry eye (ADDE) patients and control subjects by thermal imaging. We conducted our experiment on 42 patients (84 eyes) with aqueous deficient dry eyes and compared with 36 healthy volunteers (72 eyes) without any history of ocular surface disorder. Schirmer's test, Tear Break-up Time, tear Meniscus height and fluorescein staining tests were conducted. Ocular surface temperature measurement was done, using an FL-IR thermal camera and thermal fluctuation in left and right eyes was calculated and analyzed using MATLAB. The time series containing the sum of squares of the temperature fluctuation on the ocular surface were compared for aqueous deficient dry eye and control subjects. Significant statistical difference between the fluctuation patterns for control and ADDE was observed (p < 0.001 at 95% confidence interval). Thermal fluctuations in left and right eyes are significantly correlated in controls but not in ADDE subjects. The possible origin of such correlation in control and lack of correlation in the ADDE subjects is discussed in the text.