Corneal sensitivity as an ophthalmic marker of diabetic neuropathy

Purpose. The objective of this study was to explore the discriminative capacity of non-contact corneal esthesiometry (NCCE) when compared with the neuropathy disability score (NDS) score—a validated, standard method of diagnosing clinically significant diabetic neuropathy. Methods. Eighty-one participants with type 2 diabetes, no history of ocular disease, trauma, or surgery and no history of systemic disease that may affect the cornea were enrolled. Participants were ineligible if there was history of neuropathy due to non-diabetic cause or current diabetic foot ulcer or infection. Corneal sensitivity threshold was measured on the eye of dominant hand side at a distance of 10 mm from the center of the cornea using a stimulus duration of 0.9 s. The NDS was measured producing a score ranging from 0 to 10. To determine the optimal cutoff point of corneal sensitivity that identified the presence of neuropathy (diagnosed by NDS), the Youden index and “closest-to-(0,1)” criteria were used. Results. The receiver-operator characteristic curve for NCCE for the presence of neuropathy (NDS ≥3) had an area under the curve of 0.73 (p = 0.001) and, for the presence of moderate neuropathy (NDS ≥6), area of 0.71 (p = 0.003). By using the Youden index, for an NDS ≥3, the sensitivity of NCCE was 70% and specificity was 75%, and a corneal sensitivity threshold of 0.66 mbar or higher indicated the presence of neuropathy. When NDS ≥6 (indicating risk of foot ulceration) was applied, the sensitivity was 52% with a specificity of 85%. Conclusions. NCCE is a sensitive test for the diagnosis of minimal and more advanced diabetic neuropathy and may serve as a useful surrogate marker for diabetic and perhaps other neuropathies.

Model-order selection in Zernike polynomial expansion of corneal surfaces using the efficient detection criterion

Corneal-height data are typically measured with videokeratoscopes and modeled using a set of orthogonal Zernike polynomials. We address the estimation of the number of Zernike polynomials, which is formalized as a model-order selection problem in linear regression. Classical information-theoretic criteria tend to overestimate the corneal surface due to the weakness of their penalty functions, while bootstrap-based techniques tend to underestimate the surface or require extensive processing. In this paper, we propose to use the efficient detection criterion (EDC), which has the same general form of information-theoretic-based criteria, as an alternative to estimating the optimal number of Zernike polynomials. We first show, via simulations, that the EDC outperforms a large number of information-theoretic criteria and resampling-based techniques. We then illustrate that using the EDC for real corneas results in models that are in closer agreement with clinical expectations and provides means for distinguishing normal corneal surfaces from astigmatic and keratoconic surfaces.

Patient-specific computational biomechanics for simulating adolescent scoliosis surgery : predicted vs clinical correction for a preliminary series of six patients

Scoliosis is a spinal deformity that requires surgical correction in progressive cases. In order to optimize surgical outcomes, patient-specific finite element models are being developed by our group. In this paper, a single rod anterior correction procedure is simulated for a group of six scoliosis patients. For each patient, personalised model geometry was derived from low-dose CT scans, and clinically measured intra-operative corrective forces were applied. However, tissue material properties were not patient-specific, being derived from existing literature. Clinically, the patient group had a mean initial Cobb angle of 47.3 degrees, which was corrected to 17.5 degrees after surgery. The mean simulated post-operative Cobb angle for the group was 18.1 degrees. Although this represents good agreement between clinical and simulated corrections, the discrepancy between clinical and simulated Cobb angle for individual patients varied between -10.3 and +8.6 degrees, with only three of the six patients matching the clinical result to within accepted Cobb measurement error of +-5 degrees. The results of this study suggest that spinal tissue material properties play an important role in governing the correction obtained during surgery, and that patient-specific modelling approaches must address the question of how to prescribe patient-specific soft tissue properties for spine surgery simulation.

Ocular characteristics in myopic anisometropia

PURPOSE: To investigate the interocular symmetry of ocular optical, biometric and biomechanical characteristics between the more and less ametropic eyes of myopic anisometropes. METHODS: Thirty-four young, healthy myopic anisometropic adults (≥ 1 D spherical equivalent difference between eyes) without amblyopia or strabismus were recruited. A range of biometric and optical parameters were measured in the more and less ametropic eye of each subject including; axial length, ocular aberrations, intraocular pressure and corneal topography, thickness and biomechanics. Morphology of the anterior eye in primary and downward gaze was examined using custom software analysis of high resolution digital images. Ocular sighting dominance was assessed using the hole-in-the-card test. RESULTS: Mean absolute spherical equivalent anisometropia was 1.74 ± 0.74 D. There was a strong correlation between the degree of anisometropia and the interocular difference in axial length (r = 0.81, p < 0.001). The more and less ametropic fellow eyes displayed a high degree of interocular symmetry for the majority of biometric, biomechanical and optical parameters measured. When the level of anisometropia exceeded 1.75 D (n = 10), the more myopic eye was the dominant sighting eye in nine of these ten subjects. Subjects with greater levels of anisometropia (> 1.75 D) also showed high levels of correlation between the dominant and non-dominant eyes in their biometric, biomechanical and optical characteristics. CONCLUSIONS: Although significantly different in axial length, anisometropic eyes display a high degree of interocular symmetry for a range of anterior eye biometrics and optical parameters. For higher levels of anisometropia, the more myopic eye tends to be the dominant sighting eye.

Corneal markers of diabetic neuropathy

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new non-invasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and non-contact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

Interocular symmetry in myopic anisometropia

Purpose: To investigate the interocular symmetry of optical, biometric and biomechanical characteristics between the fellow eyes of myopic anisometropes. Methods: Thirty-four young, healthy myopic anisometropic adults (≥ 1 D spherical equivalent difference between eyes) without amblyopia or strabismus were recruited. A range of biometric and optical parameters were measured in both eyes of each subject including; axial length, ocular aberrations, intraocular pressure (IOP), corneal topography and biomechanics. Ocular sighting dominance was also measured. Results: Mean absolute spherical equivalent anisometropia was 1.70 ± 0.74 D and there was a strong correlation between the degree of anisometropia and the interocular difference in axial length (r = 0.81, p < 0.001). The more and less myopic eyes displayed a high degree of interocular symmetry for the majority of biometric, biomechanical and optical parameters measured. When the level of anisometropia exceeded 1.75 D, the more myopic eye was more likely to be the dominant sighting eye than for lower levels of anisometropia (p=0.002). Subjects with greater levels of anisometropia (> 1.75 D) also showed high levels of correlation between the dominant and non-dominant eyes in their biometric, biomechanical and optical characteristics. Conclusions: Although significantly different in axial length, anisometropic eyes display a high degree of interocular symmetry for a range of anterior eye biometrics and optical parameters. For higher levels of anisometropia, the more myopic eye tends to be the dominant sighting eye.

Evaluation of silk sericin as a biomaterial: In vitro growth of human corneal limbal epithelial cells on Bombyx mori sericin membranes

Sericin and fibroin are the two major proteins in the silk fibre produced by the domesticated silkworm, Bombyx mori. Fibroin has been extensively investigated as a biomaterial. We have previously shown that fibroin can function successfully as a substratum for growing cells of the eye. Sericin has been so far neglected as a biomaterial because of suspected allergenic activity. However, this misconception has now been dispelled, and sericin’s biocompatibility is currently indisputable. Aiming at promoting sericin as a possible substratum for the growth of corneal cells in order to make tissue-engineered constructs for the restoration of the ocular surface, in this study we investigated the attachment and growth in vitro of human corneal limbal epithelial cells (HLECs) on sericin-based membranes. Sericin was isolated and regenerated from the silkworm cocoons by an aqueous procedure, manufactured into membranes, and characterized (mechanical properties, structural analysis, contact angles). Primary cell cultures from two donors were established in serum-supplemented media in the presence of murine feeder cells. Membranes made of sericin and fibroin-sericin blends were assessed in vitro as substrata for HLECs in a serum-free medium, in a cell attachment assay and in a 3-day cell growth experiment. While the mechanical characteristics of sericin were found to be inferior to those of fibroin, its ability to enhance the attachment of HLECs was significantly superior to fibroin, as revealed by the PicoGreen® assay. Evidence was also obtained that cells can grow and differentiate on these substrata.

Human corneal epithelial equivalents constructed on Bombyx mori silk fibroin membranes

Membranes prepared from a protein, fibroin, isolated from domesticated silkworm (Bombyx mori) silk, support the cultivation of human limbal epithelial (HLE) cells and thus display significant potential as biomaterials for ocular surface reconstruction. We presently extend this promising avenue of research by directly comparing the attachment, morphology and phenotype of primary HLE cell cultures grown on fibroin to that observed on donor amniotic membrane (AM), the current clinical standard substrate for HLE transplantation. Fibroin membranes measuring 6.3 ± 0.5 μm (mean ± sd) in thickness and permeable to FITC dextran of a molecular weight up to 70 kDa, were used. Attachment of HLE cells to fibroin was similar to that supported by tissue culture plastic but approximately 6-fold less than that observed on AM. Nevertheless, epithelia constructed from HLE on fibroin maintained evidence of corneal phenotype (K3/K12 expression) and displayed a comparable number and distribution of ΔNp63+ progenitor cells to that seen in cultures grown on AM. These results support the suitability of membranes constructed from Bombyx mori silk fibroin as substrata for HLE cultivation and encourage progression to studies of efficacy in preclinical models.

Defining standards for modelling the biomechanics of the foot and ankle : a systematic review

The complex interaction of the bones of the foot has been explored in detail in recent years, which has led to the acknowledgement in the biomechanics community that the foot can no longer be considered as a single rigid segment. With the advance of motion analysis technology it has become possible to quantify the biomechanics of simplified units or segments that make up the foot. Advances in technology coupled with reducing hardware prices has resulted in the uptake of more advanced tools available for clinical gait analysis. The increased use of these techniques in clinical practice requires defined standards for modelling and reporting of foot and ankle kinematics. This systematic review aims to provide a critical appraisal of commonly used foot and ankle marker sets designed to assess kinematics and thus provide a theoretical background for the development of modelling standards.

A Systematic Review of kinematic models used in foot & ankle biomechanics

Over the past decade our understanding of foot function has increased significantly[1,2]. Our understanding of foot and ankle biomechanics appears to be directly correlated to advances in models used to assess and quantify kinematic parameters in gait. These advances in models in turn lead to greater detail in the data. However, we must consider that the level of complexity is determined by the question or task being analysed. This systematic review aims to provide a critical appraisal of commonly used marker sets and foot models to assess foot and ankle kinematics in a wide variety of clinical and research purposes.

Defining standards for modelling the biomechanics of the foot and ankle: A systematic review

The complex interaction of the bones of the foot has been explored in detail in recent years, which has led to the acknowledgement in the biomechanics community that the foot can no longer be considered as a single rigid segment. With the advance of motion analysis technology it has become possible to quantify the biomechanics of simplified units or segments that make up the foot. Advances in technology coupled with reducing hardware prices has resulted in the uptake of more advanced tools available for clinical gait analysis. The increased use of these techniques in clinical practice requires defined standards for modelling and reporting of foot and ankle kinematics. This systematic review aims to provide a critical appraisal of commonly used foot and ankle marker sets designed to assess kinematics and thus provide a theoretical background for the development of modelling standards.

A dual-layer silk fibroin scaffold for reconstructing the human corneal limbus

Membranes prepared from Bombyx mori silk fibroin have shown potential as a substrate for human limbal epithelial (L-EC) and stromal cell cultivation. Here we present fibroin as a dual-layer construct containing both an epithelium and underlying stroma for corneolimbal reconstruction. We have compared the growth and phenotype of L-EC on non-porous versus porous fibroin membranes. Furthermore, we have compared the growth of limbal mesenchymal stromal cells (L-MSC) in either serum-supplemented medium or the MesenCult-XF® culture system within fibroin fibrous mats. The co-culture of L-EC and L-MSC in fibroin dual-layer constructs was also examined. L-EC on porous membranes displayed a squamous monolayer; in contrast, L-EC on non-porous fibroin appeared cuboidal and stratified. Both constructs maintained evidence of corneal phenotype (cytokeratin 3/12) and distribution of ΔNp63+ progenitor cells. L-MSC cultivated within fibroin fibrous mats in serum-supplemented medium contained less than 64% of cells expressing the characteristic MSC phenotype of CD73+CD90+CD105+ after two weeks, compared with over 81% in MesenCult-XF® medium. Dual-layer fibroin scaffolds consisting of L-EC and L-MSC maintained a similar phenotype as on the separate layers. These results support the feasibility of a 3D engineered limbus constructed from B. mori silk fibroin, and warrant further studies into the potential benefits it offers to corneolimbal tissue regeneration.