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Figure 1.
Brillouin Elasticity Maps
Brillouin Elasticity Maps

A, Representative maps of the mean anterior Brillouin shift for a 53-year-old with normal corneas. B, Representative maps for a 40-year-old patient with advanced keratoconus. Insets are the respective curvature (D indicates diopter) and pachymetry maps with outlined Brillouin-scanned areas.

Figure 2.
Focal Weakening in Keratoconus
Focal Weakening in Keratoconus

The mean Brillouin shifts of the keratoconic corneas (n = 6) in the cone region vs outside the cone region compared with mean normal cornea values (n = 7). Bars represent SD.

1.
Roberts  CJ, Dupps  WJ  Jr.  Biomechanics of corneal ectasia and biomechanical treatments. J Cataract Refract Surg. 2014;40(6):991-998.
PubMedArticle
2.
Müller  LJ, Pels  E, Vrensen  GF.  The specific architecture of the anterior stroma accounts for maintenance of corneal curvature. Br J Ophthalmol. 2001;85(4):437-443.
PubMedArticle
3.
Meek  KM, Tuft  SJ, Huang  Y,  et al.  Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46(6):1948-1956.
PubMedArticle
4.
Scarcelli  G, Yun  SH.  In vivo Brillouin optical microscopy of the human eye. Opt Express. 2012;20(8):9197-9202.
PubMedArticle
5.
Scarcelli  G, Besner  S, Pineda  R, Yun  SH.  Biomechanical characterization of keratoconus corneas ex vivo with Brillouin microscopy. Invest Ophthalmol Vis Sci. 2014;55(7):4490-4495.
PubMedArticle
6.
Randleman  JB, Dawson  DG, Grossniklaus  HE, McCarey  BE, Edelhauser  HF.  Depth-dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24(1):S85-S89.
PubMed
Research Letter
April 2015

In Vivo Biomechanical Mapping of Normal and Keratoconus Corneas

Author Affiliations
  • 1Wellman Center for Photomedicine, Massachusetts General Hospital, Cambridge
  • 2Department of Dermatology, Harvard Medical School, Boston, Massachusetts
  • 3Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston
JAMA Ophthalmol. 2015;133(4):480-482. doi:10.1001/jamaophthalmol.2014.5641

Corneal mechanical strength is critical to withstanding intraocular pressure and maintaining normal shape.1,2 In keratoconus, the mechanical stability is compromised,3 which may lead to progressive morphological changes. Therefore, a noninvasive technique capable of accurately measuring the mechanical properties of the cornea may help us understand the mechanism of keratoconus development and improve detection and intervention in keratoconus. We previously developed Brillouin microscopy based on light scattering from inherent acoustic waves in tissues4 and showed that this technique can provide quantitative estimates of local longitudinal modulus,5 which correlate to the Young and/or shear moduli of the cornea.2,6 Using a clinically viable instrument, for the first time, to our knowledge, we mapped the elastic modulus of normal and keratoconic corneas in vivo. We found distinctive biomechanical features that differentiate normal and keratoconic corneas and therefore have the potential to serve as diagnostic metrics for keratoconus.

Methods

The study recruited 6 volunteers with normal corneas (mean [SD] age, 37 [15] years) and 5 patients with advanced keratoconus (mean [SD] age, 43 [7] years). All participants signed an informed consent form and the study was approved by the Partners Human Research Committee (Partners Healthcare Institutional Review Board), in accordance with the principles of the Declaration of Helsinki. We constructed a laser-scanning confocal Brillouin microscope (wavelength, 780 nm; power, 1.5 mW; lateral/axial resolution, 5 µm/30 µm; sensitivity, approximately 10 MHz). The instrument was equipped with wide field-of-view imaging to allow real-time pupil detection and beam positioning (lateral accuracy of <0.5 mm). For participants with normal corneas, areas measuring about 5 × 5 mm in the central region of the cornea were scanned. For patients with keratoconus, similar regions, but including the center of the cone, were scanned as confirmed by their topographic images (Pentacam; OCULUS). To construct Brillouin maps, axial scans were taken at various transverse locations; the anterior mean Brillouin shift was computed from each axial scan by averaging the measured Brillouin shift values of the anterior portion of the corneal stroma. A color-coded elasticity map was obtained by 2-dimensional interpolation of the mean Brillouin shift in the anterior portion.

Results

Normal corneas were found to have relatively uniform anterior Brillouin shifts in the central region (Figure 1A). By contrast, keratoconic corneas presented strong spatial variations in Brillouin shifts (Figure 1B). Figure 2 shows the average anterior Brillouin shifts of normal (n = 7) and keratoconus (n = 6) corneas in the cone region (<1 mm from thinnest point) and outside the cone region (>3 mm away from thinnest point). A highly statistically significant decrease (unpaired t test, P < .001) was found in the keratoconic cone region with respect to normal corneas. Also, a highly statistically significant difference (paired t test, P < .001) was observed between the cone region and outside the cone region. The regions outside the cone showed no statistically significant difference compared with the normal corneas.

Discussion

We have described the distribution of elastic modulus in keratoconus and normal corneas in vivo. The elasticity maps show remarkable spatial variations around the cone. The reduction of 100 MHz in the keratoconic cone region (Figure 2) corresponds to an approximately 3% decrease in longitudinal modulus and approximately 70% reduction in shear modulus.5 The regions away from the cone in the keratoconic corneas have similar Brillouin shifts as normal corneas, which is consistent with our ex vivo data.5 This finding supports the long-standing hypothesis that keratoconus involves a spatially localized mechanical alteration in the cornea.1 It also emphasizes the need for spatially resolved measurements for accurate analysis of the biomechanical anomalies in keratoconus. Future research is warranted to understand the relationship between the focal or heterogeneous mechanical weakening and morphological changes (ie, thinning and steepening) and to develop biomechanics-based metrics for improved diagnosis and prognosis of keratoconus, screening of at-risk patients for post-LASIK (laser in situ keratomileusis) ectasia, and monitoring the effects of corneal collagen cross-linking.

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Article Information

Corresponding Author: Seok Hyun Yun, PhD, Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St, Cambridge, MA 02139 (syun@mgh.harvard.edu).

Published Online: January 22, 2015. doi:10.1001/jamaophthalmol.2014.5641.

Author Contributions: Drs Scarcelli and Besner had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Scarcelli and Besner contributed equally to this work.

Study concept an design: Scarcelli, Besner, Yun.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Scarcelli, Besner, Yun.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Scarcelli, Besner.

Obtained funding: Scarcelli, Pineda, Yun.

Administrative, technical, or material support: Scarcelli, Besner, Kalout, Yun.

Study supervision: Scarcelli, Yun.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported in part by grants UL1-RR025758 (Harvard Clinical and Translational Science Center; Drs Scarcelli, Pineda, and Yun) and P41-EB015903 (Dr Yun), R21EY023043 (Dr Scarcelli), and K25EB015885 (Dr Scarcelli), from the National Institutes of Health; the American Society for Laser Medicine and Surgery (Dr Scarcelli); and the Human Frontier Science Program (Dr Scarcelli).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Roberts  CJ, Dupps  WJ  Jr.  Biomechanics of corneal ectasia and biomechanical treatments. J Cataract Refract Surg. 2014;40(6):991-998.
PubMedArticle
2.
Müller  LJ, Pels  E, Vrensen  GF.  The specific architecture of the anterior stroma accounts for maintenance of corneal curvature. Br J Ophthalmol. 2001;85(4):437-443.
PubMedArticle
3.
Meek  KM, Tuft  SJ, Huang  Y,  et al.  Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46(6):1948-1956.
PubMedArticle
4.
Scarcelli  G, Yun  SH.  In vivo Brillouin optical microscopy of the human eye. Opt Express. 2012;20(8):9197-9202.
PubMedArticle
5.
Scarcelli  G, Besner  S, Pineda  R, Yun  SH.  Biomechanical characterization of keratoconus corneas ex vivo with Brillouin microscopy. Invest Ophthalmol Vis Sci. 2014;55(7):4490-4495.
PubMedArticle
6.
Randleman  JB, Dawson  DG, Grossniklaus  HE, McCarey  BE, Edelhauser  HF.  Depth-dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24(1):S85-S89.
PubMed
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