Controllability and predictability of riboflavin-ultraviolet A collagen cross-linking: advances in experimental techniques and theoretical research_Journal of Biomedical Engineering

Authors：

LIU Xiaona ,  LI Xiaona , CHEN Weiyi , 陈维毅 , 审校

Collage of Artificial Intelligence, Taiyuan University of Technology, Taiyuan 030024, P. R. China;

Corresponding author：

LI Xiaona, Email: lixiaona@tyut.edu.cn

Keywords：

Riboflavin-ultraviolet A collagen cross-linking; Depth-dependent cross-linking; Cross-linking effect; Controllability

DOI：

10.7507/1001-5515.202402017

Video：

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Riboflavin-ultraviolet A (UVA) collagen cross-linking has not only achieved good clinical efficacy in the treatment of corneal diseases such as dilatation keratopathy, bullae keratopathy, infectious keratopathy, and in the combined treatment of corneal refractive surgeries, but also its efficacy and safety in scleral collagen cross-linking have been initially confirmed. To better promote the application of cross-linking in the clinical treatment of corneal and scleral diseases, exploring controllability and predictability of the surgical efficacy are both important for evaluating the surgical efficacy and personalized precision treatment. In this paper, the progress on the cross-linking depth of riboflavin-UVA collagen cross-linking, and its relationship with the cross-linking effect will be reviewed. It will provide the reference for further application of this procedure in ophthalmology clinics.

1.	Manns R P C, Achiron A, Knyazer B, et al. Use of corneal cross-linking beyond keratoconus: a systemic literature review. Graefes Arch Clin Exp Ophthalmol, 2023, 261(9): 2435-2453.
2.	Angelo L, Gokul Boptom A, McGhee C, et al. Corneal crosslinking: present and future. Asia Pac J Ophthalmol (Phila), 2022, 11(5): 441-452.
3.	Zhang F, Lai L. Advanced research in scleral cross-linking to prevent from progressive myopia. Asia Pac J Ophthalmol (Phila), 2021, 10(2): 161-166.
4.	Li Y, Qi Y, Sun M, et al. Clinical feasibility and safety of scleral collagen cross-linking by riboflavin and ultraviolet A in pathological myopia blindness: a pilot study. Ophthalmol Ther, 2023, 12(2): 853-866.
5.	Wollensak G, Iomdina E, Dittert D D, et al. Cross-linking of scleral collagen in the rabbit using riboflavin and UVA. Acta Ophthalmol Scand, 2005, 83(4): 477-482.
6.	Almubrad T, Mencucci R, Smedowski A, et al. Ultrastructural study of collagen fibrils, proteoglycans and lamellae of the cornea treated with iontophoresis-UVA cross-linking and hypotonic riboflavin solution. Saudi J Biol Sci, 2021, 28(12): 7160-7174.
7.	Yang M, Xu W, Chen Z, et al. Engineering hibiscus-like riboflavin/ZIF-8 microsphere composites to enhance transepithelial corneal cross-linking. Adv Mater, 2022, 34(21): e2109865.
8.	Hu Y, Huang Y, Chen Y, et al. Study on patterned photodynamic cross-linking for keratoconus. Exp Eye Res, 2021, 204: 108450.
9.	Alkhalde A, Seferovic H, Abri A, et al. Assessment of efficacy of a novel crosslinking protocol with Intracameral oxygen (bubble-CXL) in increasing the corneal stiffness using atomic force microscopy. Nanomaterials (Basel), 2022, 12(18): 3185.
10.	严梦迪, 黄锦海, 王勤美, 等. 角膜胶原交联中核黄素浓度检测方法的研究进展. 中华眼视光学与视觉科学杂志, 2021, 23(8): 636-640.
11.	Gore D M, Margineanu A, French P, et al. Two-photon fluorescence microscopy of corneal riboflavin absorption. Invest Ophthalmol Vis Sci, 2014, 55(4): 2476-2481.
12.	Søndergaard A P, Hjortdal J, Breitenbach T, et al. Corneal distribution of riboflavin prior to collagen cross-linking. Curr Eye Res, 2010, 35(2): 116-121.
13.	Mastropasqua L, Nubile M, Calienno R, et al. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol, 2014, 157(3): 623-630.
14.	Lombardo M, Bernava G M, Serrao S, et al. Predicting corneal cross-linking treatment efficacy with real-time assessment of corneal riboflavin concentration. J Cataract Refract Surg, 2023, 49(6): 635-641.
15.	Roszkowska A M, Lombardo G, Mencucci R, et al. A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol. Int Ophthalmol, 2023, 43(7): 2315-2328.
16.	Fan L, Jung O, Herrmann M, et al. Deciphering UVA/riboflavin collagen crosslinking: a pathway to improve biomedical materials. Adv Funct Mater, 2024: 2401742.
17.	Schumacher S, Mrochen M, Wernli J, et al. Optimization model for UV-riboflavin corneal cross-linking. Invest Ophthalmol Vis Sci, 2012, 53(2): 762-769.
18.	Liu X, Yan L, Wei J, et al. Permeation characteristics and cross-linking efficacy of iontophoresis-assisted riboflavin delivery for accelerated riboflavin-ultraviolet A scleral collagen cross-linking in porcine eyes. Exp Eye Res, 2024, 248: 110095.
19.	Franke M A D, Landes T, Seiler T G, et al. Corneal riboflavin gradients and UV-absorption characteristics after topical application of riboflavin in concentrations ranging from 0. 1 to 0.5%. Exp Eye Res, 2021, 213: 108842.
20.	Abrishamchi R, Abdshahzadeh H, Hillen M, et al. High-fluence accelerated epithelium-off corneal cross-linking protocol provides Dresden protocol–like corneal strengthening. Transl Vis Sci Technol, 2021, 10(5): 10.
21.	Hammer A, Richoz O, Arba Mosquera S, et al. Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances. Invest Ophthalmol Vis Sci, 2014, 55(5): 2881-2884.
22.	Borchert G A, Watson S L, Kandel H. Oxygen in corneal collagen crosslinking to treat keratoconus: a systematic review and meta-analysis. Asia Pac J Ophthalmol (Phila), 2022, 11(5): 453-459.
23.	Seiler T G, Komninou M A, Nambiar M H, et al. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. Am J ophthalmol, 2021, 223: 368-376.
24.	McQuaid R M. Diffusion of oxygen and riboflavin during corneal cross-Linking (CXL). University College Dublin (Ireland), 2017.
25.	Lombardo G, Micali N L, Villari V, et al. All-optical method to assess stromal concentration of riboflavin in conventional and accelerated UV-A irradiation of the human cornea. Invest Ophthalmol Vis Sci, 2016, 57(2): 476-483.
26.	黄仰锐, 郭勇, 杨志刚, 等. 光诱导角膜交联及检测技术的研究进展. 生物化学与生物物理进展, 2021, 48(3): 246-262.
27.	Hepfer R G, Chen P, Shi C, et al. Depth-and direction-dependent changes in solute transport following cross-linking with riboflavin and UVA light in ex vivo porcine cornea. Exp Eye Res, 2021, 205: 108498.
28.	Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea, 2006, 25(9): 1057-1059.
29.	王宁, 董巧巧. 王姝婷, 等. 圆锥角膜不同交联方法术后基质分界线发生特点及其对交联效果的影响. 中华实验眼科杂志, 2023, 41(2): 152-159.
30.	Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. J Refract Surg, 2017, 33(2): 128-136.
31.	李晓娜, 陈维毅. 角巩膜生物力学2021年度研究进展. 医用生物力学, 2022, 37(6): 993-999.
32.	Hamid A, Jahadi-Hosseini H, Khalili M R, et al. Corneal biomechanical changes after corneal cross-linking in patients with keratoconus. J Curr Ophthalmol, 2022, 34(4): 409-413.
33.	Bronte-Ciriza D, Birkenfeld J S, de la Hoz A, et al. Estimation of scleral mechanical properties from air-puff optical coherence tomography. Biomed Opt Express, 2021, 12(10): 6341-6359.
34.	Kohlhaas M, Spoerl E, Schilde T, et al. Biomechanical evidence of the distribution of cross-links in corneastreated with riboflavin and ultraviolet A light. J Cataract Refract Surg, 2006, 32(2): 279-283.
35.	Li H, Liu T, Mu B, et al. Biomechanical effect of ultraviolet-A-riboflavin cross-linking on simulated human corneal stroma model and its correlation with changes in corneal stromal microstructure. Exp Eye Res, 2020, 197: 108109.
36.	曾正, 李林, 张海霞. 角膜胶原交联后基质弹性模量与深度的定量关系. 北京生物医学工程, 2023, 42(3): 221-226.
37.	Beshtawi I M, Akhtar R, Hillarby M C, et al. Scanning acoustic microscopy for mapping the microelastic properties of human corneal tissue. Curr Eye Res, 2013, 38(4): 437-444.
38.	Webb J N, Su J P, Scarcelli G. Mechanical outcome of accelerated corneal crosslinking evaluated by Brillouin microscopy. J Cataract Refract Surg, 2017, 43(11): 1458-1463.
39.	赵雁之, 黄国富. 光学相干弹性成像在眼科学领域的应用研究进展. 中华实验眼科杂志, 2023, 41(10): 1043-1048.
40.	Ge G R, Tavakol B, Usher D B, et al. Assessing corneal cross-linking with reverberant 3D optical coherence elastography. J Biomed Opt, 2022, 27(2): 026003.
41.	Ferguson T J, Singuri S, Jalaj S, et al. Depth-resolved corneal biomechanical changes measured via optical coherence elastography following corneal crosslinking. Transl Vis Sci Techn, 2021, 10(5): 7.
42.	Regnault G, Kirby M A, Wang R K, et al. Possible depth-resolved reconstruction of shear moduli in the cornea following collagen crosslinking (CXL) with optical coherence tomography and elastography. Biomed Opt Express, 2023, 14(9): 5005-5021.
43.	Vinas-Pena M, Feng X, Li G Y, et al. In situ measurement of the stiffness increase in the posterior sclera after UV-riboflavin crosslinking by optical coherence elastography. Biomed Opt Express, 2022, 13(10): 5434-5446.
44.	Li F, Wang K, Liu Z. In vivo biomechanical measurements of the cornea. Bioengineering (Basel), 2023, 10(1): 120.
45.	Touboul D, Gennisson J L, Nguyen T M, et al. Supersonic shear wave elastography for the in vivo evaluation of transepithelial corneal collagen cross-linking. Invest Ophthalmol Vis Sci, 2014, 55: 1976-1984.
46.	Xiao X, Xiao C, Yin Y. Effect of a gradient distribution of cross-links on the deformation behaviors of corneal stroma: theoretical model and finite element simulation. Front Mater, 2022, 9: 870134.

1. Manns R P C, Achiron A, Knyazer B, et al. Use of corneal cross-linking beyond keratoconus: a systemic literature review. Graefes Arch Clin Exp Ophthalmol, 2023, 261(9): 2435-2453.
2. Angelo L, Gokul Boptom A, McGhee C, et al. Corneal crosslinking: present and future. Asia Pac J Ophthalmol (Phila), 2022, 11(5): 441-452.
3. Zhang F, Lai L. Advanced research in scleral cross-linking to prevent from progressive myopia. Asia Pac J Ophthalmol (Phila), 2021, 10(2): 161-166.
4. Li Y, Qi Y, Sun M, et al. Clinical feasibility and safety of scleral collagen cross-linking by riboflavin and ultraviolet A in pathological myopia blindness: a pilot study. Ophthalmol Ther, 2023, 12(2): 853-866.
5. Wollensak G, Iomdina E, Dittert D D, et al. Cross-linking of scleral collagen in the rabbit using riboflavin and UVA. Acta Ophthalmol Scand, 2005, 83(4): 477-482.
6. Almubrad T, Mencucci R, Smedowski A, et al. Ultrastructural study of collagen fibrils, proteoglycans and lamellae of the cornea treated with iontophoresis-UVA cross-linking and hypotonic riboflavin solution. Saudi J Biol Sci, 2021, 28(12): 7160-7174.
7. Yang M, Xu W, Chen Z, et al. Engineering hibiscus-like riboflavin/ZIF-8 microsphere composites to enhance transepithelial corneal cross-linking. Adv Mater, 2022, 34(21): e2109865.
8. Hu Y, Huang Y, Chen Y, et al. Study on patterned photodynamic cross-linking for keratoconus. Exp Eye Res, 2021, 204: 108450.
9. Alkhalde A, Seferovic H, Abri A, et al. Assessment of efficacy of a novel crosslinking protocol with Intracameral oxygen (bubble-CXL) in increasing the corneal stiffness using atomic force microscopy. Nanomaterials (Basel), 2022, 12(18): 3185.
10. 严梦迪, 黄锦海, 王勤美, 等. 角膜胶原交联中核黄素浓度检测方法的研究进展. 中华眼视光学与视觉科学杂志, 2021, 23(8): 636-640.
11. Gore D M, Margineanu A, French P, et al. Two-photon fluorescence microscopy of corneal riboflavin absorption. Invest Ophthalmol Vis Sci, 2014, 55(4): 2476-2481.
12. Søndergaard A P, Hjortdal J, Breitenbach T, et al. Corneal distribution of riboflavin prior to collagen cross-linking. Curr Eye Res, 2010, 35(2): 116-121.
13. Mastropasqua L, Nubile M, Calienno R, et al. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol, 2014, 157(3): 623-630.
14. Lombardo M, Bernava G M, Serrao S, et al. Predicting corneal cross-linking treatment efficacy with real-time assessment of corneal riboflavin concentration. J Cataract Refract Surg, 2023, 49(6): 635-641.
15. Roszkowska A M, Lombardo G, Mencucci R, et al. A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol. Int Ophthalmol, 2023, 43(7): 2315-2328.
16. Fan L, Jung O, Herrmann M, et al. Deciphering UVA/riboflavin collagen crosslinking: a pathway to improve biomedical materials. Adv Funct Mater, 2024: 2401742.
17. Schumacher S, Mrochen M, Wernli J, et al. Optimization model for UV-riboflavin corneal cross-linking. Invest Ophthalmol Vis Sci, 2012, 53(2): 762-769.
18. Liu X, Yan L, Wei J, et al. Permeation characteristics and cross-linking efficacy of iontophoresis-assisted riboflavin delivery for accelerated riboflavin-ultraviolet A scleral collagen cross-linking in porcine eyes. Exp Eye Res, 2024, 248: 110095.
19. Franke M A D, Landes T, Seiler T G, et al. Corneal riboflavin gradients and UV-absorption characteristics after topical application of riboflavin in concentrations ranging from 0. 1 to 0.5%. Exp Eye Res, 2021, 213: 108842.
20. Abrishamchi R, Abdshahzadeh H, Hillen M, et al. High-fluence accelerated epithelium-off corneal cross-linking protocol provides Dresden protocol–like corneal strengthening. Transl Vis Sci Technol, 2021, 10(5): 10.
21. Hammer A, Richoz O, Arba Mosquera S, et al. Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances. Invest Ophthalmol Vis Sci, 2014, 55(5): 2881-2884.
22. Borchert G A, Watson S L, Kandel H. Oxygen in corneal collagen crosslinking to treat keratoconus: a systematic review and meta-analysis. Asia Pac J Ophthalmol (Phila), 2022, 11(5): 453-459.
23. Seiler T G, Komninou M A, Nambiar M H, et al. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. Am J ophthalmol, 2021, 223: 368-376.
24. McQuaid R M. Diffusion of oxygen and riboflavin during corneal cross-Linking (CXL). University College Dublin (Ireland), 2017.
25. Lombardo G, Micali N L, Villari V, et al. All-optical method to assess stromal concentration of riboflavin in conventional and accelerated UV-A irradiation of the human cornea. Invest Ophthalmol Vis Sci, 2016, 57(2): 476-483.
26. 黄仰锐, 郭勇, 杨志刚, 等. 光诱导角膜交联及检测技术的研究进展. 生物化学与生物物理进展, 2021, 48(3): 246-262.
27. Hepfer R G, Chen P, Shi C, et al. Depth-and direction-dependent changes in solute transport following cross-linking with riboflavin and UVA light in ex vivo porcine cornea. Exp Eye Res, 2021, 205: 108498.
28. Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea, 2006, 25(9): 1057-1059.
29. 王宁, 董巧巧. 王姝婷, 等. 圆锥角膜不同交联方法术后基质分界线发生特点及其对交联效果的影响. 中华实验眼科杂志, 2023, 41(2): 152-159.
30. Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. J Refract Surg, 2017, 33(2): 128-136.
31. 李晓娜, 陈维毅. 角巩膜生物力学2021年度研究进展. 医用生物力学, 2022, 37(6): 993-999.
32. Hamid A, Jahadi-Hosseini H, Khalili M R, et al. Corneal biomechanical changes after corneal cross-linking in patients with keratoconus. J Curr Ophthalmol, 2022, 34(4): 409-413.
33. Bronte-Ciriza D, Birkenfeld J S, de la Hoz A, et al. Estimation of scleral mechanical properties from air-puff optical coherence tomography. Biomed Opt Express, 2021, 12(10): 6341-6359.
34. Kohlhaas M, Spoerl E, Schilde T, et al. Biomechanical evidence of the distribution of cross-links in corneastreated with riboflavin and ultraviolet A light. J Cataract Refract Surg, 2006, 32(2): 279-283.
35. Li H, Liu T, Mu B, et al. Biomechanical effect of ultraviolet-A-riboflavin cross-linking on simulated human corneal stroma model and its correlation with changes in corneal stromal microstructure. Exp Eye Res, 2020, 197: 108109.
36. 曾正, 李林, 张海霞. 角膜胶原交联后基质弹性模量与深度的定量关系. 北京生物医学工程, 2023, 42(3): 221-226.
37. Beshtawi I M, Akhtar R, Hillarby M C, et al. Scanning acoustic microscopy for mapping the microelastic properties of human corneal tissue. Curr Eye Res, 2013, 38(4): 437-444.
38. Webb J N, Su J P, Scarcelli G. Mechanical outcome of accelerated corneal crosslinking evaluated by Brillouin microscopy. J Cataract Refract Surg, 2017, 43(11): 1458-1463.
39. 赵雁之, 黄国富. 光学相干弹性成像在眼科学领域的应用研究进展. 中华实验眼科杂志, 2023, 41(10): 1043-1048.
40. Ge G R, Tavakol B, Usher D B, et al. Assessing corneal cross-linking with reverberant 3D optical coherence elastography. J Biomed Opt, 2022, 27(2): 026003.
41. Ferguson T J, Singuri S, Jalaj S, et al. Depth-resolved corneal biomechanical changes measured via optical coherence elastography following corneal crosslinking. Transl Vis Sci Techn, 2021, 10(5): 7.
42. Regnault G, Kirby M A, Wang R K, et al. Possible depth-resolved reconstruction of shear moduli in the cornea following collagen crosslinking (CXL) with optical coherence tomography and elastography. Biomed Opt Express, 2023, 14(9): 5005-5021.
43. Vinas-Pena M, Feng X, Li G Y, et al. In situ measurement of the stiffness increase in the posterior sclera after UV-riboflavin crosslinking by optical coherence elastography. Biomed Opt Express, 2022, 13(10): 5434-5446.
44. Li F, Wang K, Liu Z. In vivo biomechanical measurements of the cornea. Bioengineering (Basel), 2023, 10(1): 120.
45. Touboul D, Gennisson J L, Nguyen T M, et al. Supersonic shear wave elastography for the in vivo evaluation of transepithelial corneal collagen cross-linking. Invest Ophthalmol Vis Sci, 2014, 55: 1976-1984.
46. Xiao X, Xiao C, Yin Y. Effect of a gradient distribution of cross-links on the deformation behaviors of corneal stroma: theoretical model and finite element simulation. Front Mater, 2022, 9: 870134.

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Latest ArticlesControllability and predictability of riboflavin-ultraviolet A collagen cross-linking: advances in experimental techniques and theoretical research

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