Physical Background of Tissue Crosslinking

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Emilia Bernasconi
7 anni fa
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1 Physical Background of Tissue Crosslinking Ines Pilorz, Markus Kohlhaas Klinik für Augenheilkunde des St.-Johannes-Hospitals Dortmund

2 Keratoconic cornea 1) same collagen content as in normal cornea 2) reduced corneal stability (Andreasson 1980, Meek 2005) 3) 2 x higher degradation rate of the keratoconic cornea by pepsin compared to normal cornea (Andreasson 1980) reduced amount of crosslinks

higher degradation rate of the keratoconic cornea by pepsin

3 Possibilities of Crosslinking Lysyl oxidase (LOX) crosslinks collagen enzymatically (physiological) Transglutaminase (glaucoma) Sugar aldehydes (diabetes) (Advanced Glycation Endproducts AGEs) Chemical crosslinking (glutaraldehyde, formaldehyde, DPPA) Photochemical crosslinking (UV, ionizating radiation)

(diabetes) (Advanced Glycation Endproducts AGEs) Chemical crosslinking

4 Photooxidative Crosslinking with Riboflavin and UVA easy and safe handling short treatment time locally limited unchanged transparency of the cornea Riboflavin is available as drug and food colouring non-toxic, watersoluble good stroma penetration

transparency of the cornea Riboflavin is available as drug

5 Double function of Riboflavin 1. Absorption of UV-irradiation 2. Photosensitizer for production of reactive oxygen species (Singulet oxygen)

6 Absorption spectrum of riboflavin absorption wavelength in nm

7 Decrease of UV-intensity 3.00 mw/cm² 1.49 mw/cm² 0.74 mw/cm² 0.36 mw/cm² 0.18 mw/cm² 0.09 mw/cm²

8 Localisation of crosslinks Sung, H: J Biomed Mater Res 64A: ,2003)

9 Removal of epithelium Riboflavin does not penetrate through epithelium Epithelium acts as UV-protector and absorbs some UV-energy

10 Safety features of the method cornea lens retina UV without riboflavin 3 mw/cm² 1,95 mw/cm² 177 µw/cm² 1 mw/cm² 0,65 mw/cm² 60 µw/cm² environment 3 mw/cm² UV plus riboflavin 0,18 mw/cm² 10 µw/cm² measured values

mw/cm² 0,65 mw/cm² 60 µw/cm² environment 3 mw/cm² UV

11 Changed treatment parameters 250 stress in 10³Pa min 3 mw/cm² 20 min 4.5 mw/cm² control strain in %

12 Physico-chemical parameters Increase - stiffness - bending stiffness - thickness of collagen fibers - shrinking temperature - resistance against enzymatic degradation - turn-over time

13 Stress-Strain behaviour Stress in 10 5 Pa 2 1 untreated crosslinked Strain in % porcine corneas (Spoerl/Seiler:Exp Eye Res, 1998)

14 Riboflavin/UVA application 370 nm; 3 mw/cm²; 30 min

15 Stress - Strain treated untreated Kohlhaas, Spoerl,Wittig; J Cataract Refr Surg, 2005

16 Increase of the resistance against enzymes 10 collagenase digestion in dependance on tim e corneal diameter in mm control group 1 mw/cm² 2 mw/cm² 3 mw/cm² Time in days (Spoerl,Wollensak,Seiler: Current Eye Res. 2004)

2 control group 1 mw/cm² 2 mw/cm² 3 mw/cm² 0 0 2 4 6 8 10 12

17 Increase of diameter in nm of the collagen fibers after crosslinking 12,2 % 4,6 % (Wollensak,Spoerl,Seiler: Cornea 2004)

18 Increase of the shrinking temperature original length 4 10 mm 3 shrinkage in mm 2 1 non-crosslinked riboflavin +UVA GTA temperature in C C for untreated cornea 75 C for crosslinked cornea (Spoerl,Wollensak,Seiler,Ophthalmologica,2004)

temperature in C 0 50 60 70 80 90 70 C for untreated cornea 75

19 Crosslinking in tissue engineering Collagen is a natural biomaterial with excellent biocompatibility but unprocessed collagen has low biochemical stability and weak mechanical strength.

20 Summary Crosslinking method was developed for the cornea Generation of crosslinks is evidenced by changes of physico-chemical properties Effective crosslinking is achieved in the anterior 250 µm without damaging the endothelium

physico-chemical properties Effective crosslinking is

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