Collagen cross-linkage: a comprehensive review and directions for future research

Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QH, UK.
The British journal of ophthalmology (Impact Factor: 2.81). 09/2009; 94(8):965-70. DOI: 10.1136/bjo.2009.164228
Source: PubMed

ABSTRACT Individuals with keratoconus form a significant proportion of patients for a practitioner specialising in corneal diseases. Yet it is a disease where the pathogenesis is poorly understood, and until recently, there has been no treatment apart from transplantation that could be offered that was curative or even capable of slowing the progression of the disease. Collagen cross-linking treatment using riboflavin and UV light has been developed to address this need, and the initial results are promising. The purpose of this review is to critically evaluate this treatment in light of the scientific basis for cross-linking, to highlight the strengths and limitations of the evidence in terms of efficacy and long-term safety, and finally to identify areas for future research in this area with a significant potential to change the way we treat our keratoconus patients. In addition, we hope that our unbiased review for the first time would bring together, in a concise fashion, scientific information for a practitioner contemplating on offering this treatment and to help inform their patients of its potential risks and benefits.

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    ABSTRACT: Objectives: The poor durability of resin-dentin bonds created by contemporary adhesives is thought to be due, in part, to the enzymatic degradation of collagen by matrix metalloproteinases (MMP)s or cathepsine-K (CAT-K) in the hybrid layer. Biomodification of dentin by collagen crosslinkers should inactivate all dentin proteases simultaneously. The aim of this work was to evaluate the effect of various collagen crosslinking agents on dentin protease activity. Methods: Demineralized dentin beams (1x2x6 mm) (n=10/group) were prepared from mid-coronal dentin. The initial and final dry mass was measured for all beams. Control beams were incubated in simulated body fluid (SBF, 1 mL); experimental beams were first dipped in specified crosslinkers (Table 1) for 5 min, rinsed and then incubated for 3 or 21 days. Aliquots of the incubation medium were used to analyze solubilized telopeptide fragments using ICTP-as an indicator of MMP-mediated degradation and CTX for CAT-K-mediated degradation. Additionally, to analyze initial and residual gelatinase activity in demineralized dentin, we measured gelatin zymography and in situ zymography assays. The loss of dry mass, ICTP and CTX release rates from all groups were analyzed separately by repeated-measures ANOVA, α=0.05. Results: The dry mass loss (%), ICTP (ng telopeptide/mg dry dentin) and CTX (pg telopeptide/mg dry dentin) after 3 or 21 days were: Groups Dry Mass Loss (%) ICTP (ng/mg dentin) CTX (pg/mg dentin) 3 days 21 days 3 days 21 days 3 days 21 days GA1: 1% Glutaraldehyde (v/v) -5.2±1.3b -16.4±1.3 Ω 9.3±0.2b 10.3±1.5 Ω 125.3±32.8b 173.7±36.5¥ GA2: 5% Glutaraldehyde (v/v) -1.7±1.4b -12.7±1.3Ω 0.6±0.2f 0.8±0.1∑ 14.0±2.9c 19.2±4.7∑ GS1:1%: Grape seed extract (w/v) -3.4±1.1b -17.0±0.8Ω 3.5±1.7e 14.6±0.6¥ 23.0±8.3c 234.7±52.9¥ GS2: 5% Grape seed extract (w/v) -1.2±1.0c -13.0±1.8Ω 1.8±0.6ef 8.6±0.2Ω 14.7±5.3c 70.0±14.1∑ S: 10% Sumac berries extract (w/v) -2.1±1.7c -15.6±1.2Ω 7.7±1.1c 16.3±1.7¥ 46.0±11.2c 341.1±56.6Ω CR1: 20µM Curcumin (w/v) -8.9±0.3a -12.9±1.8Ω 5.4±0.4d 9.4±0.0 Ω 12.4±1.8c 12.4±2.2∑ CR2: 200µM Curcumin (w/v) -0.9±0.6c -6.9±2.0¥ 2.9±1.1ef 0.7±0.1∑ 48.3±18.7c 50.7±9.5∑ CM: Control -8.4±0.8a -32.1±5.9† 17.7±0.7a 29.0±3.5† 207.5±66.5a 589.1±130.2† Table 1: Values are shown by mean±SD. Groups with the same letter are not statistically significant (p > 0.05). Conclusion: The results clearly show that dentin biomodification by collagen crosslinkers significantly reduced the protease activity in demineralized dentin matrices. Both gelatin and in situ zymographic analyses revealed that all crosslinkers inhibited dentinal gelatinases. Dentin biomodification by use of collagen crosslinkers seems to be a promising approach to increase the durability of resin dentin bonds.
    IADR General Session and Exhibition 2014; 06/2014
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    ABSTRACT: This study evaluated the effect of dentin pretreatment with collagen crosslinkers on matrix metalloproteinase (MMP) and cathepsin K mediated collagen degradation. Dentin beams (1mm×2mm×6mm) were demineralized in 10% H3PO4 for 24h. After baseline measurements of dry mass, beams were divided into 11 groups (n=10/group) and, were pretreated for 5min with 1% glutaraldehyde (GA); 5% GA; 1% grape-seed extract (GS); 5% GS; 10% sumac (S); 20μM curcumin (CR); 200μM CR; 0.l% riboflavin/UV (R); 0.5% R; 0.1% riboflavin-5-phosphate/UV (RP); and control (no pretreatment). After pretreatment, the beams were blot-dried and incubated in 1mL calcium and zinc-containing medium (CM, pH 7.2) at 37°C for 3, 7 or 14 days. After incubation, dry mass was reassessed and aliquots of the incubation media were analyzed for collagen C-telopeptides, ICTP and CTX using specific ELISA kits. Data were analyzed by repeated-measures ANOVA. The rate of dry mass loss was significantly different among test groups (p<0.05). The lowest 14 day mean dry mass loss was 6.98%±1.99 in the 200μM curcumin group compared to control loss of dry mass at 32.59%±5.62, p<0.05, at 14 days. The ICTP release over the incubation period (ng/mg dry dentin) ranged between 1.8±0.51 and 31.8±1.8. CTX release from demineralized beams pretreated with crosslinkers was significantly lower than CM (5.7±0.2ng/mg dry dentin). The results of this study indicate that collagen crosslinkers tested in this study are good inhibitors of cathepsin K activity in dentin. However, their inhibitory effect on MMP activity was highly variable. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.
    Dental materials: official publication of the Academy of Dental Materials 05/2015; DOI:10.1016/ · 4.16 Impact Factor
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    ABSTRACT: Keratoconus (KC) is the most common cornea ectatic disorder. It is characterized by a cone-shaped thin cornea leading to myopia, irregular astigmatism, and vision impairment. It affects all ethnic groups and both genders. Both environmental and genetic factors may contribute to its pathogenesis. This review is to summarize the current research development in KC epidemiology and genetic etiology. Environmental factors include but are not limited to eye rubbing, atopy, sun exposure, and geography. Genetic discoveries have been reviewed with evidence from family-based linkage analysis and fine mapping in linkage region, genome-wide association studies, and candidate genes analyses. A number of genes have been discovered at a relatively rapid pace. The detailed molecular mechanism underlying KC pathogenesis will significantly advance our understanding of KC and promote the development of potential therapies.
    05/2015; 2015. DOI:10.1155/2015/795738