A bibliometric and citation network analysis of crosslinking

Abstract

Purpose: Research on crosslinking has focused mainly on trying to slow the progression of keratoconus. The objective of this bibliometric analysis is to determine the relationships between the different publications and authors. As well as to identify the different areas of research on crosslinking. Methods: Web of Science (WOS) was the database for the search of publications for the period 1972 to December 2023, using the terms: crosslinking, cross-linking, ocular, vision, visual, cornea, ectasia AND Keratoconus. The analysis of the publication was performed using the CitNetExplorer, VOSviewer and CiteSpace software. Results: 7161 publications and 59415 citation networks were found. The year with the most publications is 2021, a total of 571 (7.97%) publications and 135 citation networks. The most cited publication was “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus” published by Wollensak et al. in 2003, with a citation index of 1780. Using the Clustering function, five groups were found that cover the main research areas in this field: keratoconus, corneal transplantation, cataracts, corneal inflammation and axial growth. Conclusion: The treatment of keratoconus continues to be the topic of interest in this area of research. However, in recent years there has been an increase in research on how crosslinking helps to slow down axial growth.

Keywords

Bibliometric citation network crosslinking cornea

Introduction

Corneal cross-linking (CXL) is a physiological procedure, which causes the biomechanical alteration of tissues damaged by a range of corneal pathologies, including ectatic cornea, refractive surgical procedures, corneal transplantation, infectious keratitis or corneal oedema.^1–3

Numerous clinical studies have demonstrated the effectiveness of this procedure in slowing down the progression of keratoconus in adult patients.^4–7 Gore et al.⁸ demonstrated that it is a safe, effective, and refractively neutral intervention (when performed at 2 years), which can be used to halt the progression of this disorder. On the other hand, there are few reviewed scientific publications that address the effectiveness of crosslinking in paediatric patients. Most of the said studies covered small sample sizes with relatively short follow-up periods. Nevertheless, the results indicate that this treatment is also effective for children and that it is more effective than posterior penetrating keratoplasty.^9,10

In recent years, cross-linking has been used in combination with other procedures, for example, photorefractive keratectomy (PRK). Patients in a pilot study reported improvements in the evaluated parameters, which included spherical equivalent, defocus equivalent, uncorrected and corrected distance visual acuity, higher-order aberrations and maximum keratometry, as well as stabilization of keratoconus during a follow up of 12–24 months.^11–13 Another tested combination was CXL used in conjunction with intrastromal corneal ring segments (ICRS), which resulted in improved visual parameters, but without halting keratoconus progression.¹⁴ Discrepancies have been found in the results attained using this combination, given that several studies have showed that this combination improves visual acuity, refraction and keratometry over a period of 7–12 months,^15,16 however, other studies did not find any topographical or visual differences following ICRS implantation, either on its own or in conjunction with CXL.^17,18

In recent times, there has been an increasing amount of research that looks to assess the efficacy of cross-linking in the management of infectious keratitis. Recent studies have shown that the use of Photoactivated Chromophore for Infectious Keratitis (PACK-CXL) is effective and reduces the complete healing time for such corneal infections.^19–21 It has been suggested that this offers an increased resistance to pepsin and collagenase enzymes, which are produced by specific bacterial and fungal pathogens.^22,23 UV radiation damages both the DNA and RNA of pathogens, inhibiting their replication, and photoactivated riboflavin releases free radicals that damage cell membranes and nucleic acids.²⁴

As a result, and given the steady increase in the number of publications on the efficacy of cross-linking in ophthalmic diseases, this study aimed to identify the different research areas, determine the most cited publications, and analyse the relationships that exist between publications and the different research groups by using the Citation Network Explorer (CitNetExplorer) software, which allows us to analyse the evolution of the scientific literature on a field of research.

Material and method

Database

The search of publications was carried out in the Web of Science (WOS) database, using the following search terms: crosslinking, cross-linking, ocular, vision, visual, cornea, ectasia AND Keratoconus; allowing for a complete field search. Likewise, the Boolean AND and OR operators were used to avoid repetition of articles. As a result, the search term that was employed was: (crosslinking OR cross-linking) AND (eye OR ocular OR vision OR visual OR cornea OR ectasia OR keratoconus). In our study, the following citation indexes were used: Social Sciences Citation Index, Science Citation Index Expanded and Emerging Sources Citation Index. The exclusion criteria was early access articles.

The first articles were published in 1972, so the selected time interval was from 1972 to December 2023. The publications were searched and downloaded on 10^th November 2021.

Data analysis

The Citation Network Explorer software was used to analyse the publications and visualise the citation networks. Therefore, it was possible to use a citation network comprised of several million publications as the starting point, before conducting a more in-depth analysis that eventually yielded a smaller subnetwork containing 100 publications on the same topic.

A quantitative analysis of the most-mentioned publications was conducted using the Citation score attribute. As such, not only the internal connections within the WOS database were quantified, but also any external connections, with other databases taken into account.²⁵

Subsequently, the most connected publications were assigned to the same group using the Clustering function. The clustering functionality is achieved using the formula developed by Van Eck in 2012.²⁵

V (c_{1}, \dots, c_{n}) = \sum_{i < j} δ (c_{i}, c_{j}) (s_{i j} - γ)

The publications that are considered as the core of a citation network were analysed using the Identifying Core Publications functionality. This study considered publications that presented four or more citations in the citation network. The higher the value of this parameter, the lower the number of core publications.²⁶ Additionally, the drilling down functionality was used given that it enables researchers to conduct more in-depth analysis of each of the groups at different levels.

On the other hand, the CiteSpace software (5.6.R2) was used to perform scientometric analysis by establishing certain parameter indicators; the H index was used to evaluate the quantity and level of academic output of researchers or academic institutions.²⁶ The Degree indicated the number of connections existing among the authors (organisations, countries) in the co-occurrence knowledge graph; consequently, a higher value in this degree indicated that a greater level of communication and collaboration existed. “Intermediary centrality” measures the importance of nodes in the research cooperation network. Intermediary centrality is a measure of the number of times a node acts as a waypoint along the shortest path between two other nodes, geodetic distance. Finally, “half-life” is a parameter that represents the continuity of institutional research in time. It is defined as the number of years a post receives half of its citations since it was posted. A low citation half-life suggests citation activity that peaks and declines rapidly. A high cited half-life suggests citation activity that peaks and declines more slowly.²⁷

Results

Following the WoS search, 7161 publications and 59415 citation networks were found among all the fields.

The number of publications on crosslinking has increased significantly since 2008 (1972–2007: 39.3%; 2008–2023:60.7%). 2021 was the year with the highest number of publications, accounting for 571 publications and 135 citation networks.

Description of the publications

Of all the publications, 76.2% (n = 5545) were articles, 9.3% (n = 668) were reviews, 8.0% (n = 576) were meeting abstracts, 3.4% (n = 241) were proceedings papers, 1.2% (n = 130) were book chapters, 1.9% (n = 204) were letters.

Languages and countries

With regards to the language of the publications, 97.8% were in English, 1.5% were in German and 0.4% were in French. The countries with the highest number of publications and collaborations with other countries were: the United States (publications: 2238; degree: 59; connections: 1300), China (publications: 1039; degree: 43; connections: 496) and Germany (publications: 575; degree: 40; connections: 409).

Research areas

This is a multidisciplinary research area, and the fields of ophthalmology (55.1%) and surgery (9.9%) are particularly worth mentioning (Table 1).

Table 1.

Top 5 research areas with the highest number of publications.

Category	Frequency	Degree	Half-life
Ophthalmology	3954	23	46.5
Surgery	627	16	30.5
Biochemistry & Molecular Biology	541	45	34.5
Polymer Science	378	39	20.5
Material Science Biomaterials	350	17	21.5

Authors and institutions

As shown in Table 2, the authors with the highest number of publications were Hafezi F (2.0%), Kymionis GD (1.0%) and Spoerl E (0.9%). The institutions with the highest number of publications (Table 3) were University of California System (3.7%), National University of Singapore (3.2%) and University System of Ohio Case Western Reserve University (2.8%).

Table 2.

Top 10 authors with the highest number of publications.

Author	Number of publications	HIndex	Total Citations	Citation Average	Centrality	Degree	Connections
HAFEZI F	145	23	2267	12.52	0.16	28	389
KYMIONIS GD	75	30	2516	28.27	0.02	12	226
SPOERL E	68	27	4082	32.4	0.00	4	120
MAZZOTTA C	67	27	3667	43.14	0.06	23	186
RANDLEMAN JB	62	39	5989	27.47	0.00	4	109
SHETTY R	58	35	5547	11.98	0.03	9	151
SEILER T	57	50	13834	55.12	0.01	3	87
KLING S	53	23	1682	23.69	0.00	7	140
VINCIGUERRA P	49	31	4515	20.34	0.03	22	196
SINGH M	42	25	1182	11.27	0.00	7	259

Table 3.

Top 10 institutions with the highest number of publications.

Category	Frequency	Degree	Connections
UNIVERSITY OF CALIFORNIA SYSTEM	266	61	277
NATIONAL UNIVERSITY OF SINGAPORE	244	17	202
UNIVERSITY SYSTEM OF OHIO	203	36	92
CASE WESTERN RESERVE UNIVERSITY	201	14	56
HARVARD MEDICAL SCHOOL	194	23	159
HARVARD UNIVERSITY	182	21	90
UNIVERSITY OF LONDON	146	55	305
WENZHOU MEDICAL UNIVERSITY	146	8	112
UNIVERSITY COLLEGE LONDON	143	25	67
EGYPTIAN KNOWLEDGE BANK (EKB)	131	17	46

Journals

Table 4 shows the main journals and the number of publications in each journal according to the WoS database.

Table 4.

Top 10 journals with the most publications.

Journal	Total publications	Impact Factor(2022)	Quartile Score	SJR (2023)	Citations/Docs(2 years)	Total Citations (2023)	H Index	Country
Investigative ophthalmology & visual science	726	4.4	Q1	1.422	3.912	5356	252	United States
Cornea	370	2.8	Q1	1.019	2.072	2250	138	United States
Journal of refractive surgery	288	2.4	Q2	1.477	2.726	1097	108	United States
Journal of cataract and refractive surgery	287	2.8	Q2	1.472	1.831	2365	161	United States
Experimental eye research	180	3.4	Q2	1.02	3.287	3983	146	United States
Current eye research	107	2.1	Q3	0.741	1.986	1504	89	United Kingdom
Indian journal of ophthalmology	98	3.1	Q2	0.635	1.292	4456	73	India
American journal of ophthalmology	94	4.2	Q1	4.135	2.146	5174	214	United States
International ophthalmology	92	1.6	Q4	0.709	1.895	2420	55	Netherlands
Acta ophthalmologica	91	3.4	Q2	1.404	3.296	3290	106	United Kingdom

Keywords

Additionally, the most commonly used keywords were “Riboflavin” “Cross-linking” and “collagen cross-linkin”. Table 5 shows the most used keywords in the most relevant publications.

Table 5.

Top 20 most used keywords.

Keyword	Frequency	Degree	Total link strength
Riboflavin	1114	19	9120
Cross-linking	918	10	7765
Collagen cross-linking	778	17	6279
Keratoconus	766	9	11806
Progressive keratoconus	531	18	4275
Ultraviolet-a	378	6	2899
Collagen	356	7	3710
Ultraviolet	305	11	2430
In-vitro	286	12	2011
Light	271	15	2021
Efficacy	247	9	1958
Biomechanical properties	236	14	2130
In-situ keratomileusis	232	18	1888
In-vivo	232	11	1633
Ectasia	225	12	2403
Eyes	218	4	1539
Outcomes	216	12	1691
Management	206	12	1482
Penetrating keratoplasty	197	13	1619
Ultraviolet-a light	189	8	1471

Most cited publications

The most cited publication was the article by Wollensak et al.² (Table 6). This study examined the clinical usefulness of collagen cross-linking induced by riboflavin/UVA in order to detect keratoconus progression. The results showed that 16 eyes presented a regression of 1.14 diopters. Corneal and crystalline transparency, endothelial cells density and intraocular pression remained unaltered. Visual acuity slightly improved in 15 eyes (65%).

Table 6.

Top 20 most cited publications.

Author	Title	Journal	Year	Citation Index	Links
Wollensak et al.²	Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus	Am J Ophthalmol. 2003 May;135(5):620–7.	2003	1780	765
Raiskup Worlf et al.³⁶	Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results	J Cataract Refract Surg. 2008 May;34(5):796–801.	2008	751	346
Wollensak et al.²	Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking	J Cataract Refract Surg. 2003 Sep;29(9):1780–5.	2003	634	347
Spoerl et al.	Induction of Cross-links in Corneal Tissue	Exp Eye Res. 1998 Jan;66(1):97–103	1998	587	312
Spoerl et al.	Safety of UVA-riboflavin cross-linking of the cornea	Cornea. 2007 May;26(4):385–9.	2007	542	303
Caporossi et al.	Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study	Am J Ophthalmol. 2010 Apr;149(4):585–93.	2010	464	275
Spoerl et al.	Increased resistance of crosslinked cornea against enzymatic digestion	Curr Eye Res. 2004 Jul;29(1):35–40.	2004	425	248
Wollensak et al.²	Crosslinking treatment of progressive keratoconus: new hope	Curr Opin Ophthalmol. 2006 Aug;17(4):356–60.	2006	417	212
Koller et al.	Complication and failure rates after corneal crosslinking	J Cataract Refract Surg. 2009 Aug;35(8):1358–62.	2009	367	201
Hersh et al.	Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results	J Cataract Refract Surg. 2011 Jan;37(1):149–60	2011	306	172
Wittig-Silva et al.³³	A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results	J Refract Surg. 2008 Sep;24(7):S720–5.	2008	300	164
Caporossi et al.	Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study	J Cataract Refract Surg. 2006 May;32(5):837–45.	2006	284	174
Vinciguerra et al.	Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking	Ophthalmology. 2009 Mar;116(3):369–78.	2009	279	183
Gomes et al.	Global Consensus on Keratoconus and Ectatic Diseases	Cornea. 2015 Apr;34(4):359–69	2015	279	82
Hafezi et al.	Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis	J Cataract Refract Surg. 2007 Dec;33(12):2035–40.	2007	277	168
Seiler et al.	Corneal Cross-Linking-Induced Stromal Demarcation Line	Cornea. 2006 Oct;25(9):1057–9	2006	276	188
Raiskup et al.³⁶	Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results	J Cataract Refract Surg. 2015 Jan;41(1):41–6.	2015	274	132
Wollensak et al.²	Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment	Cornea. 2004 Jan;23(1):43–9.	2004	273	164
Wittig-Silva et al.³³	A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results	Ophthalmology. 2014 Apr;121(4):812–21.	2014	273	172
Mazzotta et al.	Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans	Cornea. 2007 May;26(4):390–7.	2007	256	153

Clustering

The clustering function identified 8 groups, 5 of which presented a significant number of publications. However, the remaining 3 groups only represented 1.5% of the publications. The colour of the article represents the group they belong to and the lines between elements represent bonds. In other words, each group has a different colour, and the lines are the unions with other groups. Also, the larger the circle means the greater the number of citations.

- In Group 1, 3149 publications and 46826 citations were found across the whole network. The most cited publication was the article by Wollensak et al.,² which was published in 2003 in the American Journal of Ophthalmology, which is the top cited publication amongst the 20 most cited publications. Therefore, the articles in this group analyses the collagen cross-linking induced by riboflavin/UVA in order to detect keratoconus progression (Figure 1).

- In Group 2, 629 publications and 1935 citations were found across the whole network. The most cited publication was the article by Meek et al.,²⁸ which was published in 2015 in Progress in retinal and eye research. This study provided a three-dimensional description of the stroma at a microscopic level and the control mechanisms at a nanoscopic level that allow optic transparency.

Figure 1.

Citation network in Group 1.

The articles in this group looked to review and analyse the development of artificial corneas (protheses and equivalent tissues) in transplants (Figure 2)

- In Group 3, 399 publications and 3130 citations were found across the whole network. The most cited publication was the article by Nagaraj et al.,²⁹ which was published in 1991 in the Proceedings of the National Academy of Sciences of the United States of America. This publication analysed the pentosidine formation in an aged crystalline. Thus, it was found a high relationship between the pentosidine crosslinking and the pigmentation degree in the crystalline with cataracts. Likewise, it was also found that pentosidine is mainly associated with alpha-crystal fractions from 300 to 5000 kDa. This data suggested that the redox imbalance in the senescent cellular systems could contribute to an irreversible oxidation of the ascorbate and the protein crosslinking due to xylitol.

Figure 2.

Citation network in Group 2.

The article in this group analysed the importance of crosslinking in order to reduce the evolution of cataracts (Figure 3).

- In Group 4, 382 publications and 1371 citations were found across the whole network. The most cited publication was the article by Iseli et al.,³⁰ which was published in 2008 in Cornea. This publication assessed the efficiency of crosslinking with ultraviolet light in order to treat infectious keratitis. It was found that it is a promising alternative in patients who are treatment-resistant; therefore, avoiding emergency keratoplasty.

Figure 3.

Citation network in Group 3.

The articles in this group analysed the efficiency of crosslinking in corneal inflammations (Figure 4).

- In Group 5, 303 publications and 1363 citations were found across the whole network. The most cited publication was the article by Wollensak et al.,³¹ which was published in 2004 in the Journal of cataract and refractive surgery. In this group collagen crosslinking methods in the sclera were developed in order to increase the biomechanical force and treat the myopia progression. Thus, it was found out that collagen crosslinking induced by riboflavin-UVA, glyceraldehyde and glutaraldehyde led to a significant increase in the biomechanical force in the human and porcine sclera. Therefore, it was concluded that it could be a treatment option, although better application methods should be determined.

Figure 4.

Citation network in Group 4.

The articles in this group analysed the crosslinking efficiency in the sclera in order to reduce axial growth (Figure 5).

Figure 5.

Citation network in Group 5.

Core function

4105 publications with 4 or more citations were found across the whole network, which was comprised of 57315 publications, representing 57.3%. This showed that it exists a clear approach in the research area, being collagen crosslinking efficiency to reduce keratoconus progression the most common topic.

Discussion

The main aim of this study was to analyse the existing literature on the importance of the crosslinking technique. The data used to create the citation network was obtained from the WOS database, given that it is one of the most extensive databases, with a search range that dates back to 1900. However, it is worth noting that the WOS only accepts international journals that have passed a rigorous selection process.

The CitNetExplorer and CiteSpace softwares enabled us to determine the connections that exist between the fields of study and the different research groups. Subsequently, the clustering functionality was used to group publications according to the relationships existing between the citations. The drilling down functionality was used to conduct a more in-depth analysis of the existing bibliography for each of the groups, and by using the core publications functionality it was possible to identify the main publications in each group. Likewise, by conducting scientometric analysis we obtained an important qualitative analysis about the existing bibliography in order to improve the understanding of this area of rapid growth.

The first publication in this field of research was the article published by Buckingham³² in which it was determined that the yellow pigmentation of cataracts was caused by protein cross-linking. The number of publications on this subject matter increased from 2008 onwards, as clinicians began to consider cross-linking as a valid treatment method for keratoconus.^33–35 In this year, the study by Raiskup-Wolf,³⁶ which showed that collagen cross-linking is an effective therapeutical option for progressive keratoconus, was particularly worth mentioning. Considering the high number of publications which emerged in 2021, it was considered as a “key year”. The article by Larkin et al.³⁷ is significant, demonstrating that corneal cross-linking is effective in stabilizing progressive keratoconus in young patients. The results from this randomized controlled trial showed that CXL significantly reduces the progression of keratoconus, improves maximum keratometry values, and enhances both corrected and uncorrected visual acuity 18 months post-treatment, with an excellent safety profile. Seiler et al.³⁸ conducted an experimental study on oxygen kinetics during CXL with and without supplementary oxygen, utilizing a femtosecond-laser-generated tunnel to measure local oxygen concentrations in de-epithelialized porcine eyes. They observed that supplementary oxygen significantly increases oxygen availability during CXL, particularly at higher irradiances, potentially enhancing the cross-linking process. Therefore, after years of research in this field, the efficacy and safety of corneal cross-linking for the treatment of keratoconus remain pivotal topics of investigation.

With regards to the journals and countries with the highest number of publications, our results concurred with the findings of another bibliometric study on keratoconus.³⁹ However, in the study by Zhao et al.³⁹ the journal with the highest number of publications was Cornea, which ranked in second place on our list. This difference may be due to the fact that keratoconus analysis encompasses other research topics, whereas the analysis of cross-linking focuses mainly on treatment. The countries with the highest number of publications were China and the United States. Approximately 180,000 cases of corneal transplantations are performed worldwide each year, of which 40,000 to 50,000 of said surgical interventions take place in the United States. In China, corneal diseases are the second leading cause of blindness.^40–42 Xu et al.⁴³ found that, in 2012, the prevalence of keratoconus in Beijing in individuals over the age of 50 years was 0.9 ± 0.2%.

Nowadays, other topics of interest within this field include the effectiveness of cross-linking in the treatment of keratitis with Escherichia coli,⁴⁴ Acanthamoeba,^45,46 Pseudomonas aeruginosa,⁴⁷ Staphylococcus aureus, Aspergillus,⁴⁸ Fusarium,⁴⁸ other types of bacteria and herpes viruses.⁴⁹ Current studies have shown that corneal cross-linking can be used, not only as an adjuvant treatment, but also as a rescue or stand-alone treatment in cases of infectious keratitis. Cross-linking is an effective solution for the management of bacterial keratitis thanks to its considerable number of bactericidal properties and the fact that it increases the corneal resistance to proteolytic enzymes.⁵⁰ However, its effectiveness against viral keratitis has not been demonstrated.^50–52 In fact, it remains a controversial topic and there is still no protocol for infectious keratitis. It is only applied in severe infections which do not respond to antimicrobial treatment, in order to avoid or postpone emergency keratoplasty. Khoo et al.⁵³ found a predominant association with gram-positive bacteria in patients with microbial keratitis who had undergone cross-linking treatment, and in some cases these patients presented with delayed epithelialization. Therefore, they concluded that microbial keratitis post-CXL may lead to moderate to poor patient outcomes.

Another topic of growing interest in recent years is the effectiveness of cross-linking as a means of controlling progressive myopia by mechanically stabilizing the sclera. This is because it is thought that pathologic myopia is caused by uncontrolled, progressive scleral remodelling which leads to posterior staphylomas. Levy et al.'s study⁵⁴ determined that axial elongation may involve a biomechanical weakening mechanism, which causes the softening of the sclera. The use of genipin in corneal cross-linking procedure can restore scleral stiffness. In contrast, a study conducted by Chu et al.⁵⁵ found that treatment increased stiffness of the sclera, nonetheless, myopia development was not affected. Therefore, it is anticipated that in the future there will be an increased number of research studies involving human patients in order to confirm the benefits of this procedure in myopia. One of the longest follow-up clinical studies was the one conducted by Aslanides et al..⁵⁶ After five years, it was determined that refractive surgery by PRK combined with corneal cross-linking offers safe and effective results. Refractive stability is one of the main advantages of this new combination, as well as the fact that it has a sterilization effect on the treated cornea without the potential side effects of mitomycin. In the future, the main research on this topic will look to explore the potential of increasing the effectiveness and safety of cross-linking in order to reduce patient discomfort. On the one hand, research will focus on developing transepithelial delivery systems for the absorption of riboflavin through healthy epithelium, which will therefore reduce associated morbidity. There will also be an increased amount of research on the idea of conducting cross-linking through contact lenses in order to improve the safety of the treatment in thin corneas. On the other hand, other research groups will conduct longer follow-up studies in order to analyse the effectiveness of cross-linking as a treatment for infectious keratitis using PACK-CXL, and for the treatment of corneal oedema. On the one hand, research will focus on developing transepithelial delivery systems for the absorption of riboflavin through healthy epithelium, which will therefore reduce associated morbidity. Research on cross-linking through contact lenses to improve the safety of the treatment in thin corneas will also increase. On the other hand, some research groups will conduct longer follow-up studies to analyse the effectiveness of cross-linking as a treatment for infectious keratitis using PACK-CXL, as well as for the treatment of corneal oedema. Finally, studies will focus on the use of cross-linking in conjunction with LASIK or PRK for better refractive stability, or they will look into ways in which it can be applied directly to the corneal curvature using Photorefractive Intrastromal Cross-linking (PiXL), without the need for corneal tissue ablation.

The trends identified in this study have significant practical implications. For instance, the widespread adoption of cross-linking for treating keratoconus could lead to standardized protocols that enhance patient outcomes globally. The combination treatments, such as cross-linking with PRK, suggest a move towards more comprehensive and effective treatment strategies, potentially improving visual acuity and long-term stability for patients. The research on cross-linking for infectious keratitis highlights its potential as a less invasive alternative to traditional treatments, which could reduce the need for emergency keratoplasty and associated complications. Furthermore, the exploration of cross-linking for controlling myopia progression indicates a promising avenue for managing a prevalent condition, potentially reducing the burden of high myopia in the population. The continuous advancements in delivery methods and safety improvements, such as transepithelial delivery systems and cross-linking through contact lenses, are likely to make the treatment more accessible and safer for a broader range of patients, including those with thinner corneas.

One limitation of this study is the high percentage of English publications, which might overlook significant research in other languages. While 97.8% of the publications analyzed are in English, this reflects a global trend towards publishing in this language in high-impact journals. However, it is important to recognize that valuable research in other languages, such as German (1.5%) and French (0.4%), may not be adequately represented. This linguistic bias can limit access to relevant studies and findings that could be crucial for a comprehensive understanding of the field. Future research could benefit from including databases that index publications in a wider range of languages, thereby improving the representativeness and completeness of bibliometric analyses.

In conclusion, this study provided a comprehensive and objective analysis on the effectiveness of crosslinking. The five main groups indicated what the main research topics were in this field. The most relevant one was the effectiveness of crosslinking in the treatment of keratoconus (5.4%), followed by the effectiveness of crosslinking in corneal transplants (0.84%), evolution of the cataracts (0.8) and in treating infectious keratitis (0.6%). Other topics of interest, which may have greater impact in the coming years included the effectiveness of crosslinking in reducing axial growth (0.3%).

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Clara Martínez Pérez

Cristina Alvarez-Peregrina

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