Significance of Crosslinking Approaches in the Development of Next Generation Hydrogels for Corneal Tissue Engineering
Open accessAbstract
Medical conditions such as trachoma, keratoconus and Fuchs endothelial dystrophy can damage the cornea, leading to visual deterioration and blindness and necessitating a cornea transplant. Due to the shortage of donor corneas, hydrogels have been investigated as potential corneal replacements. A key factor that influences the physical and biochemical properties of these hydrogels is how they are crosslinked. In this paper, an overview is provided of different crosslinking techniques and crosslinking chemical additives that have been applied to hydrogels for the purposes of corneal tissue engineering, drug delivery or corneal repair. Factors that influence the success of a crosslinker are considered that include material composition, dosage, fabrication method, immunogenicity and toxicity. Different crosslinking techniques that have been used to develop injectable hydrogels for corneal regeneration are summarized. The limitations and future prospects of crosslinking strategies for use in corneal tissue engineering are discussed. It is demonstrated that the choice of crosslinking technique has a significant influence on the biocompatibility, mechanical properties and chemical structure of hydrogels that may be suitable for corneal tissue engineering and regenerative applications.
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GA application confronts significant hurdles associated with its immunogenicity, cytotoxicity, and calcifying effects.
“Undesirably, GA application per se confronts significant hurdles associated with its immunogenicity, cytotoxicity, and calcifying effects.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [201]
Section 2.3.1 (page unavailable) identifies cytotoxicity and the immune response elicited by glutaraldehyde (GA) as limitations, supporting two of the three stated hurdles. Our copy does not report a calcifying effect of GA (searched: calcification and calcifying effects), so that part is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenipin's cytotoxicity is dose-dependent but time-independent, and in concentrations up to 0.5 mM it has optimal biocompatibility and is considered safe in most tissues.
“Its cytotoxicity is dose-dependent but time-independent, and in concentrations up to 0.5 mM has optimal biocompatibility and is considered safe in most tissues [199, 201].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [201]
Section 2.3.3 says genipin’s cytotoxicity appears dose-dependent but time-independent and recommends 0.5 mM for most tissue-engineering applications. It does not establish that all concentrations up to 0.5 mM have optimal biocompatibility or are safe in most tissues. Section 4.3 cautions that safety varies by cell type and concentrations require tissue-specific optimization. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEDC/NHS treated dECM scaffolds have shown remarkable mechanical similarity to native tissue and biocompatibility for mesenchymal stem cells in different tissues without induction of adverse immune response.
“EDC/NHS treated dECM scaffolds have shown remarkable mechanical similarity to native tissue and biocompatibility for mesenchymal stem cells in different tissues without induction of adverse immune response [189, 201, 210].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [201]
Section 2.3 reports improved mechanical integrity and cellular biocompatibility for collagen-based scaffolds at reduced EDC concentrations; Section 4.3 describes mechanically strong EDC/NHS-crosslinked collagen hydrogels. Neither passage establishes native-tissue mechanical similarity for EDC/NHS-treated dECM scaffolds, biocompatibility with mesenchymal stem cells across different tissues, or an absence of adverse immune responses. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBoth EDC and NHS are water-soluble, and ease of elimination via simple washing steps provides additional superiority for EDC/NHS treated scaffolds biocompatibility.
“Both EDC and NHS are water-soluble, and the ease of their elimination via simple washing steps provides additional superiority for EDC/NHS treated scaffolds biocompatibility [201].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [201]
Section 2.3.4 says NHS is water-soluble and that a water-soluble byproduct of EDC crosslinking can be removed by washing. It does not say that both EDC and NHS themselves are eliminated by washing. Section 4.3 links their absence from the final product to reduced potential toxicity, but does not establish the claimed washing mechanism for both reagents. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLong-standing leach of GA residues and free aldehyde groups out of GA-treated scaffold prolongs detrimental effects.
“Long-standing leach of GA residues and free aldehyde groups out of GA-treated scaffold prolongs these detrimental effects [197, 199, 201].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [201]
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Recent Advances in Hydroxyapatite-Based Biocomposites for Bone Tissue Regeneration in Orthopedics
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- Authors
- Bhattacharjee, P., & Ahearne, M.
- Affiliations
- Trinity College Dublin (IE)
- Corresponding author
- Ahearne, Mark
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2021-02-28
- Volume
- 13
- Issue
- 3
- Pages
- 319
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC7997321
- OpenAlex
- W3134749897
- Cited by
- 66
- References
- 148
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 11 · 2021: 6
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- European Research Council (637460)
- Science Foundation Ireland (15/ERC/3269)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Corneal Surgery and Treatments
- Physical Sciences › Materials Science › Biomaterials › Silk-based biomaterials and applications
- Keywords
- hydrogels, crosslinking, corneal tissue engineering, corneal regeneration, injectable hydrogel, corneal transplantation, crosslinking agents, biocompatibility, mechanical properties, drug delivery, keratoconus, trachoma, Fuchs endothelial corneal dystrophy, immunogenicity, toxicity
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