Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Lagali, Neil

doi:10.1080/02713683.2019.1663874

Cited by 74 publications

(57 citation statements)

References 69 publications

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“…Although 4 years after implantation the implanted materials were stably integrated without rejection, vision recovery was limited in some patients due to surgical suture-induced delayed re-epithelialization of implants and ocular surface irregularities 11 . Host cells did not appear to repopulate the implanted material to induce a stromal regenerative response 3,11 , while corneal nerve regeneration, critical for wound healing and long-term corneal homeostasis, was achieved to the extent expected following standard transplantation but not to normal levels 11 .…”

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confidence: 92%

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A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

Xeroudaki

Thangavelu

Lennikov

et al. 2020

Sci Rep

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Biomaterials designed to replace the diseased cornea could be used to treat corneal blindness where human donor tissue is in short supply, but challenges are the integration of biomaterials with host tissue and cells, avoiding a rapid material degradation and maintaining corneal transparency. Additionally, implantation surgery often triggers an aggressive wound healing response that can lead to corneal thinning and opacity. Here, we report a collagen-based hydrogel with transparency and mechanical properties suitable for replacing a substantial portion of a damaged or diseased corneal stroma. The porous hydrogel permitted migration and population by host cells while maintaining transparency and thickness six months after surgical implantation in an in vivo model of human corneal surgery. With a novel hybrid surgical implantation technique inspired by LASIK refractive surgery, rapid wound healing occurred around implants to maintain biomaterial integrity, transparency and function. Host stromal cell repopulation and regeneration of host epithelium and nerves were observed, as necessary steps towards corneal regeneration. Finally, as a proof-of-principle, the hydrogel loaded with a neuroregenerative drug achieved sustained slow-release drug delivery in vitro. The proposed hydrogel and novel implantation technique together represent a therapeutic approach with translational potential for replacing and regenerating diseased corneal stromal tissue.

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confidence: 92%

“…In cases where the indication for vision-restoring surgery is corneal stromal pathology such as keratoconus, corneal scarring or dystrophies, the least invasive procedure is to replace only the affected stromal tissue 3 .…”

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confidence: 99%

A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

Xeroudaki

Thangavelu

Lennikov

et al. 2020

Sci Rep

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“…Injuries and diseases of the cornea that lead to stromal defects are significant causes of disability, morbidity and vision loss worldwide 1 , 2 . In cases of corneal thinning or melt situations where perforation is imminent, off-label use of cyanoacrylate is employed to stabilize the cornea prior to a definitive but invasive corneal transplant 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Penetrating and lamellar keratoplasty are invasive procedures and the waiting lists for human corneal transplantation include more than 10 million people globally 5 . Numerous efforts to create pre-formed biosynthetic donor corneal buttons using collagen, gelatin, and hyaluronic acid have been made 2 , 6 – 10 . Recently, Holoclar, a fibrin-based disc with stem cells was approved for use throughout the European Union to restore vision in patients with physical injuries and chemical burns 11 .…”

Section: Introductionmentioning

confidence: 99%

In situ-forming collagen hydrogel crosslinked via multi-functional PEG as a matrix therapy for corneal defects

Fernandes-Cunha

Chen

et al. 2020

Sci Rep

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Visually significant corneal injuries and subsequent scarring collectively represent a major global human health challenge, affecting millions of people worldwide. Unfortunately, less than 2% of patients who could benefit from a sight-restoring corneal transplant have access to cadaveric donor corneal tissue. Thus, there is a critical need for new ways to repair corneal defects that drive proper epithelialization and stromal remodeling of the wounded area without the need for cadeveric donor corneas. Emerging therapies to replace the need for donor corneas include pre-formed biosynthetic buttons and in situ-forming matrices that strive to achieve the transparency, biocompatibility, patient comfort, and biointegration that is possible with native tissue. Herein, we report on the development of an in situ-forming hydrogel of collagen type I crosslinked via multi-functional polyethylene glycol (PEG)-N-hydroxysuccinimide (NHS) and characterize its biophysical properties and regenerative capacity both in vitro and in vivo. The hydrogels form under ambient conditions within minutes upon mixing without the need for an external catalyst or trigger such as light or heat, and their transparency, degradability, and stiffness are modulated as a function of number of PEG arms and concentration of PEG. In addition, in situ-forming PEG-collagen hydrogels support the migration and proliferation of corneal epithelial and stromal cells on their surface. In vivo studies in which the hydrogels were formed in situ over stromal keratectomy wounds without sutures showed that they supported multi-layered surface epithelialization. Overall, the in situ forming PEG-collagen hydrogels exhibited physical and biological properties desirable for a corneal stromal defect wound repair matrix that could be applied without the need for sutures or an external trigger such as a catalyst or light energy.

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“…These findings demonstrate the therapeutic potential of hCSSC in repairing stromal damages and regenerating the transparent cornea. The ex vivo propagation allows cells from one donor cornea to be used for multiple recipients or for multiple treatments, thus obviating the shortage of donor materials [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

The anti-scarring effect of corneal stromal stem cell therapy is mediated by transforming growth factor β3

et al. 2020

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Background Corneal stromal stem cells (CSSC) reduce corneal inflammation, prevent fibrotic scarring, and regenerate transparent stromal tissue in injured corneas. These effects rely on factors produced by CSSC to block the fibrotic gene expression. This study investigated the mechanism of the scar-free regeneration effect. Methods Primary human CSSC (hCSSC) from donor corneal rims were cultivated to passage 3 and co-cultured with mouse macrophage RAW264.7 cells induced to M1 pro-inflammatory phenotype by treatment with interferon-γ and lipopolysaccharides, or to M2 anti-inflammatory phenotype by interleukin-4, in a Transwell system. The time-course expression of human transforming growth factor β3 (hTGFβ3) and hTGFβ1 were examined by immunofluorescence and qPCR. TGFβ3 knockdown for > 70% in hCSSC [hCSSC-TGFβ3(si)] was achieved by small interfering RNA transfection. Naïve CSSC and hCSSC-TGFβ3(si) were transplanted in a fibrin gel to mouse corneas, respectively, after wounding by stromal ablation. Corneal clarity and the expression of mouse inflammatory and fibrosis genes were examined. Results hTGFβ3 was upregulated by hCSSC when co-cultured with RAW cells under M1 condition. Transplantation of hCSSC to wounded mouse corneas showed significant upregulation of hTGFβ3 at days 1 and 3 post-injury, along with the reduced expression of mouse inflammatory genes (CD80, C-X-C motif chemokine ligand 5, lipocalin 2, plasminogen activator urokinase receptor, pro-platelet basic protein, and secreted phosphoprotein 1). By day 14, hCSSC treatment significantly reduced the expression of fibrotic and scar tissue genes (fibronectin, hyaluronan synthase 2, Secreted protein acidic and cysteine rich, tenascin C, collagen 3a1 and α-smooth muscle actin), and the injured corneas remained clear. However, hCSSC-TGFβ3(si) lost these anti-inflammatory and anti-scarring functions, and the wounded corneas showed intense scarring. Conclusion This study has demonstrated that the corneal regenerative effect of hCSSC is mediated by TGFβ3, inducing a scar-free tissue response.

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Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Cited by 74 publications

References 69 publications

A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

In situ-forming collagen hydrogel crosslinked via multi-functional PEG as a matrix therapy for corneal defects

The anti-scarring effect of corneal stromal stem cell therapy is mediated by transforming growth factor β3

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