Delayed healing & persistent epithelial defect

Certain backgrounds weaken re-epithelialization: loss of corneal sensation (neurotrophic keratitis), diabetes, severe dry eye, limbal stem-cell insufficiency, chemical-burn sequelae or poor lid closure (exposure). A persistent epithelial defect (PED) fails to heal after about one week; unclosed, it thins the stroma and leads to a corneal ulcer ^[1,4].

Mechanisms of the main backgrounds

Neurotrophic keratitis reflects loss of the trophic support of corneal nerves (substance P, CGRP, IGF-1, NGF), essential to epithelial migration and adhesion. Diabetes combines hypoaesthesia, basement-membrane abnormalities and matrix glycation. Limbal insufficiency, congenital (aniridia) or acquired (burn), dries up epithelial renewal and lets the conjunctiva invade the cornea. Basement-membrane integrity is decisive: dystrophic abnormalities (e.g. Cogan / map-dot-fingerprint) sustain recurrent erosions.

Dry eye: barrier breakdown via the EMMPRIN–MMP-9–occludin axis

Dry eye epitomizes epithelial fragility. Tear hyperosmolarity activates the surface and, as we showed, raises EMMPRIN/CD147 and MMP-9, causing occludin cleavage and tight-junction disruption; genetic knockout of MMP-9 (or EMMPRIN) protects from this barrier breakdown (Huet et al., Am J Pathol 2011). This mechanism links surface inflammation directly to defective healing.

Iatrogenic factors

Several treatments slow healing: preservatives (benzalkonium, polyquaternium-1), topical NSAIDs, aminoglycosides, steroids and surface anaesthetics (proparacaine inhibits actin synthesis and hence migration). Finally, migration/proliferation desynchronization produces heaped-up edges that must be debrided.

Corneal fibrosis (haze) & myofibroblasts

When the epithelium fails to close — or the basement membrane fails to regenerate — keratocytes remain continuously exposed to epithelium-derived TGF-β1/β2 and PDGF, so differentiation into mature myofibroblasts runs to completion ^[3,5].

Present in large numbers near the wound, they deposit a disorganized matrix (fibronectin, collagen III, tenascin, glycosaminoglycans) and express, besides α-SMA, vimentin and desmin. These cells and their matrix scatter light: this is corneal fibrosis, clinically haze. One schematically distinguishes early haze (cellular, often regressive) from late haze (matrix, more stubborn).

The process is not always permanent. If the epithelial basement membrane reforms, stromal TGF-β and PDGF fall, myofibroblasts undergo apoptosis, and keratocytes recolonize and reorganize the matrix — the opacity may regress or clear over several years. After severe injuries it may instead remain permanent despite re-epithelialization ^[6].

Haze is best studied after surface ablation (PRK): the intensity of the wound-healing response (keratocyte apoptosis then myofibroblast density) explains the differences in haze and regression between PRK and LASIK, and underlies the use of intra-operative mitomycin C for large corrections ^[13,14].

Ulceration, stromal melting & direct epithelial–stromal interactions (CD147/MMP)

Without closure, stromal thinning can progress to perforation, faster on an inflammatory background or with iatrogenic agents. Prolonged delay prevents basement-membrane maturation: the epithelium then comes into direct contact with subepithelial keratocytes — the direct epithelial–stromal interactions (DESI) ^[4,5].

EMMPRIN/CD147: metalloproteinase inducer

This pathological dialogue is largely mediated by the transmembrane glycoprotein EMMPRIN/CD147 (Extracellular Matrix Metalloproteinase Inducer, basigin). In direct contact with fibroblasts, the epithelium expresses CD147, which induces stromal MMP synthesis (MMP-1, -2, -3, -9) and promotes myofibroblast differentiation. Weakly present in the healthy cornea (mostly epithelial), it is strongly overexpressed in ulcerated corneas, induced in the anterior stroma and co-localized with MMP-2 at the epithelial–stromal boundary; in vitro, direct contact of fibroblasts with EMMPRIN-rich epithelial membranes induces MMP-1/-2, an effect abolished by a blocking anti-EMMPRIN antibody — evidence of CD147's causal role (Gabison et al., Am J Pathol 2005). This deregulated induction sustains collagenolysis and delayed healing, making CD147 a therapeutic target (Gabison et al., Prog Retin Eye Res 2009). The same EMMPRIN → MMP-9 axis also destabilizes the epithelial barrier by cleaving occludin (Huet et al., 2011).

Melting or fibrosis? The inversion of TGF-β's role

In diffusible signalling, TGF-β outweighs IL-1, inhibits collagenases and drives matrix accumulation: the fibrotic myofibroblast (haze). But in direct contact, EMMPRIN is under TGF-β control — so TGF-β flips into a pro-lytic signal by inducing CD147 → MMP, yielding a lytic myofibroblast (MMP-producing), α-SMA⁺ like the former but with the opposite fate: the one found in ulcerated corneas where degradation predominates (Gabison et al., 2009). One marker, two cells: it is the differentiation pathway (diffusible TGF-β vs contact EMMPRIN) that decides whether the myofibroblast builds or destroys the matrix.

MMP / TIMP balance and vicious circle

MMPs are zinc-dependent endopeptidases that degrade matrix and basement membrane; their activity is normally reined in by tissue inhibitors (TIMP) and serum inhibitors (α2-macroglobulin) — hence the value of autologous serum. In inflammation, excessive infiltration of monocytes, macrophages and neutrophils releases surplus MMP: the balance shifts to collagenolysis and the stroma thins. Rheumatoid arthritis, often TIMP-deficient, is the classic example (central melts). A vicious circle sets in: collagen-degradation products are chemotactic for neutrophils, summoning a fresh inflammatory wave and more MMP ^[5,4].