Table 1.

Cell-based and cell-free approaches to modulate corneal fibrosis and scarring.

Approach	Types	Mechanisms of Action	Risks/Potential Side Effects	Limitations
Cell-based	Corneal stromal keratocytes	Produce and deposit native stromal collagen and proteoglycans to restore ECM composition	Transit to fibroblasts and MyoF under wound conditions, need to apply after pro-inflammatory and fibrotic cytokines are suppressed [9]	Low cell yield due to slow ex vivo expansion [15]
	Corneal stromal stem cells	Anti-inflammatory with TSG-6 expression; anti-fibrosis with TGFβ3 expression; differentiation to keratocytes [98,137]	Cell fate and phenotypic variation in response to pH changes and inflammatory response in corneal wound	Donor to donor variation in cell characteristics and functions [99]
	Mesenchymal stem cells from adipose, bone marrow	Anti-inflammatory; immuno-modulatory; keratocyte differentiation [76,78,89]	Uncertainty in ECM production specific to corneal stroma;risk of angiogenesis [88]	Donor to donor variation in cell features
Cell-free	Extracellular vesicles from CSSCs, MSCs	Anti-fibrosis microRNAs (miR19a, 29a, 381) to prevent M1 macrophage activation, suppress JNK fibrotic and TGFβ pathways [110,111,112,190]	Easy application with minimal immunogenic effects. However, uncharacterized EV content results in unwanted effects.	Large-scale cell culture to prepare EVs; clearance or binding of EVs to ECM restricts cellular uptake [191]
	Extracellular matrix	ECM microparticles reduced inflammatory and fibrotic gene expression; prevented MyoF generation [114]	Wide range of applications in different physical forms—sheets, suspension; easy to modify and functionalize	Material heterogeneity; need to develop isolation methods with high yield and purity [192]