Collagenase-based topical therapy to restore stem cell niche stiffness in skin epithelial disorders

Overview

This solution addresses chronic inflammatory skin epithelial disorders by targeting pathological changes in the biomechanical properties of the stem cell niche. The underlying science recognizes that epithelial stem cells require a specific, softer extracellular matrix environment to maintain their undifferentiated state and drive proper tissue regeneration. When tissues experience chronic inflammation or wounding, the extracellular matrix surrounding stem cells can become pathologically stiffened, leading to loss of stem cell function, impaired wound healing, and persistent inflammation.

The approach leverages localized, topical application of low-concentration collagenase for short treatment durations to selectively remove pathological matrix stiffening. This restores the natural mechanical environment required for stem cell maintenance and function. Originally developed and validated for corneal surface diseases and limbal stem cell deficiency, the therapy is now being extended to skin epithelial disorders based on shared biological principles between corneal and skin epithelial-stromal systems.

Technical specifications

Mechanism of action:

• Targets pathological stiffening of the extracellular matrix within the epithelial stem cell niche
• Uses localized, topical collagenase application at very low concentrations for approximately 10 minutes
• Restores appropriate substrate stiffness to support stem cell phenotype through mechanotransduction pathways, specifically YAP/TAZ signaling

Scientific basis:

• The extracellular matrix beneath undifferentiated epithelial cells is naturally softer than the matrix beneath differentiated cells
• Appropriate stiffness preserves stem cell identity and drives controlled differentiation
• Loss of correct niche stiffness contributes to stem cell deficiency in chronic inflammatory conditions

Validation status in cornea:

• In vitro collagen gel models of varying stiffness with human limbal stem cells, assessed by immunocytochemistry
• Ex vivo human cornea models with artificial stiffening and softening, measured by Brillouin spectromicroscopy and immunohistochemistry
• In vivo rabbit alkali burn model demonstrating recovery following topical collagenase treatment
• Ongoing clinical study in patients with limbal stem cell dysfunction

Planned validation for skin application:

• In vitro 3D tissue culture models using human epithelial skin stem cells from the bulge region
• Compressed collagen gel models to confirm safe collagenase application and retention of undifferentiated cell states
• Ex vivo human or pig skin models demonstrating loss of stem cells with matrix stiffening and recovery following collagenase treatment
• Mouse model validation following ex vivo proof of concept

Technology readiness level

The therapy has reached clinical study stage for corneal applications, with in vitro, ex vivo, and in vivo animal model validation completed. The underlying biomechanical mechanism and collagenase treatment protocol are established. Extension to skin epithelial disorders is at an early translational stage, requiring in vitro proof of concept, ex vivo tissue validation, and subsequent in vivo animal studies before clinical translation. This represents a strong opportunity for collaboration with partners interested in advancing novel mechanotherapy approaches for chronic inflammatory skin conditions.