Method for Fibroblast Rejuvenation by Mechanical Reprogramming and Redifferentiation

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This invention describes a non-genetic method to rejuvenate aged fibroblasts, the cells vital for connective tissue strength. The process involves mechanically reprogramming aged fibroblasts by growing them on special micro-patterned surfaces into spheroids with stem cell-like properties. These spheroids are then embedded in a 3D collagen matrix, mimicking tissue environments, which induces the cells to regain youthful fibroblast functions. As a result, rejuvenated fibroblasts exhibit increased contractility, better matrix remodeling, reduced DNA damage, and enhanced production of key proteins such as collagen, laminin, and fibronectin.

Use CasesContent extracted from patent full text and abstract with AI.

• Regenerative medicine for treating age-related degeneration of connective tissues (e.g., skin, tendons, scars).
• Development of patient-specific cell therapies for tissue engineering and wound healing.
• Improving the quality of in vitro skin models and tissue grafts with rejuvenated fibroblasts for research or transplantation.
• Potential enhancement of cosmetic and anti-aging products by providing rejuvenated fibroblasts for dermal applications.
• Studying aging mechanisms and testing anti-aging drug candidates in vitro using rejuvenated fibroblast models.

BenefitsContent extracted from patent full text and abstract with AI.

• Non-genetic and non-chemical approach, reducing risk of unwanted mutations or oncogenic transformations compared to iPSCs or other genetic reprogramming.
• Generates fibroblasts with improved contractility and enhanced tissue remodeling abilities, restoring tissue function closer to that of young fibroblasts.
• Decreases age-related DNA damage and restores healthy nuclear architecture, potentially improving cell longevity and safety.
• Enables patient-specific cell therapy by rejuvenating a patient’s own fibroblasts, minimizing risk of immune rejection.
• Scalable and potentially compatible with current tissue engineering and cell manufacturing workflows.

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Patent Abstract

Over the course of the aging process fibroblasts lose contractility, leading to reduced connective tissue stiffness. A promising therapeutic avenue for functional rejuvenation of connective tissue is reprogrammed fibroblast replacement, although major hurdles still remain. Towards this, it is demonstrated that the laterally confined growth of fibroblasts on micro-patterned substrates induces stem-cell like spheroids. In the present invention, these partially reprogrammed spheroids are embedded in Collagen-I matrices of varying densities, mimicking different 3D tissue constraints. In response to such matrix constraints, these spheroids regained their fibroblastic properties and sprouted to form 3D connective tissue networks. Interestingly, it was found that these differentiated fibroblasts exhibit reduced DNA damage, enhanced cytoskeletal gene expression and acto-myosin contractility. In addition, the rejuvenated fibroblasts show increased matrix protein (fibronectin and laminin) deposition and collagen remodelling compared to the parental fibroblast tissue network. Furthermore, it is shown that the partially reprogrammed cells have comparatively open chromatin compaction states and may be more poised to redifferentiation into contractile fibroblasts in 3D-collagen matrix. Collectively, these results highlight efficient fibroblast rejuvenation through laterally confined reprogramming which has important implications in regenerative medicine.