Genetically Modified MSC Cardiovascular Grafts

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Solution Overview

Problem

Current treatments for calcific aortic valve disease (CAVD) lack effective methods to halt or reverse pathologic calcification, leading to significant medical and financial burdens, with existing valve replacements prone to calcification and complications such as thrombogenic events and infection.

Innovation Solution

A cardiovascular graft is developed by seeding a bioerodible cell growth scaffold with mesenchymal stem cells (MSCs) that have been modified to reduce or eliminate telomerase reverse transcriptase (TERT) expression, which are then implanted to create a tissue-engineered heart valve resistant to calcification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of stationary object

If mechanical valves are used for valve replacement, then durability is improved, but thrombogenic events and infection risk increase requiring life-long anticoagulation therapy

Engineering Contradiction:

Improvevalve durabilityVSAvoidthrombogenic events and infection risk

Core Design Contradiction:

Duration of action of stationary objectVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the biochemical parameters of valve tissue by genetically altering mesenchymal stem cells to reduce TERT expression, thereby changing the tissue's susceptibility to calcification and thrombogenicity while maintaining mechanical durability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite tissue-engineered valve combining genetically modified mesenchymal stem cells with a bioerodible scaffold, integrating the benefits of biological compatibility with structural durability

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If bioprosthetic heart valves are used for valve replacement, then thrombogenicity is reduced and functionality is improved, but calcification develops leading to eventual failure

Engineering Contradiction:

ImprovethrombogenicityVSAvoidvalve longevity

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The patent changes the biochemical parameter of TERT expression in valve tissue to prevent calcification, thereby extending valve longevity while maintaining the low thrombogenicity of bioprosthetic valves

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses a bioerodible scaffold that is intentionally designed to degrade over time, replacing the need for lifelong anticoagulation and avoiding the calcification problem of permanent bioprosthetic valves

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Productivity

If mesenchymal stem cells with normal TERT expression are used in cardiovascular grafts, then cell proliferation and tissue regeneration are enhanced, but pathologic calcification is promoted

Engineering Contradiction:

Improvecell proliferation and tissue regenerationVSAvoidpathologic calcification

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent modifies the TERT expression parameter in mesenchymal stem cells to reduce or eliminate it, thereby preventing calcification while maintaining sufficient cell proliferation and tissue regeneration capabilities for graft formation

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11634716B2Genetically modified mesenchymal stem cells for use in cardiovascular prosthetics

Publication Date: 2023.04.25 UNIV OF PITTSBURGH OF THE COMMONWEALTH SYST OF HIGHER EDUCATION

AI summary

A cardiovascular graft is provided, such as a prosthetic heart valve or blood vessel, that comprises mesenchymal stem cells (MSCs) and/or progeny thereof, modified to knock down or knockout expression of the telomerases reverse transcriptase gene (TERT), or otherwise reduce activity of TERT. Also provided are a method of making the cardiovascular graft, and a method of implanting the cardiovascular graft.