High-Density Engineered Cardiac Tissue for Heart Repair

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Solution Overview

Problem

Current methods for manufacturing engineered cardiac tissue (ECT) face challenges in scaling up to clinically relevant sizes and cell densities, leading to compromised electromechanical function and structural organization, with a lack of robust protocols for delivering sufficient cardiomyocytes to restore heart function after myocardial infarction.

Innovation Solution

The development of an engineered cardiac tissue construct comprising cardiomyocytes at a density of 5 million to 75 million cells per milliliter, mixed with human cardiac fibroblasts in a collagen-1 hydrogel, which is assessed for electromechanical function and mechanical properties, allowing for increased cell density and therapeutic impact.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If cell density in ECTs is increased to deliver sufficient cardiomyocytes for therapeutic impact, then therapeutic efficacy is improved, but tissue compaction decreases (6-fold increase in cross-sectional area)

Engineering Contradiction:

Improvecardiomyocyte densityVSAvoidtissue compaction

Core Design Contradiction:

Quantity of substanceVSShape

Solution Approach 1:

The patent systematically varies cell density as a key parameter (from 5 to 50 million cells/mL) to map the design space and understand its effects on tissue formation, compaction, and function, enabling optimization of therapeutic dosage while accounting for structural changes

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent recognizes that tissue compaction is a dynamic process that continues after fabrication, and accounts for this temporal evolution by measuring compaction at multiple time points and incorporating it into the design methodology

Inventive Principle:

Principle #15Dynamics

2Quantity of substance

If cell density in ECTs is increased to deliver sufficient cardiomyocytes for therapeutic impact, then therapeutic efficacy is improved, but elastic modulus decreases (20-fold decrease)

Engineering Contradiction:

Improvecardiomyocyte densityVSAvoidelastic modulus

Core Design Contradiction:

Quantity of substanceVSStrength

Solution Approach 1:

The patent examines how cell density changes affect mechanical properties including elastic modulus, enabling selection of appropriate density ranges that balance therapeutic cell delivery with acceptable tissue mechanical strength

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses collagen hydrogel as a structural matrix that provides mechanical support to the cell population, creating a composite material system where the hydrogel compensates for reduced cell-mediated structural support at higher cell densities

Inventive Principle:

Principle #40Composite materials

3Quantity of substance

If cell density in ECTs is increased to deliver sufficient cardiomyocytes for therapeutic impact, then therapeutic efficacy is improved, but active stress generation decreases (6.5-fold decrease)

Engineering Contradiction:

Improvecardiomyocyte densityVSAvoidactive stress generation

Core Design Contradiction:

Quantity of substanceVSForce

Solution Approach 1:

The patent maps the relationship between cell density and functional output including active stress generation, identifying optimal density ranges that maximize therapeutic benefit while maintaining adequate contractile function

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent delivers a high total number of cells (up to 1 billion) through a single ECT implant to ensure sufficient therapeutic impact, accepting that per-cell efficiency may be reduced but total functional output remains adequate for clinical benefit

Inventive Principle:

Principle #16Partial or excessive action

4Quantity of substance

If ECTs are scaled up in size and cell number to restore sufficient cardiomyocytes after MI, then therapeutic impact is improved, but manufacturing robustness decreases

Engineering Contradiction:

Improvetotal cardiomyocyte numberVSAvoidmanufacturing robustness

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The patent develops standardized ECT fabrication protocols that can be repeatedly applied to manufacture multiple tissues with consistent quality, enabling scaling from small research samples to large clinical implants through systematic process standardization

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent establishes defined parameter ranges for cell density, hydrogel concentration, and fabrication conditions that ensure robust and reproducible manufacturing across different batch sizes and scales

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach enables the creation of clinically feasible ECTs that can be implanted to remuscularize the heart, improving cardiac function and reducing the risk of arrhythmias, with successful engraftment and maturation of cells in preclinical models.

Implementation Method 1

ECTs were fabricated by mixing hiPSC-CMs with 5% human cardiac fibroblasts in a collagen-1 hydrogel

Methodology Applied

Scientific EffectHydrogel: Hydrogel

Data Source

PatentUS20240165301A1Cell and collagen compositions for engineered cardiac tissue

Publication Date: 2024.05.23 BROWN UNIVERSITY

AI summary

Compositions for generating cardiac tissue are provided. The compositions may improve cardiac tissue function.