Biological Tissue Decellularization for Heart Valve Prostheses

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Solution Overview

Problem

Biological heart valve prostheses tend to calcify and have a shorter lifespan due to immune reactions and mechanical stress, leading to increased risk of thromboembolic complications and bleeding, despite efforts to minimize these issues through decellularization and cross-linking.

Innovation Solution

A method involving decellularization using a detergent like surfactin, followed by treatment with alkaline α-galactosidases to remove α-gal epitopes, and cross-linking of collagen fibers with a suitable agent to create a stable, non-immunogenic tissue for heart valve prostheses, which reduces calcification and enhances mechanical properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If harsh decellularization conditions are used to remove α-Gal epitopes, then calcification risk is reduced, but mechanical properties of the tissue are significantly degraded

Engineering Contradiction:
Improvecalcification riskVSAvoidmechanical properties
Core Design Contradiction:
Object-affected harmful factorsVSStrength

Solution Approach 1:

The patent changes the chemical parameters of the decellularization process by using mild detergents (such as Tween 20, Tween 80, or Triton X-100) at controlled concentrations and temperatures, replacing harsh conditions with optimized gentle conditions that achieve epitope removal while preserving mechanical integrity

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent replaces mechanical/physical harsh treatment methods with chemical enzymatic treatment using α-galactosidase enzymes to remove α-Gal epitopes, substituting mechanical force with specific biochemical reactions that are gentler on the tissue structure

Inventive Principle:
Principle #28Mechanics substitution (Replace mechanical system)

2Strength

If gentle decellularization is used to preserve mechanical properties, then tissue structure is maintained, but α-Gal epitopes remain and trigger immune responses

Engineering Contradiction:
Improvemechanical propertiesVSAvoidimmune response
Core Design Contradiction:
StrengthVSObject-generated harmful factors

Solution Approach 1:

The patent implements a continuous multi-step process where mild decellularization is followed by enzymatic treatment with α-galactosidase, ensuring that both mechanical property preservation and immune response reduction are achieved through sequential continuous actions rather than single harsh treatments

Inventive Principle:
Principle #20Continuity of useful action

Solution Approach 2:

The patent introduces α-galactosidase enzyme as an intermediary agent that specifically targets and removes α-Gal epitopes without affecting the mechanical structure, acting as a mediator between the tissue and the immune system by eliminating the harmful epitopes while preserving the beneficial structural components

Inventive Principle:
Principle #24Intermediary (Mediator)

3Manufacturing precision

If multiple processing steps are used to thoroughly clean and prepare tissue, then purity is improved, but processing time and complexity increase

Engineering Contradiction:
Improvetissue purityVSAvoidprocessing time
Core Design Contradiction:
Manufacturing precisionVSLoss of time

Solution Approach 1:

The patent merges multiple processing functions into an integrated workflow where decellularization, enzymatic treatment, and cross-linking are combined in a sequence that achieves thorough purification without excessive time loss, consolidating steps that work synergistically rather than independently

Inventive Principle:
Principle #5Merging (Combining)

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

The method results in a tissue with significantly improved mechanical stability and reduced calcification risk, minimizing immune reactions and extending the lifespan of biological heart valve prostheses.

Implementation Method 1

The first essential processing step is the so-called decellularization of the tissue. In this step, cell membranes, intracellular proteins, cell nuclei, and other cell components are removed from the tissue as completely as possible

Methodology Applied
Scientific EffectSurfactant action: Surfactant

Implementation Method 2

a step of treating the tissue with at least one α-galactosidase. Treatment with at least one α-galactosidase removes α-gal epitopes from the tissue surface

Methodology Applied
Scientific EffectEnzymatic hydrolysis: Hydrolysis

Implementation Method 3

the collagen fibers are cross-linked using a suitable cross-linking agent by incorporating chemical bonds. The cross-linking agent binds to the amino groups of the collagen fibers, forming chemically stable bonds between them

Methodology Applied
Scientific EffectCross-linking: Chemical Bonding

Data Source

PatentEP3103484B1Method for the treatment of biological tissue
Publication Date: 2019.07.31 BIOTRONIK AG
  • EP3103484B1 patent drawingFigure 1~2
  • EP3103484B1 patent drawingFigure 3~4
  • EP3103484B1 patent drawingFigure 5~6a

AI summary

The invention describes a method for preparing tissue for medical applications, in particular tissue for use in an artificial heart valve.