Cross-linked Gelatin Composition for Hemostasis

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Solution Overview

Problem

Current biomaterials for in situ gel formation, particularly for soft tissue adhesives and hemostasis, face limitations in controlling gel properties and achieving rapid and effective sealing of wounds, especially under moderate to high blood flow conditions, due to thermoreversible gelation and interference with enzyme activity by denaturants like urea.

Innovation Solution

A composition comprising a cross-linkable protein, such as gelatin, combined with a calcium-independent microbial transglutaminase and a denaturing agent like urea, in a specific buffer system, which allows for controlled cross-linking and enhanced mechanical properties, including rapid hemostasis and improved adhesive strength.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If thermoreversible gelation is used for in situ gel formation, then the material can be injected and form gels in situ, but the gel properties cannot be effectively controlled and enzyme activity is interfered with by denaturants

Engineering Contradiction:

Improveinjectability and in situ gel formationVSAvoidcontrol of gel properties and enzyme activity

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent changes the crosslinking mechanism from thermoreversible physical gelation to enzymatic crosslinking, allowing control of gel properties through enzyme concentration and reaction conditions rather than temperature alone. This enables reliable control of mechanical properties while maintaining injectability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces an enzyme as an intermediary catalyst to mediate the crosslinking reaction between gelatin molecules, replacing direct thermoreversible gelation. This intermediary enables controlled gel formation with predictable properties and maintains enzyme activity despite the presence of denaturants like urea

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If rapid cross-linking is achieved for effective hemostasis, then wound sealing speed is improved, but control over gelation time becomes difficult

Engineering Contradiction:

Improvewound sealing speedVSAvoidgelation time control

Core Design Contradiction:

ProductivityVSLoss of time

Solution Approach 1:

The patent creates a dynamic system where gelation time can be adjusted by changing enzyme concentration, substrate availability, or reaction conditions. This allows the system to adapt between rapid gelation for hemostasis and controlled gelation for other applications, solving the contradiction between speed and controllability

Inventive Principle:

Principle #15Dynamics

3Strength

If denaturants like urea are used to enhance mechanical properties, then gel strength is improved, but enzyme activity is inhibited

Engineering Contradiction:

Improvegel mechanical propertiesVSAvoidenzyme activity

Core Design Contradiction:

StrengthVSReliability

Solution Approach 1:

The patent converts the harmful effect of denaturants on enzyme activity into a beneficial outcome by using calcium-independent transglutaminase that is resistant to denaturants. The denaturants that would normally inhibit enzyme activity instead enhance gel mechanical properties through improved crosslinking, while the enzyme remains active

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 composition enables rapid and effective sealing of wounds with improved mechanical properties and adhesive strength, overcoming the limitations of thermoreversible gelation and enzyme inhibition, while maintaining enzyme activity, thus providing effective hemostasis and tissue sealing.

Implementation Method 1

a calcium-independent microbial transglutaminase

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

controlled cross-linking and enhanced mechanical properties

Methodology Applied

Scientific EffectCross-linking: Chemical Bonding

Data Source

PatentUS9044456B2Cross-linked compositions

Publication Date: 2015.06.02 BARD SHANNON LTD

AI summary

Improved compositions comprising a cross-linkable protein or polypeptide, and a non-toxic material which induces cross-linking of the cross-linkable protein. The compositions are optionally and preferably prepared in a non-phosphate buffer solvent. Optionally and preferably, the cross-linkable protein includes gelatin and any gelatin variant or variant protein as described herein. Optionally and preferably, the non-toxic material comprises transglutaminase (TG), which may optionally comprise any type of calcium dependent or independent transglutaminase, which may for example optionally be a microbial transglutaminase (mTG).