Cyclic Thioester Macromonomers for Byproduct-Free Hydrogel Synthesis
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Solution Overview
Problem
Existing methods for forming hydrogels using native chemical ligation produce cytotoxic thiol by-products, limiting their application in biomedical uses such as injectable materials and drug delivery due to dose-dependent cytotoxicity.
Innovation Solution
The use of cyclic thioester macromonomers in native chemical ligation reactions eliminates the formation of soluble thiol side products, allowing for the creation of biocompatible hydrogels through a catalyst-free and side-product-free process, enabling robust and biocompatible hydrogel formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If native chemical ligation is used to form hydrogels from thioester and cysteine macromonomers, then robust cross-linked hydrogels are formed, but cytotoxic thiol by-products are released
Solution Approach 1:
The patent converts the harmful linear thioester into a beneficial cyclic thioester structure. The cyclic structure undergoes Native Chemical Ligation with cysteine macromonomers to form the desired cross-links, but the ring opening consumes the thioester group without releasing free thiol by-products, thus converting the potential harm into a beneficial outcome.
Solution Approach 2:
The patent changes the molecular structure parameter of the thioester from linear to cyclic form. This structural parameter change fundamentally alters the reaction outcome: cyclic thioesters undergo NCL without releasing soluble thiol by-products, while maintaining the ability to form stable amide bond cross-links with cysteine groups.
2Ease of manufacture
If conventional NCL with linear thioesters is used, then hydrogel formation occurs, but additional toxin removal steps are required
Solution Approach 1:
The cyclic thioester structure is designed to inherently prevent the formation of harmful by-products during cross-linking. The ring opening mechanism consumes the thioester group to form the cross-link without releasing free thiols, eliminating the need for additional purification steps and simplifying the overall manufacturing process.
3Object-affected harmful factors
If cyclic thioester macromonomers are used in NCL, then no thiol by-products are formed, but the synthesis of cyclic thioester precursors is required
Solution Approach 1:
The cyclic thioester precursors are synthesized and characterized before the hydrogel formation step. This preliminary synthesis allows the cyclic structures to be prepared, purified, and stored as ready-to-use macromonomers, simplifying the actual hydrogel formation process and ensuring no thiol by-products will be generated during cross-linking.
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 results in hydrogels that are significantly more biocompatible, reducing cytotoxicity and enabling their use in various biomedical applications, including tissue engineering and drug delivery, without the need for additional toxin removal steps.
Implementation Method 1
the method encompasses a chemoselective reaction between a cyclic thioester structure and a cysteine structure. Such reaction follows the mechanism of native chemical ligation, where transthioesterification between the two reactants first gives a linked thioester-intermediate, and then this intermediate rearranges irreversibly under the usual reaction conditions to form a native amide ('peptide') bond at the ligation site
Data Source
AI summary
A method of synthesizing a biocompatible hydrogel by covalently cross-linking an effective amount of a first macromonomer including a cyclic thioester group with an effective amount of a second macromonomer including a terminal cysteine group is disclosed. In addition, the synthesis and use of the following specific cyclic thioester macromonomer that can be used in the method, as well as specific hydrogels made using this macromonomer are disclosed. The disclosed method produces a biocompatible hydrogel, while producing substantially no toxic free thiol by-product. Accordingly, the method can be used in making biomedical products, such as sutures and tissue replacement biomaterials, and for encapsulating therapeutic cells and pharmaceuticals.