Chemical Ligations in the Design of Hydrogel Materials

Medina, Scott H.; Schneider, Judith C.

doi:10.1002/9783527683451.ch16

Cited by 6 publications

(5 citation statements)

References 247 publications

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“…As a consequence, a suitable ECM mimic is formed since the natural ECM also consists of proteins and polysaccharides. Furthermore, the Schiff's base is prone to hydrolysis resulting in reversible degradation of the crosslinks afterwards [114]. In order to render gelatin water soluble at room temperature (vide infra) while introducing additional amines to increase the crosslink density, Pan et al reacted the carboxylic acids in gelatin with ethylene diamine using carbodiimide coupling chemistry [5].…”

Section: Schiff's-base Reactionmentioning

confidence: 99%

(Photo-)crosslinkable gelatin derivatives for biofabrication applications

et al. 2019

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Over the recent decades gelatin has proven to be very suitable as an extracellular matrix mimic for biofabrication and tissue engineering applications. However, gelatin is prone to dissolution at typical cell culture conditions and is therefore often chemically modified to introduce (photo-)crosslinkable functionalities. These modifications allow to tune the material properties of gelatin, making it suitable for a wide range of biofabrication techniques both as a bioink and as a biomaterial ink (component).The present review provides a non-exhaustive overview of the different reported gelatin modification strategies to yield crosslinkable materials that can be used to form hydrogels suitable for 2 biofabrication applications. The different crosslinking chemistries are discussed and classified according to their crosslinking mechanism including chain-growth and step-growth polymerization.The step-growth polymerization mechanisms are further classified based on the specific chemistry including different (photo-)click chemistries and reversible systems. The benefits and drawbacks of each chemistry are also briefly discussed. Furthermore, focus is placed on different biofabrication strategies applying inkjet, deposition and light-based additive manufacturing techniques, and the applications of the obtained 3D constructs.

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Section: Schiff's-base Reactionmentioning

confidence: 99%

(Photo-)crosslinkable gelatin derivatives for biofabrication applications

et al. 2019

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“…Hydrogels are 3D cross-linked soft biomaterials that have been used widely in diverse biomedical applications, such as controlled drug delivery, cell encapsulation, and tissue engineering. − Among the countless strategies to cross-link the 3D network structure, chemical ligations have afforded hydrogels with extensive versatility and intelligence. In the past decades, in situ forming hydrogels have attracted widespread attention in the biomedical community owing to their distinctive advantages, such as minimally invasive implantation, which reduces patient’s discomfort, as well as the ease of homogeneous encapsulation of cells and bioactive molecules by mimicking their native extracellular matrix (ECM) microenvironment. , More recently, “click” chemistry has emerged as a powerful and advantageous strategy for the in situ fabrication of hydrogels due to its high selectivity and specificity. − Unfortunately, many common click reactions fail to meet the requirements of a suitable hydrogel cross-linking reaction, such as bioorthogonality, use of safe reagents/triggers, formation of a benign side product, mild temperature, and high reaction efficiency . For example, thiol–ene coupling reactions (Scheme A) require external photoinitiators and long UV exposure time, which could potentially damage cells and tissues; − strain-promoted azide–alkyne cycloadditions (SPAAC) (Scheme B) are still restricted by slow reaction kinetics and a tedious synthesis of reactants; , Diels–Alder reactions (Scheme C) require high temperatures and long reaction times; , tetrazines are sensitive to water and cellular thiols; , and the tetrazine–norbornene inverse-electron demand Diels–Alder cycloaddition (IEDDA) (Scheme D) produces N 2 as side product, which may ultimately affect the material’s mechanical integrity. , Despite all these efforts to eliminate external catalysis/triggers and to improve reaction rates, there is yet no ideal chemical ligation reaction for the preparation of bioorthogonal click hydrogels.…”

Section: Introductionmentioning

confidence: 99%

In Situ Forming, Dual-Crosslink Network, Self-Healing Hydrogel Enabled by a Bioorthogonal Nopoldiol–Benzoxaborolate Click Reaction with a Wide pH Range

Wang

Diaz‐Dussan

et al. 2019

Chem. Mater.

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The use of click chemistry as a hydrogel cross-linking reaction is often limited by slow reaction rates and harsh conditions, such as exposure to UV light and/or use of nonspecific or toxic reagents. On the other hand, the process of boronic ester formation between arylboronic acids and diols suffers from its intrinsic reversibility and low binding affinity at low pH, which impede its potential in many biomedical applications where a fast and stable click reaction is needed. Herein, we report a new concept of click hydrogel fabrication that combines a traditional sugar-based boronic ester and a novel nopoldiol-based benzoxaborolate as a dual-crosslink network (DCN) system. The cooperation of dynamic and rigid networks and the unique sensitivity of benzoxaborolate cross-links toward stimulus provide an intelligent hydrogel with a set of interesting features: (i) catalyst/light-free nopoldiol–benzoxaborolate bioorthogonal click cross-linking, (ii) rapid in situ formation within 26 s, (iii) wide self-healing pH range from 8.5 to 1.5, (iv) exceptional stability under acidic condition and polyol solutions, (v) reactive oxygen species/pH-responsive degradation, (vi) pH-responsive drug release, and (vii) capability for viable cell encapsulation. The complementary click partners, a rigid diol monomer [1R)-(−)-nopol-methacrylamido-diol (nopoldiol)] and a benzoxaborole-based monomer [5-methacrylamido-1,2-benzoxaborole (MAAmBO)], can be easily incorporated into a variety of synthetic polymers through free-radical polymerization with poly(ethylene glycol) methyl ether methacrylate (PEGMA) as the backbone component. The shortened gelation time, improved mechanical properties, and excellent self-healing properties of the resulting DCN hydrogel PBNG were evaluated through rheological measurements. The stability/degradation of PBNG under low pH buffer and H2O2 were monitored via hydrogel weight changes, and the potential of PBNG as a drug-releasing carrier was assessed by the pH-responsive release of doxorubicin. Finally, HeLa cells were successfully encapsulated and cultured in the 3D network to confirm the hydrogel’s biocompatibility as a cell culture scaffold. The nontoxic components and their fast click reaction under mild conditions make the nopoldiol–benzoxaborolate click hydrogels promising candidates for future biomedical applications such as gene delivery, cell therapy, and tissue engineering.

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“…Hydrogel biomaterials are commonly used as mimics of the native extracellular matrix (ECM) due to their high water content and biocompatibility. , Numerous studies in recent years have revealed the ability of several hydrogel properties to regulate cellular behaviors, including matrix stiffness, viscoelasticity, cell-adhesive ligand concentration, growth factor presentation, and matrix degradation . To facilitate cross-linking and chemical functionalization of hydrogels for cell encapsulation, reactions from the broad class of “click chemistry” reactions have grown in popularity due to their robust and selective reactivity in the presence of water and living cells. − These reactions are characterized by rapid reaction kinetics and good hydrolytic stability, both of which are essential qualities for cross-linking reactions used to generate cell-encapsulating hydrogels.…”

Section: Introductionmentioning

confidence: 99%

Rapid Diels–Alder Cross-linking of Cell Encapsulating Hydrogels

Madl

Heilshorn

2019

Chem. Mater.

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Recent efforts in the design of hydrogel biomaterials have focused on better mimicking the native cellular microenvironment to direct cell fate. To simultaneously control multiple material parameters, several orthogonal chemistries may be needed. However, present strategies to prepare cell-encapsulating hydrogels make use of relatively few chemical reactions. To expand this chemical toolkit, we report the preparation of hydrogels based on a Diels-Alder reaction between fulvenes and maleimides with markedly improved gelation kinetics and hydrolytic stability. Fulvene-maleimide gels cross-link up to 10-times faster than other commonly used DA reaction pairs and remain stable for months under physiological conditions. Furthermore, fulvenemaleimide gels presenting relevant biochemical cues, such as cell-adhesive ligands and proteolytic degradability, support the culture of human mesenchymal stromal cells. Finally, this rapid DA reaction was combined with an orthogonal click reaction to demonstrate how the use of selective chemistries can provide new avenues to incorporate multiple functionalities in hydrogel materials.

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Chemical Ligations in the Design of Hydrogel Materials

Cited by 6 publications

References 247 publications

(Photo-)crosslinkable gelatin derivatives for biofabrication applications

(Photo-)crosslinkable gelatin derivatives for biofabrication applications

In Situ Forming, Dual-Crosslink Network, Self-Healing Hydrogel Enabled by a Bioorthogonal Nopoldiol–Benzoxaborolate Click Reaction with a Wide pH Range

Rapid Diels–Alder Cross-linking of Cell Encapsulating Hydrogels

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