Controlling the kinetics of thiol-maleimide Michael-type addition gelation kinetics for the generation of homogenous poly(ethylene glycol) hydrogels

Darling, Nicole; Hung, Yiu-Sun; Sharma, Shruti; Segura, Tatiana

doi:10.1016/j.biomaterials.2016.05.053

Cited by 108 publications

(130 citation statements)

References 27 publications

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“…This indicates that lower concentrations of reactive groups slow gelation more effectively than the small pH change observed [18]. However, even at low polymer wt% and in a weaker base, hydrogels polymerized within 5 seconds, which is comparable to the speeds others have reported [14]. This is still faster than most users, or automated systems, could uniformly mix the precursor solutions, and the resulting hydrogels are visibly wrinkled ( Figure 1a ).…”

Section: Resultssupporting

confidence: 59%

“…At pH values between 5.8-7.4, the conjugate base is hydrogen phosphate in PBS, and sodium citrate in citrate ( Figure 2a ). The thiolmaleimide reaction is reliant on the thiol pKa, because the thiol/thiolate equilibrium is modulated by buffer pH, as described by the Henderson-Hasselbalch relationship [14,17,18]. We explored pHs between 5.8 and 10 because this is the range where physiological reactions occur [26].…”

Section: Resultsmentioning

confidence: 99%

“…Although mostly overlooked by the field, two key studies have begun to address the kinetics of these Michael-type addition reactions, with the goal of finding new ways to control or slow the crosslinking speed of these networks to achieve more uniform gels [13,14]. Their main suggestion is to change the pKa of the thiol, or change the buffer/solvent conditions to interfere with thiolate formation, all of which slow the reaction [14,17-19]. Lowering pH and changing buffer conditions are easy to implement and can slow the gelation kinetics, but the pH range tolerated by cells is rather limited.…”

Section: Introductionmentioning

confidence: 99%

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Control of Thiol-Maleimide Reaction Kinetics in PEG Hydrogel Networks

Jansen

Negrón-Piñeiro

Galarza

et al. 2017

Preprint

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Michael-type addition reactions are widely used to polymerize biocompatible hydrogels. The thiol-maleimide modality achieves the highest macromer coupling efficiency of the reported Michael-type pairs, but the resulting hydrogel networks are heterogeneous, because polymerization is faster than the individual components can be manually mixed. The reactivity of the thiol dictates the overall reaction speed, which can be slowed in organic solvents and acidic buffers. Since these modifications also reduce the biocompatibility of resulting hydrogels, we investigated a series of biocompatible buffers and crosslinkers to decelerate gelation while maintaining high cell viability. We found that lowering the polymer weight percentage (wt%), buffer concentration, and pH slowed gelation kinetics, but crosslinking with an electronegative peptide was optimal for both kinetics and cell viability. Slowing the speed of polymerization resulted in more uniform hydrogels, both in terms of visual inspection and the diffusion of small molecules through the network. However, reactions that were too slow resulted in non-uniform particle dispersion due to settling, thus there is a trade-off in hydrogel network uniformity versus cell distribution in the hydrogels when using these networks in cell applications.

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Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Control of Thiol-Maleimide Reaction Kinetics in PEG Hydrogel Networks

Jansen

Negrón-Piñeiro

Galarza

et al. 2017

Preprint

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“…The conjugative reaction occurs under mild conditions, which is critical for in vitro and in vivo applications. Segura and colleagues (104) developed similar PEG hydrogels through a thiol-maleimide Michael-type addition by using zinc, thereby demonstrating the multitunable properties of the hydrogel matrices, such as kinetics of hydrogel formation and matrix stiffness. Using this matrix, these authors investigated the impact of matrix stiffness on cellular activities of human dermal fibroblasts.…”

Section: Polymeric Hydrogels As Engineered Three-dimensional Micromentioning

confidence: 99%

Bioinspired Hydrogels to Engineer Cancer Microenvironments

Park

Lewis

Gerecht

2017

Annu. Rev. Biomed. Eng.

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Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

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“…Modi cation of JR2E by replacing Val22 → Cys (JR2EC) in the loop region provides a thiol moitety that allows for further post-modi cations. Examples of common thiol reactions include maleimide-thiol reactions, 157 thiol-ene reactions, 158 and disul de bridge formation. Using the la er, two JR2EC polypeptides were covalently linked via a disul de bridge by reacting the thiols in ammonium hydrogen carbonate bu er (10 mM, pH 8.5).…”

Section: Polymeric Network With the Ekiv-polypeptide System (Paper Ii)mentioning

confidence: 99%

Tunable and modular assembly of polypeptides and polypeptide-hybrid biomaterials

Aronsson¹

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Biomaterials are materials that are speci cally designed to be in contact with biological systems and have for a long time been used in medicine. Examples of biomaterials range from sophisticated prostheses used for replacing outworn body parts to ordinary contact lenses. Currently it is possible to create biomaterials that can e.g. speci cally interact with cells or respond to certain stimuli. Peptides, the shorter version of proteins, are excellent molecules for fabrication of such biomaterials. By following and developing design rules it is possible to obtain peptides that can self-assemble into well-de ned nanostructures and biomaterials. e aim of this thesis is to create "smart" and tunable biomaterials by molecular self-assembly using dimerizing α-helical polypeptides. Two di erent, but structurally related, polypeptide-systems have been used in this thesis. e EKIV-polypeptide system was developed in this thesis and consists of four 28-residue polypeptides that can be mixed-and-matched to self-assemble into four di erent coiled coil heterodimers. e dissociation constant of the di erent heterodimers range from µM to < nM. Due to the large di erence in a nities, the polypeptides are prone to thermodynamic social self-sorting. e JR-polypeptide system, on the other hand, consists of several 42-residue de novo designed helix-loop-helix polypeptides that can dimerize into four-helix bundles. In this work, primarily the glutamic acid-rich polypeptide JR2E has been explored as a component in supramolecular materials. Dimerization was induced by exposing the polypeptide to either Zn 2+ , acidic conditions or the complementary polypeptide JR2K.By conjugating JR2E to hyaluronic acid and the EKIV-polypeptides to star-shaped poly(ethylene glycol), respectively, highly tunable hydrogels that can be self-assembled in a modular fashion have been created. In addition, self-assembly of spherical superstructures has been investigated and were obtained by linking two thiol-modi ed JR2E polypeptides via a disul de bridge in the loop region.e thesis also demonstrates that the polypeptides and the polypeptide-hybrids can be used for encapsulation and release of molecules and nanoparticles. In addition, some of the hydrogels have been explored for 3D cell culture. By using supramolecular interactions combined with bio-orthogonal I covalent crosslinking reactions, hydrogels were obtained that enabled facile encapsulation of cells that retained high viability.e results of the work presented in this thesis show that dimerizing α-helical polypeptides can be used to create modular biomaterials with properties that can be tuned by speci c molecular interactions. e modularity and the tunable properties of these smart biomaterials are conceptually very interesting and make them useful in many emerging biomedical applications, such as 3D cell culture, cell therapy, and drug delivery. II Populärvetenskaplig sammanfattningBiomaterialär material somär designade för a vara i kontakt med biologiskt material och har använts länge inom m...

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Controlling the kinetics of thiol-maleimide Michael-type addition gelation kinetics for the generation of homogenous poly(ethylene glycol) hydrogels

Cited by 108 publications

References 27 publications

Control of Thiol-Maleimide Reaction Kinetics in PEG Hydrogel Networks

Control of Thiol-Maleimide Reaction Kinetics in PEG Hydrogel Networks

Bioinspired Hydrogels to Engineer Cancer Microenvironments

Tunable and modular assembly of polypeptides and polypeptide-hybrid biomaterials

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