Investigation of the Diels–Alder reaction as a cross-linking mechanism for degradable poly(ethylene glycol) based hydrogels

Kirchhof, Susanne; Brandl, Fabian; Hammer, Nadine; Goepferich, Achim

doi:10.1039/c3tb20831a

Cited by 97 publications

(124 citation statements)

References 47 publications

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“…[7] More recently, catalyst-free bio-orthogonal crosslinking strategies have been developed for a wide range of hydrogel materials that eliminate the potential of cytotoxicity and permit cell encapsulation within the materials. [3,10] Both synthetic materials, such as poly(ethylene glycol) (PEG) [11–13] and naturally derived polymers, such as hyaluronic acid [14–16] and alginate, [17,18] have been functionalized to crosslink by Staudinger ligation, [18] SPAAC, [11] tetrazine ligation, [12,17,19] and Diels–Alder reactions. [13–16] While these previous systems have overcome the issue of copper cytotoxicity associated with CuAAC crosslinking, several limitations remain.…”

Section: Introductionmentioning

confidence: 99%

“…The gelation kinetics of many bio-orthogonal chemistries are not conducive to cell encapsulation. For instance, Diels–Alder reactions between furan and maleimide moieties result in gelation times ranging from tens to hundreds of minutes, [13,15,16] which is too slow to achieve homogeneous cell dispersion within the gel and can result in decreased cell viability. [15] On the other hand, the reaction between tetrazines and trans -cyclooctenes proceeds too rapidly to achieve uniform gelation and cell encapsulation by simple mixing.…”

Section: Introductionmentioning

confidence: 99%

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Bio‐Orthogonally Crosslinked, Engineered Protein Hydrogels with Tunable Mechanics and Biochemistry for Cell Encapsulation

Madl

Katz

Heilshorn

2016

Adv Funct Materials

138

135

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Covalently-crosslinked hydrogels are commonly used as 3D matrices for cell culture and transplantation. However, the crosslinking chemistries used to prepare these gels generally cross-react with functional groups present on the cell surface, potentially leading to cytotoxicity and other undesired effects. Bio-orthogonal chemistries have been developed that do not react with biologically relevant functional groups, thereby preventing these undesirable side reactions. However, previously developed biomaterials using these chemistries still possess less than ideal properties for cell encapsulation, such as slow gelation kinetics and limited tuning of matrix mechanics and biochemistry. Here, engineered elastin-like proteins (ELPs) are developed that cross-link via strain-promoted azide-alkyne cycloaddition (SPAAC) or Staudinger ligation. The SPAAC-crosslinked materials form gels within seconds and complete gelation within minutes. These hydrogels support the encapsulation and phenotypic maintenance of human mesenchymal stem cells, human umbilical vein endothelial cells, and murine neural progenitor cells. SPAAC-ELP gels exhibit independent tuning of stiffness and cell adhesion, with significantly improved cell viability and spreading observed in materials containing a fibronectin-derived arginine-glycine-aspartic acid (RGD) domain. The crosslinking chemistry used permits further material functionalization, even in the presence of cells and serum. These hydrogels are anticipated to be useful in a wide range of applications, including therapeutic cell delivery and bioprinting.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bio‐Orthogonally Crosslinked, Engineered Protein Hydrogels with Tunable Mechanics and Biochemistry for Cell Encapsulation

Madl

Katz

Heilshorn

2016

Adv Funct Materials

138

135

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“…30 The resulting PEG-amine was then functionalized with furyl (8armPEG40k-furan) or maleimide groups (8armPEG40k-maleimide) as described for 8armPEG20k-NH 2 . 24 However, higher reagent concentrations were required due to the lower concentrations of amino groups. For the synthesis of 8armPEG40k-furan, 16 equivalents of 3-(2-furyl)propanoic acid, NHS, DCC, and NaHCO 3 were used; for the preparation of 8armPEG40k-maleimide, 40 equivalents of N-methoxycarbonylmaleimide were used.…”

Section: Synthesis Of Unmodified Macromonomers (Scheme 1)mentioning

confidence: 99%

“…Rheological characterization was performed using a TA Instruments AR 2000 rheometer (TA Instruments, Eschborn, Germany) as previously described. 24 Storage (G 0 ) and loss modulus (G 00 ) were recorded over time; the crossover of G 0 and G 00 was regarded as the gel point. The average mesh size (x) was determined as previously described.…”

Section: Hydrogel Preparation and Characterizationmentioning

confidence: 99%

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Design of hydrogels for delayed antibody release utilizing hydrophobic association and Diels–Alder chemistry in tandem

et al. 2016

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Biodegradable hydrogels were prepared from furan-and maleimide-functionalized eight-armed poly-(ethylene glycol) with an average molecular mass of 40 000 Da (8armPEG40k-furan and 8armPEG40k-maleimide) using the Diels-Alder (DA) reaction as a cross-linking mechanism. Hydrophobic 6-aminohexanoic acid (C 6 ) and 12-aminododecanoic acid (C 12 ) spacers were introduced between the polymer backbone and the functional end-groups; the influence on the gel properties was studied. Modification with C 6 and C 12 spacers induced hydrophobic interactions between the macromonomers leading to association and increased viscosity of the polymer solutions; both effects were influenced by the spacer length. In combination with DA cross-linking, hydrophobic derivatives of 8armPEG40k-furan and 8armPEG40k-maleimide led to hydrogels with improved properties. Upon introduction of C 12 spacers, gelation of 8armPEG40k hydrogels occurred twice as fast. Interestingly, no effect was observed when only one of the two components had been modified. Our experiments suggest that the association of macromonomers by hydrophobic interactions facilitates chemical cross-linking via DA chemistry. This hypothesis is supported by calculations of the network mesh size and the Young's modulus of compression, which showed an increased cross-linking density of hydrophobically modified hydrogels. As a consequence of the increased cross-linking density, the degradation stability of C 12 -modified hydrogels increased by a factor of 4.Moreover, hydrophobic modification improved the hydrolytic resistance of maleimides; this also contributes to gel stability. The in vitro release of bevacizumab, which served as a model antibody, could be delayed for almost 60 days using modification with C 12 . Similar trends were observed for C 6 -modified 8armPEG40k hydrogels; however, the effects were considerably weaker. In summary, utilizing hydrophobic association and chemical cross-linking in tandem is a promising approach to create biodegradable hydrogels for delayed antibody release.

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Responsive Dynamic Covalent Polymers

Mukherjee¹,

Cash²,

Sumerlin³

2017

Dynamic Covalent Chemistry

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Investigation of the Diels–Alder reaction as a cross-linking mechanism for degradable poly(ethylene glycol) based hydrogels

Cited by 97 publications

References 47 publications

Bio‐Orthogonally Crosslinked, Engineered Protein Hydrogels with Tunable Mechanics and Biochemistry for Cell Encapsulation

Bio‐Orthogonally Crosslinked, Engineered Protein Hydrogels with Tunable Mechanics and Biochemistry for Cell Encapsulation

Design of hydrogels for delayed antibody release utilizing hydrophobic association and Diels–Alder chemistry in tandem

Responsive Dynamic Covalent Polymers

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