Design of Hydrolytically Degradable Polyethylene Glycol Crosslinkers for Facile Control of Hydrogel Degradation

Abstract

matrix-type devices, without requiring surgical removal. [7-9] Enzymatic and hydrolytic degradation are the two major physiologically relevant mechanisms that confer degradability to hydrogel matrices. Enzymatic degradation is generally preferred in tissue engineering, where matrix degradation must be synchronized with native cell infiltration and tissue deposition. [10,11] Enzymatically degradable gels have also shown great potential for celldemanded growth factor delivery, where growth factors are released upon local proteolytic gel degradation by cells. [12,13] Hydrolytic degradation is also advantageous in controlled release applications, such as drug or protein delivery, because the rate of degradation does not depend on enzymes and can be controlled by the hydrogel's chemical and physical properties. [14] In addition, hydrolytically degradable materials could be made at lower cost compared to enzymatically degradable ones. Degradable hydrogels can be formed from both natural and synthetic polymers. Synthetic hydrogels offer advantages in reproducibility, availability, and tailoring physical and chemical properties to specific applications. [15] The synthetic hydrogel poly(ethylene glycol) (PEG) is widely used due to the advantages of being non-immunogenic, inert, and biocompatible. [16] However, the PEG polymer is not readily degradable under physiologic conditions at physiologically relevant time frames. Note that in the long-term PEG can be degradable by oxidative degradation from reactive oxygen species. [17] For short-term degradation, degradable moieties must be introduced to fabricate degradable PEG hydrogels and several techniques have been employed, such as incorporating enzymatically cleavable peptide crosslinkers [18,19] or hydrolytically degradable monomers or copolymers, such as polylactic (PLA) and polyglycolic acid (PGA) to either linear [20,21] or star PEG. [22] Each method has advantages and drawbacks. A reliance on enzymes to cleave crosslinkers can result in inconsistent degradation rates. PEG-PLA and PEG-PGA hydrogels are hydrolytically degradable, but copolymer hydrophobicity and acidic degradation products can denature proteins. [23] Hydrogels prepared from PEG-diacrylate (PEGDA) have also been shown degradable by hydrolytic degradation of the endgroup acrylate esters, when implanted subcutaneously in a rat model. [24] In another example, multiarm PEG-amine crosslinked with an ester-containing amine-reactive PEG derivative has been described as a hydrolytically degradable scaffold for Hydrogels, whose degradability can be controlled while also preserving cell viability or biomolecule stability, are in demand. Degradable polyethylene glycol crosslinkers are hydrolytically designed for use in hydrogels. Degradation is controlled by crosslinker chemical structure, such as introducing local hydrophobicity, steric hindrance, or electron-withdrawing moieties near a degradable ester moiety. Hydrogels made using these crosslinkers have gelation times from 1 to 22 min, storage moduli from 3 to 1...

Development of Nanosilicate–Hydrogel Composites for Sustained Delivery of Charged Biopharmaceutics

“…Due to its dual ionic nature, SPP is commonly used to de-gel self-gelling grades of laponite when added at a concentration of 1–10% by mass of NS. , In particular, pyrophosphate anions in SPP shield the NS particle edges, leading to the entire particle having a negative charge. , Then, sodium cations in SPP loosely associate around the particles, causing mutual repulsion between them. PBS is a common physiological buffer, and TEA is a mild base needed for PEG hydrogel formation. , …”

“…PBS is a common physiological buffer, and TEA is a mild base needed for PEG hydrogel formation. 4,34 The buffer in which NS was dispersed had a significant effect on NS dispersion (Figure 1). PBS and TEA were ineffective at dispersing NS particles, with large aggregates remaining even after sonication.…”

Facile Synthesis of Rapidly Degrading PEG-Based Thiol-Norbornene Hydrogels

“…Alternatively, hydrolytic degradation of PEG-based hydrogels may be engineered by synthesizing ester-containing cross-linkers with different hydrolytic susceptibility, such as groups with steric hindrance, local hydrophobicity, and electron-withdrawing moieties. 3,7 Among the various cross-linking chemistries, PEG-based hydrogels fabricated by orthogonal thiol-norbornene photopolymerization are increasingly used in drug delivery and tissue engineering applications. 8 In particular, multiarm PEGnorbornene (PEGNB) can be cross-linked into an idealized network using a multifunctional thiol cross-linker through a radical-medicated thiol-norbornene reaction initiated by ultraviolet light, 9−12 visible light, 13,14 or enzymatic reaction.…”

“…On the other hand, labile motifs (e.g., poly­(lactic acid), PLA) are routinely copolymerized with functionalized PEG to render the otherwise stable network hydrolytically labile. Alternatively, hydrolytic degradation of PEG-based hydrogels may be engineered by synthesizing ester-containing cross-linkers with different hydrolytic susceptibility, such as groups with steric hindrance, local hydrophobicity, and electron-withdrawing moieties. , …”

Mechanics of 3D Cell–Hydrogel Interactions: Experiments, Models, and Mechanisms

“…The authors demonstrated that degradation could be decoupled from the initial mechanical properties. Kroger et al 434 showed that for hydrogels crosslinked via thiol−acrylate Michael-type reaction, the degradation rate could be controlled by modifying the chemistry adjacent to the carbonyl carbon in the cross-link without substantially changing the initial mechanical properties. The authors showed that these modifications led to degradation times that ranged from hours to weeks.…”