Nanoscale physicochemical properties of chain‐ and step‐growth polymerized PEG hydrogels affect cell‐material interactions

Vats, Kanika; Marsh, Graham; Harding, Kristen; Zampetakis, Ioannis; Waugh, Richard E.; Benoit, Danielle S. W.

doi:10.1002/jbm.a.36007

Cited by 25 publications

(16 citation statements)

References 75 publications

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“…This level is much greater than expected based on loosely-associated siRNA/NPs considering the surface area to volume ratios of the gels. In addition to surface-assocated siRNA/NPs, chain-polymerized hydrogels, which are employed here, contain significant network heterogeneities, which underpins variable mesh sizes [47]. Thus, it is likely that some embedded siRNA/NP have lower diffusional hindrance, contributing to this apparent deviation.…”

Section: Discussionmentioning

confidence: 99%

“…This likelihood is further supported by sustained siRNA/NP release observed from some degradable gels despite overall gel mesh sizes exceeding siRNA/NP size. Greater consistency between mesh size and release may be afforded by use of alternative crosslinking chemistries including click-based thiol-ene polymerizations which form networks with greater homogeneity [47].…”

Section: Discussionmentioning

confidence: 99%

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Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery

Wang

Zhang

Benoit

2018

Journal of Controlled Release

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Despite great therapeutic potential and development of a repertoire of delivery approaches addressing degradation and cellular uptake limitations, small interfering RNA (siRNA) exhibits poorly controlled tissue-specific localization. To overcome this hurdle, siRNA was complexed to nanoparticles (siRNA/NP) embedded within poly(ethylene glycol)-poly(lactic acid)-dimethacrylate (PEG-PLA-DM) hydrogels with the hypothesis that hydrolytic degradation of ester bonds within the PLA crosslinks would provide tunable, sustained siRNA/NP release. Hydrogels formed from macromers with increasing PLA repeats (e.g., 0 or non-degradable to 5 PLA repeats flanking PEG cores) and mixtures of nondegradable PEG-DM (0 PLA) and degradable PEG-PLA-DM macromers were investigated. Hydrogels formed only with fully degradable crosslinks degraded rapidly over 6-14 days with limited control over siRNA/NP release. However, hydrogels formed with mixtures of nondegradable and 20%, 50%, and 100% degradable macromers resulted in siRNA/NP release over 3 to 28 days. Subsequently, gene silencing mediated by released siRNA/NP from 20% and 50% degradable hydrogels was sustained for ~28 days. Furthermore, in vivo imaging showed that hydrogel degradation controlled siRNA/NP localization, with sustained siRNA/NP release from 0%, 20% and 50% degradable hydrogels over 28, 21, and 15 days. A model, which accounts for hydrogel degradation rate and siRNA/NP diffusion, was developed to enable rational design of siRNA/NP delivery depots. Overall, this study shows that siRNA/NP release can be sustained via encapsulation in hydrogels with tunable degradation kinetics and modeled for a priori design of delivery depots.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery

Wang

Zhang

Benoit

2018

Journal of Controlled Release

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“…[57] These results agree with recent studies which showed that chain versus step-growth polymerizations impact cellular morphology and function. [58,59] The influence of the LM content on cell morphology was also studied. Gels with different concentrations of LM 521 (100 and 500 µg mL -1 ) were prepared and compared with gels without LM521 after 7 days in culture.…”

Section: D Hybrid Laminin Hydrogels With Controlled Degradability and Mechanical Propertiesmentioning

confidence: 99%

A Hydrogel Platform that Incorporates Laminin Isoforms for Efficient Presentation of Growth Factors – Neural Growth and Osteogenesis

Dobre

Oliva

Ciccone

et al. 2021

Adv Funct Materials

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Laminins (LMs) are important structural proteins of the extracellular matrix (ECM). The abundance of every LM isoform is tissue-dependent, suggesting that LM has tissue-specific roles. LM binds growth factors (GFs), which are powerful cytokines widely used in tissue engineering due to their ability to control stem cell differentiation. Currently, the most commonly used ECM mimetic material in vitro is Matrigel, a matrix of undefined composition containing LM and various GFs, but subjected to batch variability and lacking control of physicochemical properties. Inspired by Matrigel, a new and completely defined hydrogel platform based on hybrid LM-poly(ethylene glycol) (PEG) hydrogels with controllable stiffness (1-25 kPa) and degradability is proposed. Different LM isoforms are used to bind and efficiently display GFs (here, bone morphogenetic protein (BMP-2) and beta-nerve growth factor (β-NGF)), enabling their solid-phase presentation at ultralow doses to specifically target a range of tissues. The potential of this platform to trigger stem cell differentiation toward osteogenic lineages and stimulate neural cells growth in 3D, is demonstrated. These hydrogels enable 3D, synthetic, defined composition, and reproducible cell culture microenvironments reflecting the complexity of the native ECM, where GFs in combination with LM isoforms yield the full diversity of cellular processes.

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“…In addition, thiol–ene PEG hydrogels exhibit high cytocompatibility, precise spatiotemporal control of gelation, tunable degradation, and versatile modulation of biophysical and biochemical properties. The versatility of these hydrogels is demonstrated through extensive applications, ranging from protein and drug delivery, cartilage development, osteogenic differentiation, endothelial tubulogenesis, brain tumor models, synthetic matrix mimics, 2D culture substrates, and islet and cell encapsulation . However, these applications have been exclusively conducted in vitro, yielding little insight into the in vivo behavior of these hydrogels.…”

mentioning

confidence: 99%

Linkage Groups within Thiol–Ene Photoclickable PEG Hydrogels Control In Vivo Stability

Hunckler

Medina

Coronel

et al. 2019

Adv Healthcare Materials

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step-growth photopolymerization based on the orthogonal reaction between thiol and norbornene has emerged as an attractive strategy for many biomedical applications. [7,8] These step-growth photoinitiated (thiol-ene) hydrogels have shown great promise in 2D and 3D cell culture and organoid development, due, in part, to the low radical concentration and physiological pH required for crosslinking. [9] In addition, thiol-ene PEG hydrogels exhibit high cytocompatibility, precise spatiotemporal control of gelation, tunable degradation, and versatile modulation of biophysical and biochemical properties. The versatility of these hydrogels is demonstrated through extensive applications, ranging from protein and drug delivery, [10][11][12][13][14][15][16][17] cartilage development, [18,19] osteogenic differentiation, [20,21] endothelial tubulogenesis, [22] brain tumor models, [23] synthetic matrix mimics, [8,[24][25][26][27][28][29][30][31][32] 2D culture substrates, [33][34][35] and islet and cell encapsulation. [36][37][38][39][40][41][42][43] However, these applications have been exclusively conducted in vitro, yielding little insight into the in vivo behavior of these hydrogels. Our initial exploratory studies with these widely used 4-arm, ester-linked, thiol-ene PEG (PEG-4eNB) hydrogels implanted into the intraperitoneal space of mice unexpectedly showed that the hydrogels undergo rapid degradation in vivo ( Figure S1, Supporting Information). Hypothesizing that the poor in vivo stability may result from the hydrolysis of the ester linkage between the PEG backbone and norbornene functional end group, we replaced this connection with a more hydrolytically stable amide linkage. Here, we describe the characterization and implementation of 4-arm, amide-linked, thiol-ene PEG (PEG-4aNB) hydrogels that retain long-term stability in both in vitro and in vivo environments. We demonstrate rapid (<24 h) in vivo degradation of PEG-4eNB and gradual (>35 days) in vitro degradation. Conversely, PEG-4aNB retains long-term in vitro and in vivo stability while maintaining high cytocompatibility, and this material can be utilized as an appropriate replacement in many biomedical applications.The ester linkage in PEG hydrogels has been reported to be hydrolytically labile over the course of many weeks in cell culture. [44] This feature has been exploited further by introducing ester-containing poly(caprolactone) linkage groups to accelerate in vitro degradation of PEG hydrogels to within a Thiol-norbornene (thiol-ene) photoclickable poly(ethylene glycol) (PEG) hydrogels are a versatile biomaterial for cell encapsulation, drug delivery, and regenerative medicine. Numerous in vitro studies with these 4-arm ester-linked PEG-norbornene (PEG-4eNB) hydrogels demonstrate robust cytocompatibility and ability to retain long-term integrity with nondegradable crosslinkers. However, when transplanted in vivo into the subcutaneous or intraperitoneal space, these PEG-4eNB hydrogels with nondegradable crosslinkers rapidly degrade within 24 h. This char...

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Nanoscale physicochemical properties of chain‐ and step‐growth polymerized PEG hydrogels affect cell‐material interactions

Cited by 25 publications

References 75 publications

Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery

Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery

A Hydrogel Platform that Incorporates Laminin Isoforms for Efficient Presentation of Growth Factors – Neural Growth and Osteogenesis

Linkage Groups within Thiol–Ene Photoclickable PEG Hydrogels Control In Vivo Stability

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