Biomedical Hydrogels Fabricated Using Diels–Alder Crosslinking

Cadamuro, Francesca; Russo, Laura; Nicotra, Francesco

doi:10.1002/ejoc.202001042

Cited by 27 publications

(23 citation statements)

References 56 publications

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“…Common diene-dienophile pairs used in biomaterials are maleimide-furan and tetrazine-norbornene for normal and inverse electron-demand Diels-Alder reactions (IEDDA), respectively. For a more in-depth review of these reactions and applications in biomaterials, see [ 196 , 197 ].…”

Section: Bioorthogonal ‘Click’ Chemistry and Neural Biomaterials Appl...mentioning

confidence: 99%

Clickable Biomaterials for Modulating Neuroinflammation

Cornelison

Fadel

2022

IJMS

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Crosstalk between the nervous and immune systems in the context of trauma or disease can lead to a state of neuroinflammation or excessive recruitment and activation of peripheral and central immune cells. Neuroinflammation is an underlying and contributing factor to myriad neuropathologies including neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease; autoimmune diseases like multiple sclerosis; peripheral and central nervous system infections; and ischemic and traumatic neural injuries. Therapeutic modulation of immune cell function is an emerging strategy to quell neuroinflammation and promote tissue homeostasis and/or repair. One such branch of ‘immunomodulation’ leverages the versatility of biomaterials to regulate immune cell phenotypes through direct cell-material interactions or targeted release of therapeutic payloads. In this regard, a growing trend in biomaterial science is the functionalization of materials using chemistries that do not interfere with biological processes, so-called ‘click’ or bioorthogonal reactions. Bioorthogonal chemistries such as Michael-type additions, thiol-ene reactions, and Diels-Alder reactions are highly specific and can be used in the presence of live cells for material crosslinking, decoration, protein or cell targeting, and spatiotemporal modification. Hence, click-based biomaterials can be highly bioactive and instruct a variety of cellular functions, even within the context of neuroinflammation. This manuscript will review recent advances in the application of click-based biomaterials for treating neuroinflammation and promoting neural tissue repair.

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Section: Bioorthogonal ‘Click’ Chemistry and Neural Biomaterials Appl...mentioning

confidence: 99%

Clickable Biomaterials for Modulating Neuroinflammation

Cornelison

Fadel

2022

IJMS

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“…A major advantage of DA chemical crosslinking is that it occurs under physiological conditions avoiding the use of potentially toxic catalysts and initiators, commonly used in many existing crosslinking strategies for controlled-release hydrogel delivery systems. 46 , 47 However, maleimide functional groups present in the furan-maleimide DA crosslinks can potentially react with SH and NH 2 groups of the loaded protein, 48 creating protein conjugates. Despite this limitation, the unique properties and advantages of DA chemistry have been gaining increasing recognition, especially when applied in biomedical applications.…”

Section: Introductionmentioning

confidence: 99%

“…Despite this limitation, the unique properties and advantages of DA chemistry have been gaining increasing recognition, especially when applied in biomedical applications. 46 Although some DA-based hydrogels for ocular drug delivery have been previously studied as long-acting sustained delivery systems for bevacizumab 31 , 32 with release profiles up to 100 days, there is limited information available on the influence of hydrogel composition on material’s physicochemical and structural properties and how that relates to the release profiles of therapeutic proteins.…”

Section: Introductionmentioning

confidence: 99%

Hyaluronic Acid-PEG-Based Diels–AlderIn SituForming Hydrogels for Sustained Intraocular Delivery of Bevacizumab

et al. 2022

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Retinal diseases are the leading cause of visual impairment worldwide. The effectiveness of antibodies for the treatment of retinal diseases has been demonstrated. Despite the clinical success, achieving sufficiently high concentrations of these protein therapeutics at the target tissue for an extended period is challenging. Patients suffering from macular degeneration often receive injections once per month. Therefore, there is a growing need for suitable systems that can help reduce the number of injections and adverse effects while improving patient complacency. This study systematically characterized degradable “ in situ ” forming hydrogels that can be easily injected into the vitreous cavity using a small needle (29G). After intravitreal injection, the formulation is designed to undergo a sol–gel phase transition at the administration site to obtain an intraocular depot system for long-term sustained release of bioactives. A Diels–Alder reaction was exploited to crosslink hyaluronic acid-bearing furan groups (HAFU) with 4 arm-PEG10K-maleimide (4APM), yielding stable hydrogels. Here, a systematic investigation of the effects of polymer composition and the ratio between functional groups on the physicochemical properties of hydrogels was performed to select the most suitable formulation for protein delivery. Rheological analysis showed rapid hydrogel formation, with the fastest gel formation within 5 min after mixing the hydrogel precursors. In this study, the mechanical properties of an ex vivo intravitreally formed hydrogel were investigated and compared to the in vitro fabricated samples. Swelling and degradation studies showed that the hydrogels are biodegradable by the retro-Diels–Alder reaction under physiological conditions. The 4APM-HAFU (ratio 1:5) hydrogel formulation showed sustained release of bevacizumab > 400 days by a combination of diffusion, swelling, and degradation. A bioassay showed that the released bevacizumab remained bioactive. The hydrogel platform described in this study offers high potential for the sustained release of therapeutic antibodies to treat ocular diseases.

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“…For such purpose, several click reactions have been investigated, exploiting linkers of different length bearing functional groups complementary to those already present in polymers backbone or previously chemically introduced [14,[21][22][23][24]. Among the established approaches, Diels Alder reaction has already been widely used with a significant assortment of biopolymers to control cross-linking and conjugations between polymers displaying diene and dienophile moieties [25][26][27][28][29][30][31][32][33][34]. However, the reported studies are often focused on homopolymer formulations [32,[35][36][37].…”

Section: Introductionmentioning

confidence: 99%

“…However, the reported studies are often focused on homopolymer formulations [32,[35][36][37]. In our group, a hybrid hydrogel was developed employing gelatin and chitosan functionalized with methylfuran and then cross-linking them by Diels Alder reaction with 4-arm-PEG10K-maleimide [15,34]. The obtained hydrogel (GelChiDA) showed stability over time in cell culture conditions, in both 3D scaffolds and 3D-bioprinted cell-embedded formulations.…”

Section: Introductionmentioning

confidence: 99%

Combined Analytical Approaches to Standardize and Characterize Biomaterials Formulations: Application to Chitosan-Gelatin Cross-Linked Hydrogels

et al. 2021

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A protocol based on the combination of different analytical methodologies is proposed to standardize the experimental conditions for reproducible formulations of hybrid hydrogels. The final hybrid material, based on the combination of gelatin and chitosan functionalized with methylfuran and cross-linked with 4-arm-PEG-maleimide, is able to mimic role, dynamism, and structural complexity of the extracellular matrix. Physical–chemical properties of starting polymers and finals constructs were characterized exploiting the combination of HP-SEC-TDA, UV, FT-IR, NMR, and TGA.

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Biomedical Hydrogels Fabricated Using Diels–Alder Crosslinking

Abstract: Dedicated to Prof. Franco Cozzi for his 70th birthday.

Cited by 27 publications

References 56 publications

Clickable Biomaterials for Modulating Neuroinflammation

Clickable Biomaterials for Modulating Neuroinflammation

Hyaluronic Acid-PEG-Based Diels–AlderIn SituForming Hydrogels for Sustained Intraocular Delivery of Bevacizumab

Combined Analytical Approaches to Standardize and Characterize Biomaterials Formulations: Application to Chitosan-Gelatin Cross-Linked Hydrogels

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