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Bermejo, Daniel
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Bermejo-Velasco, D., Kadekar, S., Tavares da Costa, M. V., Oommen, O. P., Gamstedt, E. K., Hilborn, J. & Varghese, O. P. (2019). First Aldol Cross-Linked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Hydrogel with Tissue Adhesive Properties. ACS Applied Materials and Interfaces, 11(41), 38232-38239
Öppna denna publikation i ny flik eller fönster >>First Aldol Cross-Linked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Hydrogel with Tissue Adhesive Properties
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2019 (Engelska)Ingår i: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, nr 41, s. 38232-38239Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Currently, there are limited approaches to tailor 3D scaffolds cross-linked with a stable covalent C-C bond that does not require any catalysts or initiators. We present here the first hydrogels employing aldol condensation chemistry that exhibit exceptional physicochemical properties. We investigated the aldol-cross-linking chemistry using two types of aldehyde-modified hyaluronic acid (HA) derivatives, namely, an enolizable HA-aldehyde (HA-EaI) and a non-enolizable HA-aldehyde (HA-NaI). Hydrogels formed using HA-EaI demonstrate inferior cross linking efficiency (due to intramolecular loop formation), when compared with hydrogels formed by mixing HA-EaI and HA-NaI leading to a cross-aldol product. The change in mechanical properties as a result of cross-linking at different pH values is determined using rheological measurements and is interpreted in terms of molecular weight between cross-links (Me). The novel HA cross-aldol hydrogel demonstrate excellent hydrolytic stability and favorable mechanical properties but allow hyaluronidase-mediated enzymatic degradation. Interestingly, residual aldehyde functionality within the aldol product rendered the tissue adhesive properties by bonding two bone tissues. The aldehyde functionality also facilitated facile post-synthetic modifications with nucleophilic reagents. Finally, we demonstrate that the novel hydrogel is biocompatible with encapsulated stem cells that show a linear rate of expansion in our 3-6 days of study.

Nyckelord
hyaluronic acid, hydrogel, aldol chemistry, tissue adhesive, biomaterial
Nationell ämneskategori
Polymerkemi Materialkemi
Identifikatorer
urn:nbn:se:uu:diva-397131 (URN)10.1021/acsami.9b10239 (DOI)000491219700090 ()31550878 (PubMedID)
Forskningsfinansiär
EU, FP7, Sjunde ramprogrammet, FP7/2007-2013/607868EU, FP7, Sjunde ramprogrammet, 607868Stiftelsen för strategisk forskning (SSF), SBE13-0028Stiftelsen för strategisk forskning (SSF), StemTherapy 2009-1035
Tillgänglig från: 2019-11-28 Skapad: 2019-11-28 Senast uppdaterad: 2019-11-28Bibliografiskt granskad
Bermejo-Velasco, D. (2019). Insights into Covalent Chemistry for the Developmen­t of Biomaterials. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Insights into Covalent Chemistry for the Developmen­t of Biomaterials
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Covalent cross-linking chemistry is currently exploited in the preparation of biomaterial for biomedical applications. Choice of these chemistries for the preparation of biomaterials and bioconjugates strongly influences the biological output of these materials. Therefore, this thesis aims to develop novel bioconjugation strategies understanding their advantages and drawbacks. Our results provide new insight to adapt these chemical transformations for a specific application.

The first part of this thesis points out the relevance of tuning different properties of biomaterials with specific emphasis on the development of hyaluronic acid (HA) hydrogels. The second part of the thesis describes how different chemical transformations including hydrazone formation (Paper I), thiazolidine formation (Paper II), cross-aldol addition reaction (Paper III) and disulfide formation (Paper IV) dictate material properties.

This thesis explores both basic organic reaction mechanism and application of these reactions to influence material characteristics. The detailed study of the reaction conditions, kinetics, and stability of the products will help to understand the mechanical properties, hydrolytic stability, and degradability of the materials described here.

Additionally, we performed degradation studies of gadolinium labeled HA hydrogels using magnetic resonance imaging. Furthermore, we also explored post-synthetic modification of hydrogels to link model fluorescent moieties as well as explored the tissue adhesive properties using Schiff-base formation.

In summary, this thesis presents a selection of different covalent chemistries for the design of advanced biomaterials. The advantages and disadvantages of these chemistries are rigorously investigated. We believe, such an investigation provides a better understanding of the bioconjugation strategies for the preparation of biomaterials with potential clinical translation.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 64
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1768
Nyckelord
hyaluronic acid, hydrogel, biomaterials, covalent chemistry, biomedical applications, MRI
Nationell ämneskategori
Materialkemi Polymerkemi Organisk kemi
Forskningsämne
Kemi med inriktning mot materialkemi; Kemi med inriktning mot polymerkemi
Identifikatorer
urn:nbn:se:uu:diva-375002 (URN)978-91-513-0564-6 (ISBN)
Disputation
2019-03-14, Häggsalen, 10132, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-02-21 Skapad: 2019-01-24 Senast uppdaterad: 2019-02-21
Bermejo-Velasco, D., Azémar, A., Oommen, O. P., Hilborn, J. & Varghese, O. P. (2019). Modulating thiol pKa promotes disulfide formation at physiological pH: An elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels. Biomacromolecules, 20(3), 1412-1420
Öppna denna publikation i ny flik eller fönster >>Modulating thiol pKa promotes disulfide formation at physiological pH: An elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels
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2019 (Engelska)Ingår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, nr 3, s. 1412-1420Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The disulfide bond plays a crucial role in protein biology and has been exploited by scientists to develop antibody-drug conjugates, sensors and for the immobilization other biomolecules to materials surfaces. In spite of its versatile use, the disulfide chemistry suffers from some inevitable limitations such as the need for basic conditions (pH > 8.5), strong oxidants and long reaction times. We demonstrate here that thiol-substrates containing electron-withdrawing groups at the β-position influence the deprotonation of the thiol group, which is the key reaction intermediate in the formation of disulfide bonds. Evaluation of reaction kinetics using small molecule substrate such as L-cysteine indicated disulfide formation at a 2.8-fold higher (k1 = 5.04 x 10-4 min-1) reaction rate as compared to the conventional thiol substrate, namely 3-mercaptopropionic acid (k1 = 1.80 x 10-4 min-1) at physiological pH (pH 7.4). Interestingly, the same effect could not be observed when N-acetyl-L-cysteine substrate (k1 = 0.51 x 10-4 min-1) was used. We further grafted such thiol-containing molecules (cysteine, N-acetyl-cysteine, and 3-mercaptopropionic acid) to a biopolymer namely hyaluronic acid (HA) and determined the pKa value of different thiol groups by spectrophotometric analysis. The electron-withdrawing group at the β-position reduced the pKa of the thiol group to 7.0 for HA-cysteine (HA-Cys); 7.4 for N-acetyl cysteine (HA-ActCys) and 8.1 for HA-thiol (HA-SH) derivatives respectively. These experiments further confirmed that the concentration of thiolate (R-S-) ions could be increased with the presence of electron-withdrawing groups, which could facilitate disulfide cross-linked hydrogel formation at physiological pH. Indeed, HA grafted with cysteine or N-acetyl groups formed hydrogels within 3.5 minutes or 10 hours, respectively at pH 7.4. After completion of crosslinking reaction both gels demonstrated a storage modulus G’ ≈3300–3500 Pa, indicating comparable levels of crosslinking. The HA-SH gel, on the other hand, did not form any gel at pH 7.4 even after 24 h. Finally, we demonstrated that the newly prepared hydrogels exhibited excellent hydrolytic stability but can be degraded by cell-directed processes (enzymatic and reductive degradation). We believe our study provides a valuable insight on the factors governing the disulfide formation and our results are useful to develop strategies that would facilitate generation of stable thiol functionalized biomolecules or promote fast thiol oxidation according to the biomedical needs.

Nationell ämneskategori
Materialkemi
Forskningsämne
Kemi med inriktning mot materialkemi
Identifikatorer
urn:nbn:se:uu:diva-375001 (URN)10.1021/acs.biomac.8b01830 (DOI)000461270500028 ()30726668 (PubMedID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), 139400127EU, FP7, Sjunde ramprogrammet, 607868Stiftelsen för strategisk forskning (SSF), 139400126
Tillgänglig från: 2019-01-24 Skapad: 2019-01-24 Senast uppdaterad: 2019-04-11Bibliografiskt granskad
Bermejo-Velasco, D., Dou, W., Heerschap, A., Ossipov, D. A. & Hilborn, J. (2018). Injectable hyaluronic acid hydrogels with the capacity for magnetic resonance imaging. Carbohydrate Polymers, 197, 641-648
Öppna denna publikation i ny flik eller fönster >>Injectable hyaluronic acid hydrogels with the capacity for magnetic resonance imaging
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2018 (Engelska)Ingår i: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 197, s. 641-648Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Monitoring hydrogel degradation in real time using noninvasive imaging techniques is of great interest for designing a scaffold in tissue engineering. We report the preparation of gadolinium (Gd)-labeled and injectable hyaluronic acid (HA) hydrogels that can be visualized using T-1- and T-2-weighted magnetic resonance imaging (MRI). An HA derivative functionalized with thiol and hydrazide was labeled using a diethylenetriaminepentaacetate complex modified with "clickable" dithiopyridyl functionalities (degree of modification was 3.77% with respect to HA repeat units). The HA derivative modified with cross-linkable groups and Gd complex exhibited relaxivities r(1) = 3.78 mM(-1)s(-1) and r(2) = 56.3 mM(-1)s(-1). A hydrazone hydrogel network was obtained by mixing Gd-labeled HA-hydrazide and HA-aldehyde derivatives. Enzymatic hydrogel degradation could be followed using MRI because the MR images showed great correlation with the hydrogel mass loss. Ex vivo MRI of injected Gd-labeled hydrogels demonstrated that they show a significant contrast difference (SNRcoronal = 456; SNRaxial = 459) from the surrounding tissues. These results indicate that our Gd-labeled HA hydrogel has great potential as an injectable biocompatible hydrogel that can be used for longitudinal tracking in vivo using MRI.

Ort, förlag, år, upplaga, sidor
ELSEVIER SCI LTD, 2018
Nyckelord
Gadolinium complex, Hyaluronic acid, Injectable hydrogels, Magnetic resonance imaging, Biodegradation
Nationell ämneskategori
Polymerkemi
Identifikatorer
urn:nbn:se:uu:diva-361020 (URN)10.1016/j.carbpol.2018.06.028 (DOI)000438466500070 ()30007657 (PubMedID)
Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2019-01-24
Bermejo-Velasco, D., Nawale, G. N., Oommen, O. P., Hilborn, J. & Varghese, O. P. (2018). Thiazolidine chemistry revisited: a fast, efficient and stable click-type reaction at physiological pH. Chemical Communications, 54(88), 12507-12510
Öppna denna publikation i ny flik eller fönster >>Thiazolidine chemistry revisited: a fast, efficient and stable click-type reaction at physiological pH
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2018 (Engelska)Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, nr 88, s. 12507-12510Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We describe the fast reaction kinetics between 1,2-aminothiols and aldehydes. Under physiological conditions such a click-type reaction afforded a thiazolidine product that remains stable and did not require any catalyst. This type of bioorthogonal reaction offers enormous potential for the coupling of biomolecules in an efficient and biocompatible manner.

Nationell ämneskategori
Polymerkemi
Identifikatorer
urn:nbn:se:uu:diva-364896 (URN)10.1039/c8cc05405c (DOI)000448947000019 ()30345438 (PubMedID)
Tillgänglig från: 2018-11-06 Skapad: 2018-11-06 Senast uppdaterad: 2019-06-26Bibliografiskt granskad
Sjögren, F., Bermejo, D., Sehlstedt, V., Hilborn, J., Ossipov, D. & Tenje, M. (2015). Micropatterning of photocrosslinkable hyaluronic acid. In: 26th Micromechanics and Microsystems Europe workshop (MME 2015), Toledo, Spain, September 20-23 2015: . Paper presented at 26th Micromechanics and Microsystems Europe workshop (MME 2015), Toledo, Spain, September 20-23 2015.
Öppna denna publikation i ny flik eller fönster >>Micropatterning of photocrosslinkable hyaluronic acid
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2015 (Engelska)Ingår i: 26th Micromechanics and Microsystems Europe workshop (MME 2015), Toledo, Spain, September 20-23 2015, 2015Konferensbidrag, Poster (med eller utan abstract) (Refereegranskat)
Nationell ämneskategori
Annan teknik
Forskningsämne
Teknisk fysik med inriktning mot mikrosystemteknik
Identifikatorer
urn:nbn:se:uu:diva-264345 (URN)
Konferens
26th Micromechanics and Microsystems Europe workshop (MME 2015), Toledo, Spain, September 20-23 2015
Forskningsfinansiär
Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning
Tillgänglig från: 2015-10-09 Skapad: 2015-10-09 Senast uppdaterad: 2015-11-27Bibliografiskt granskad
Bermejo, D., Kadekar, S., Tavares da Costa, M. V., Podiyan, O., Gamstedt, E. K., Hilborn, J. & Varghese, O. P. First Aldol-Crosslinked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Gel with Tissue Adhesive Properties. Chemical Sciences Journal
Öppna denna publikation i ny flik eller fönster >>First Aldol-Crosslinked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Gel with Tissue Adhesive Properties
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(Engelska)Ingår i: Chemical Sciences Journal, ISSN 2150-3494Artikel i tidskrift (Refereegranskat) Submitted
Abstract [en]

Currently, there are limited approaches to tailor 3D scaffolds crosslinked with a stable covalent C-C bond that does not require any catalysts or initiators. We present here the first hydrogels employing aldol condensation chemistry that exhibit exceptional physicochemical properties. We investigated the aldol-crosslinking chemistry using two types of aldehyde-modified hyaluronic acid (HA) derivatives, namely; an enolizable HA-aldehyde (HA-Eal) and a non-enolizable HA-aldehyde (HA-Nal). Hydrogels formed using HA-Eal demonstrate inferior crosslinking efficiency (due to intramolecular loop formation), when compared with hydrogels formed by mixing HA-Eal and HA-NaI leading to a cross-aldol product. The change in mechanical properties as a result of crosslinking at different pH is determined using rheological measurements and is interpreted in terms of molecular weight between cross-links (Mc). The novel HA cross-aldol hydrogels demonstrate excellent hydrolytic stability and favorable mechanical properties but allow hyaluronidase mediated enzymatic degradation. Interestingly, residual aldehyde functionality within the aldol product leads to adhesion to tissue as demonstrated by bonding two bone tissues. The aldehyde functionality also permits facile post-synthetic modifications with nucleophilic reagents such as Alexa FluorTM 488. Finally, we demonstrate that the novel hydrogel is biocompatible with encapsulated stem cells that show a linear rate of expansion in our 3–6 days of study.

Nyckelord
hyaluronic acid, aldol chemisty, stable hydrogels, tissue adhesive
Nationell ämneskategori
Materialkemi
Forskningsämne
Kemi med inriktning mot materialkemi
Identifikatorer
urn:nbn:se:uu:diva-374999 (URN)
Tillgänglig från: 2019-01-24 Skapad: 2019-01-24 Senast uppdaterad: 2019-01-24
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