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Han, Y., Li, H., Jafri, S. H., Ossipov, D. A., Hilborn, J. & LEIFER, K. (2019). Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization.
Open this publication in new window or tab >>Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization
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2019 (English)In: Article in journal, News item (Other academic) Submitted
Abstract [en]

Herein we demonstrate a novel methodology to achieve mechanical biosensor by employing the distinguished interaction forces between the atomic force microscope (AFM) probe and sensor surfaces as the response signal. This mechanical biosensor is fabricated by utilizing the non-covalent π-π stacking of pyrene-maltose onto graphene surfaces with Concanavalin A (Con A) as a target protein. The atomic resolution scanning tunneling microscopy (STM) images indicate the successful formation of the self-assembled and densely packed pyrene-maltose layer on the sensor surface, which gives distinct atomic lattice structure as compared to pristine graphene. This mechanical biosensor exhibits detection of Con A with the sensitivity down to nanomolar level. Therefore, this proposed mechanical biosensor has the potential to be employed in a variety of bio-sensing applications.

National Category
Nano Technology Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-378559 (URN)
Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-04-24
Paidikondala, M., Wang, S., Hilborn, J., Larsson, S. & Varghese, O. P. (2019). Impact of Hydrogel Cross-Linking Chemistry on the in Vitro and in VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2. ACS Applied Bio Materials
Open this publication in new window or tab >>Impact of Hydrogel Cross-Linking Chemistry on the in Vitro and in VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2
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2019 (English)In: ACS Applied Bio Materials, ISSN 2576-6422Article in journal, Editorial material (Refereed) Published
Abstract [en]

Designing strategies to deliver functional proteins at physiologically relevant concentrations using chemically cross-linked biocompatible hydrogels is a major field of research. However, the impact of cross-linking chemistry on the encapsulated protein bioactivity is rarely studied. Here we examine the two well-known cross-linking reactions namely; hydrazone cross-linking chemistry and thiol-Michael addition reaction to form hyaluronic acid (HA) hydrogels. As a therapeutic protein, we employed recombinant human bone morphogenetic protein-2 (rhBMP-2) for this study. Incubation of rhBMP-2 with HA functionalized with a thiol diminished phosphorylation of Smad 1/5/8, a signal transducer for osteogenic differntiation, whereas an aldehyde functionalized HA had no effect. This indicates that thiol functionalized polymers indeed has an impact on protein function. To validate this result in an in vivo setting we performed BMP-2 induced bone formation in a rat ectopic model. These experiments revealed that the hydrazone-cross-linked HA-hydrogel induced significantly higher bone formation (18.90 ± 4.25 mm3) as compared to the HA-thiol-Michael hydrogels (1.25 ± 0.52 mm3) after 8 weeks as determined by micro-computed tomography. The histological examination of the neo-bone indicated that hydrazone-hydrogels promoted a better quality of bone formation with improved mineralization and collagen formation as compared to the thiol-Michael hydrogels. We believe such a direct comparison of two cross-linking chemistries will provide new insight for developing biomaterials for protein delivery for in vivo applications.

Keywords
bone tissue engineering; cross-linking chemistry; drug delivery; hyaluronic acid; regenerative medicine
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-382321 (URN)10.1021/acsabm.9b00060 (DOI)
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-04-24
Han, Y., Qiu, Z., Nawale, G. N., Varghese, O. P., Hilborn, J., Tian, B. & Leifer, K. (2019). MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification. Biosensors & bioelectronics, 127, 188-193
Open this publication in new window or tab >>MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification
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2019 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 127, p. 188-193Article in journal (Refereed) Published
Abstract [en]

DNA technology based bio-responsive nanomaterials have been widely studied as promising tools for biomedical applications. Gold nanoparticles (AuNPs) and graphene oxide (GO) sheets are representative zero- and two-dimensional nanomaterials that have long been combined with DNA technology for point-of-care diagnostics. Herein, a cascade amplification system based on duplex-specific nuclease (DSN)-assisted target recycling and electrocatalytic water-splitting is demonstrated for the detection of microRNA. Target microRNAs can form DNA: RNA heteroduplexes with DNA probes on the surface of AuNPs, which can be hydrolyzed by DSN. MicroRNAs are preserved during the reaction and released into the suspension for the digestion of multiple DNA probes. After the DSN-based reaction, AuNPs are collected and mixed with GO to form AuNP/GO nanocomposite on an electrode for the following electrocatalytic amplification. The utilization of AuNP/GO nanocomposite offers large surface area, exceptional affinity to water molecules, and facilitated mass diffusion for the water-splitting reaction. For let-7b detection, the proposed biosensor achieved a limit detection of 1.5 fM in 80 min with a linear detection range of approximately four orders of magnitude. Moreover, it has the capability of discriminating non-target microRNAs containing even single-nucleotide mismatches, thus holding considerable potential for clinical diagnostics.

Keywords
Gold nanoparticles, Graphene oxide, MicroRNA detection, Electrocatalytic amplification, Duplex-specific nuclease
National Category
Analytical Chemistry Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-377203 (URN)10.1016/j.bios.2018.12.027 (DOI)000457508800026 ()30611105 (PubMedID)
Funder
Swedish Research Council, 2016-05259Knut and Alice Wallenberg FoundationEU, Horizon 2020, 713683
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-04-24Bibliographically approved
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
Open this publication in new window or tab >>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 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 3, p. 1412-1420Article in journal (Refereed) 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.

National Category
Materials Chemistry
Research subject
Chemistry with specialization in Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-375001 (URN)10.1021/acs.biomac.8b01830 (DOI)000461270500028 ()30726668 (PubMedID)
Funder
Swedish Foundation for Strategic Research , 139400127EU, FP7, Seventh Framework Programme, 607868Swedish Foundation for Strategic Research , 139400126
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-04-11Bibliographically approved
Shi, L., Ding, P., Wang, Y., Zhang, Y., Ossipov, D. & Hilborn, J. (2019). Self-Healing Polymeric Hydrogel Formed by Metal-Ligand Coordination Assembly: Design, Fabrication, and Biomedical Applications. Macromolecular rapid communications, 40(7), Article ID 1800837.
Open this publication in new window or tab >>Self-Healing Polymeric Hydrogel Formed by Metal-Ligand Coordination Assembly: Design, Fabrication, and Biomedical Applications
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2019 (English)In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 40, no 7, article id 1800837Article in journal (Refereed) Published
Abstract [en]

Self-healing hydrogels based on metal-ligand coordination chemistry provide new and exciting properties that improve injectability, rheological behaviors, and even biological functionalities. The inherent reversibility of coordination bonds improves on the covalent cross-linking employed previously, allowing for the preparation of completely self-healing hydrogels. In this article, recent advances in the development of this class of hydrogels are summarized and their applications in biology and medicine are discussed. Various chelating ligands such as bisphosphonate, catechol, histidine, thiolate, carboxylate, pyridines (including bipyridine and terpyridine), and iminodiacetate conjugated onto polymeric backbones, as well as the chelated metal ions and metal ions containing inorganic particles, which are used to form dynamic networks, are highlighted. This article provides general ideas and methods for the design of self-healing hydrogel biomaterials based on coordination chemistry.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2019
Keywords
biomaterials, coordination chemistry, hydrogels, self-healing materials
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-385569 (URN)10.1002/marc.201800837 (DOI)000467997700006 ()30672628 (PubMedID)
Funder
Swedish Research Council, 2017-04651
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved
Cantoni, F., Hilborn, J., Johansson, S., Pohlit, H., Porras, A. M., Samanta, A. & Tenje, M. (2018). 2D and 3D patterning of biological hydrogels for organ-on-chip applications. In: : . Paper presented at 44th International Conference on Micro and Nano Engineering (MNE 2018), Copenhagen, Denmark, September 24-27 2018..
Open this publication in new window or tab >>2D and 3D patterning of biological hydrogels for organ-on-chip applications
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2018 (English)Conference paper, Oral presentation with published abstract (Other academic)
Keywords
Organs-on-chip, Hydrogels, UV lithography, Microfluidics, TEER
National Category
Engineering and Technology Other Medical Engineering
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-369364 (URN)
Conference
44th International Conference on Micro and Nano Engineering (MNE 2018), Copenhagen, Denmark, September 24-27 2018.
Funder
Knut and Alice Wallenberg Foundation, WAF 2016-0112EU, European Research Council
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2018-12-13Bibliographically approved
Trbakovic, A., Hedenqvist, P., Mellgren, T., Ley, C., Hilborn, J., Ossipov, D. A., . . . Thor, A. (2018). A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model. Journal of Dentistry, 70, 31-39
Open this publication in new window or tab >>A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model
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2018 (English)In: Journal of Dentistry, ISSN 0300-5712, E-ISSN 1879-176X, Vol. 70, p. 31-39Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The aim of this study was to investigate if a synthetic granular calcium phosphate compound (CPC) and a composite bisphosphonate-linked hyaluronic acid-calcium phosphate hydrogel (HABP·CaP) induced similar or more amount of bone as bovine mineral in a modified sinus lift rabbit model.

MATERIAL AND METHODS: Eighteen adult male New Zeeland White rabbits, received randomly one of the two test materials on a random side of the face, and bovine mineral as control on the contralateral side. In a sinus lift, the sinus mucosa was elevated and a titanium mini-implant was placed in the alveolar bone. Augmentation material (CPC, HABP·CaP or bovine bone) was applied in the space around the implant. The rabbits were euthanized three months after surgery and qualitative and histomorphometric evaluation were conducted. Histomorphometric evaluation included three different regions of interest (ROIs) and the bone to implant contact on each installed implant.

RESULTS: Qualitative assessment (p = <.05), histomorphometric evaluations (p = < .01), and implant incorporation (p = <.05) showed that CPC and bovine mineral induced similar amount of bone and more than the HABP·CaP hydrogel.

CONCLUSION: CPC induced similar amount of bone as bovine mineral and both materials induced more bone than HABP·CaP hydrogel.

CLINICAL SIGNIFICANCE: The CPC is suggested as a synthetic alternative for augmentations in the maxillofacial area.

Keywords
Animal experiments, Bone implant interactions, Bone regeneration, Bone substitutes, Ceramic granules
National Category
Dentistry
Identifiers
urn:nbn:se:uu:diva-341457 (URN)10.1016/j.jdent.2017.12.009 (DOI)000425888900004 ()29258851 (PubMedID)
Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-10-28Bibliographically approved
Ajalloueian, F., Lemon, G., Hilborn, J., Chronakis, I. S. & Fossum, M. (2018). Bladder biomechanics and the use of scaffolds for regenerative medicine in the urinary bladder. Nature reviews. Urology, 15(3), 155-174
Open this publication in new window or tab >>Bladder biomechanics and the use of scaffolds for regenerative medicine in the urinary bladder
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2018 (English)In: Nature reviews. Urology, ISSN 1759-4812, E-ISSN 1759-4820, Vol. 15, no 3, p. 155-174Article, review/survey (Refereed) Published
Abstract [en]

The urinary bladder is a complex organ with the primary functions of storing urine under low and stable pressure and micturition. Many clinical conditions can cause poor bladder compliance, reduced capacity, and incontinence, requiring bladder augmentation or use of regenerative techniques and scaffolds. To replicate an organ that is under frequent mechanical loading and unloading, special attention towards fulfilling its biomechanical requirements is necessary. Several biological and synthetic scaffolds are available, with various characteristics that qualify them for use in bladder regeneration in vitro and in vivo, including in the treatment of clinical conditions. The biomechanical properties of the native bladder can be investigated using a range of mechanical tests for standardized assessments, as well as mathematical and computational bladder biomechanics. Despite a large body of research into tissue engineering of the bladder wall, some features of the native bladder and the scaffolds used to mimic it need further elucidation. Collection of comparable reference data from different animal models would be a helpful tool for researchers and will enable comparison of different scaffolds in order to optimize characteristics before entering preclinical and clinical trials.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-351589 (URN)10.1038/nrurol.2018.5 (DOI)000426368800016 ()29434369 (PubMedID)
Funder
Stockholm County CouncilSwedish Society of MedicineDanish National Research Foundation, DFF-4093-00282ADanish National Research Foundation, 4217-00048A
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Shi, L., Yannan, Z., Qifan, X., Caixia, F., Hilborn, J., Jianwu, D. & Ossipov, D. A. (2018). Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal–Bisphosphonate Coordination Chemistry for Wound Healing. Advanced Healthcare Materials, 7(5), Article ID 1700973.
Open this publication in new window or tab >>Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal–Bisphosphonate Coordination Chemistry for Wound Healing
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2018 (English)In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 7, no 5, article id 1700973Article in journal (Refereed) Published
Abstract [en]

Biomaterial-based regenerative approaches would allow for cost-effective off-the-shelf solution for the treatment of wounds. Hyaluronan (HA)-based hydrogel is one attractive biomaterial candidate because it is involved in natural healing processes, including inflammation, granulation, and reepi-thelialization. Herein, dynamic metal–ligand coordination bonds are used to fabricate moldable supramolecular HA hydrogels with self-healing properties. To achieve reversible crosslinking of HA chains, the biopolymer is modified with pendant bisphosphonate (BP) ligands using carbodiimide coupling and chemoselective “click” reactions. Hydrogel is formed immediately after simple addition of silver (Ag+) ions to the solution of HA containing BP groups (HA-BP). Compared with previous HA-based wound healing hydrogels, the HA-BP·Ag+ hydrogel is highly suitable for clinical use as it can fill irregularly shaped wound defects without the need for premolding. The HA-BP·Ag+ hydrogel shows antimicrobial properties to both Gram-positive and Gram-negative bacterial strains, enabling prevention of infections in wound care. In vivo evaluation using a rat full-thickness skin wound model shows sig-nificantly lower wound remaining rate and a thicker layer of regenerated epidermis as compared with the group left without treatment. The presented moldable and self-healing supramolecular HA hydrogel with “ready-to-use” properties possesses a great potential for regenerative wound treatment.

Keywords
antibacterial, bisphosphonate, hyaluronan, moldable, wound healing
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-338080 (URN)10.1002/adhm.201700973 (DOI)000426758500016 ()
Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-06-27Bibliographically approved
Pupkaite, J., Griffith, M., Hilborn, J., Suuronen, E. & Samanta, A. (2018). Non-toxic chemically crosslinked collagen hydrogels for cell delivery. In: Journal of Molecular and Cellular Cardiology: . Paper presented at Journal of Molecular and Cellular Cardiology.
Open this publication in new window or tab >>Non-toxic chemically crosslinked collagen hydrogels for cell delivery
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2018 (English)In: Journal of Molecular and Cellular Cardiology, 2018Conference paper, Published paper (Refereed)
Series
Journal of Molecular and Cellular Cardiology, ISSN 0022-2828 ; 124
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-374199 (URN)10.1016/j.yjmcc.2018.07.066 (DOI)
Conference
Journal of Molecular and Cellular Cardiology
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-01-18
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6947-9601

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