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Yan, Hongji
Publikasjoner (6 av 6) Visa alla publikasjoner
Yan, H., Casalini, T., Hulsart Billström, G., Wang, S., Oommen, O. P., Salvalaglio, M., . . . Varghese, O. P. (2018). Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation. Biomaterials, 161, 190-202
Åpne denne publikasjonen i ny fane eller vindu >>Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation
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2018 (engelsk)Inngår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 161, s. 190-202Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Synthetic scaffolds that possess an intrinsic capability to protect and sequester sensitive growth factors is a primary requisite for developing successful tissue engineering strategies. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) is highly susceptible to premature degradation and to provide a meaningful clinical outcome require high doses that can cause serious side effects. We discovered a unique strategy to stabilize and sequester rhBMP-2 by enhancing its molecular interactions with hyaluronic acid (HA), an extracellular matrix (ECM) component. We found that by tuning the initial protonation state of carboxylic acid residues of HA in a covalently crosslinked hydrogel modulate BMP-2 release at physiological pH by minimizing the electrostatic repulsion and maximizing the Van der Waals interactions. At neutral pH, BMP-2 release is primarily governed by Fickian diffusion, whereas at acidic pH both diffusion and electrostatic interactions between HA and BMP-2 become important as confirmed by molecular dynamics simulations. Our results were also validated in an in vivo rat ectopic model with rhBMP-2 loaded hydrogels, which demonstrated superior bone formation with acidic hydrogel as compared to the neutral counterpart. We believe this study provides new insight on growth factor stabilization and highlights the therapeutic potential of engineered matrices for rhBMP-2 delivery and may help to curtail the adverse side effects associated with the high dose of the growth factor.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-343820 (URN)10.1016/j.biomaterials.2018.01.041 (DOI)000427100300017 ()29421555 (PubMedID)
Forskningsfinansiär
Swedish Foundation for Strategic Research , 139400126, 139400127EU, FP7, Seventh Framework Programme, NMP3-LA-2011-262948
Merknad

De två första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2018-03-01 Laget: 2018-03-01 Sist oppdatert: 2018-05-16bibliografisk kontrollert
Zhao, Y., Yan, H., Qiao, S., Zhang, L., Wang, T., Meng, Q., . . . Tian, W. (2016). Hydrogels bearing bioengineered mimetic embryonic microenvironments for tumor reversion. Journal of materials chemistry. B, 4(37), 6183-6191
Åpne denne publikasjonen i ny fane eller vindu >>Hydrogels bearing bioengineered mimetic embryonic microenvironments for tumor reversion
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2016 (engelsk)Inngår i: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 4, nr 37, s. 6183-6191Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Embryonic microenvironments can reverse the metastatic phenotype of aggressive tumors by inhibiting the Nodal signaling pathway. Here, we hypothesize that embryonic microenvironments can be transplanted for the purpose of oncotherapy. We report the development of an injectable bioactive hydrogel system containing the key antagonists of Nodal signaling-Cripto-1 receptor antibodies (2B11)-for the creation of embryonic microenvironments and the examination of their effect on tumor reversion treatment using a mouse model. Our in vitro results show that the hydrogel system can reduce the mitochondrial membrane potential of MDA-MB-231 and MCF-7, promote cell apoptosis, and reduce the invasive ability of cells. Our in vivo results illustrate that the hydrogel system can significantly inhibit tumor growth in both breast cancer and melanoma tumor-bearing mouse models, as well as transform the cell morphology of melanoma B16 cells to melanin-like cells. Furthermore, the results of the up-regulation of tumor suppressor genes and the down-regulation of oncogenes by high-throughput sequencing confirm that the developed system can also selectively turn on some tumor suppressor genes and turn off certain oncogenes so as to prompt the benign reversion of the tumor phenotype. Taken together, our results demonstrate the injectable biomaterial system is able to create an effective microenvironment for melanoma and breast tumor therapy.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-305959 (URN)10.1039/c6tb00927a (DOI)000384444800003 ()
Tilgjengelig fra: 2016-10-31 Laget: 2016-10-24 Sist oppdatert: 2017-11-29
Yan, H. (2016). New insights into principles of scaffolds design for bone application. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Åpne denne publikasjonen i ny fane eller vindu >>New insights into principles of scaffolds design for bone application
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

This thesis presents deeper insights into bone applicable biomaterials’ design. Poor affinity of BMP-2 towards scaffolds required supra-physiological dose administration. Though molecules containing sulfate could sustain BMP-2 release, side effects occurred due to BMP-2 supra-dose, or these sulfate-containing biomolecules.

Improved affinity between BMP-2 and scaffolds was first witnessed by using an acidic carrier (paper I). Hyaluronic acid (HA) hydrazone derived hydrogels having a pH of 4.5-loaded BMP-2 showed sustained release of bioactive BMP-2 in vitro and enhanced bone formation in vivo, while pH 7 HA hydrogels showed Fickian behavior and less bone formation in vivo. Computational evaluation revealed stronger electrostatic interactions between BMP-2, and HA were predominant at pH 4.5, whereas, weaker Van der Waals interactions played a key role at pH 7.

During the pre-bone formation phase, endogenous cell responses to pH 4.5 and 7 with or without BMP-2 were investigated. HA hydrogels exhibited extraordinary biocompatibility and recruitment of neutrophils, monocytes, macrophages and stromal cells regardless of hydrogels’ pH and BMP-2 presence.  The different inflammatory responses to HA hydrogels were observed (Appendix).

Thiol derivatives can cleave the disulfide bond of BMP-2 to generate inactive monomeric BMP-2. In paper II, thiol-acrylate chemistry-based HA hydrogels (HA-SH) were compared to hydrazone-based HA hydrogels as BMP-2 carriers. Thiol modified HA disrupted BMP-2 integrity and bioactivity. HA-SH hydrogels with BMP-2 exhibited less bioactive BMP-2 release in vitro and induced less bone formation in vivo.

Accumulated evidence has shown great osteogenic potential of lithium ions (Li). In paper III, we coordinated Li onto HA-PVA hydrazone hydrogels (Li-gel); Li-gel enhanced 3D cultured hMSCs osteogenic differentiation and induced higher bone formation in CAM defect model.

Instead of BMP-2 protein, delivery of BMP-2-coding-plasmid can produce BMP-2 over a long term at a closer physiological level. Yet, efficient gene delivery reagents are needed. In paper IV, two novel gene delivery nanoplexes were developed by post coating DNA-nanoplexes with chondroitin sulfate (CS). To ensure the stability, aldehyde-modified CS (CS-CHO) reacted with free amines of pDNA/PEI complexes. We provided first evidence that CS-CHO coated nanoplexes controlled the release from endosomes, which is essential for higher transfection efficiency.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 87
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1459
Emneord
Chondroitin sulfate, hyaluronic acid, pH, cross-linking chemistry, bone morphogenetic protein, lithium, mesenchymal stem cell, in vivo.
HSV kategori
Forskningsprogram
Teknisk fysik med inriktning mot nanoteknologi och funktionella material
Identifikatorer
urn:nbn:se:uu:diva-308318 (URN)978-91-554-9767-5 (ISBN)
Disputas
2017-01-17, Room 80121, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-12-20 Laget: 2016-11-24 Sist oppdatert: 2016-12-20
Yan, H., Podiyan, O., Yu, D., Hilborn, J., Qian, H. & Varghese, O. P. (2015). Chondroitin Sulfate-Coated DNA-Nanoplexes Enhance Transfection Efficiency by Controlling Plasmid Release from Endosomes: A New Insight into Modulating Nonviral Gene Transfection. Advanced Functional Materials, 25(25), 3907-3915
Åpne denne publikasjonen i ny fane eller vindu >>Chondroitin Sulfate-Coated DNA-Nanoplexes Enhance Transfection Efficiency by Controlling Plasmid Release from Endosomes: A New Insight into Modulating Nonviral Gene Transfection
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2015 (engelsk)Inngår i: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 25, nr 25, s. 3907-3915Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Degradation of plasmid DNA (pDNA) in the endosome compartment and its release to the cytosol are the major hurdles for efficient gene transfection. This is generally addressed by using transfection reagents that can overcome these limitations. In this article, the first report is presented which suggests that controlling the release of pDNA from endosome is the key for achieving efficient transfection. In this study, chondroitin sulfate (CS)-coated DNA-nanoplexes are developed using a modular approach where CS is coated post-pDNA/PEI nanoplex formation. To ensure good stability of the nanoplexes, imine/enamine chemistry is exploited by reacting aldehyde-modified chondroitin sulfate (CS-CHO) with free amines of pDNA/PEI complex. This supramolecular nanocarrier system displays efficient cellular uptake, and controlled endosomal pDNA release without eliciting any cytotoxicity. On the contrary, burst release of pDNA from endosome (using chloroqine) results in significant reduction in gene expression. Unlike pDNA/PEI-based transfection, the nanoparticle design presented here shows exceptional stability and gene transfection efficiency in different cell lines such as human colorectal cancer cells (HCT116), human embryonic kidney cells (HEK293), and mouse skin-derived mesenchymal stem cells (MSCs) using luciferase protein as a reporter gene. This new insight will be valuable in designing next generation of transfection reagents.

Emneord
chondroitin sulfate, endosomal escape, gene delivery, mesenchymal stem cells, nanoparticles
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-259095 (URN)10.1002/adfm.201500695 (DOI)000357268900013 ()
Forskningsfinansiär
EU, FP7, Seventh Framework Programme
Tilgjengelig fra: 2015-07-28 Laget: 2015-07-27 Sist oppdatert: 2017-12-04bibliografisk kontrollert
Wang, S., Oommen, O. P., Yan, H. & Varghese, O. P. (2013). Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor. Biomacromolecules, 14(7), 2427-2432
Åpne denne publikasjonen i ny fane eller vindu >>Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor
2013 (engelsk)Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, nr 7, s. 2427-2432Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aldehydes have been used as an important bioorthogonal chemical reporter for conjugation of large polymers and bioactive substances. However, generating aldehyde functionality on carbohydrate-based biopolymers without changing its native chemical structure has always persisted as a challenging task. The common methods employed to achieve this require harsh reaction conditions, which often compromise the structural integrity and biological function of these sensitive molecules. Here we report a mild and simple method to graft aldehydes groups on glycosaminoglycans (GAGs) in a site-selective manner without compromising the structural integrity of the biopolymer. This regio-selective modification was achieved by conjugating the amino-glycerol moiety on the carboxylate residue of the polymer, which allowed selective cleavage of pendent diol groups without interfering with the C2C3 diol groups of the native glucopyranose residue. Kinetic evaluation of this reaction demonstrated significant differences in second-order reaction rate for periodate oxidation (by four-orders of magnitude) between the two types of vicinal diols. We employed this chemistry to develop aldehyde modifications of sulfated and nonsulfated GAGs such as hyaluronic acid (HA), heparin (HP), and chondroitin sulfate (CS). We further utilized these aldehyde grafted GAGs to tailor extracellular matrix mimetic injectable hydrogels and evaluated its rheological properties. The composition of the hydrogels was also found to modulate release of therapeutic protein such as FGF-2, demonstrating controlled release (60%) for over 14 days. In short, our result clearly demonstrates a versatile strategy to graft aldehyde groups on sensitive biopolymers under mild conditions that could be applied for various bioconjugation and biomedical applications such as drug delivery and regenerative medicine.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-204978 (URN)10.1021/bm400612h (DOI)000321793700035 ()
Merknad

De två (2) första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2013-08-16 Laget: 2013-08-13 Sist oppdatert: 2017-12-06bibliografisk kontrollert
Paidikondala, M., Wang, S., Yan, H., Podiyan, O., Hilborn, J., Larsson, S. & Varghese, O. P.Rational Design of Biomaterials for Growth Factor Delivery: Impact of Hydrogel Crosslinking Chemistry on the In Vitroand In VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2.
Åpne denne publikasjonen i ny fane eller vindu >>Rational Design of Biomaterials for Growth Factor Delivery: Impact of Hydrogel Crosslinking Chemistry on the In Vitroand In VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-369656 (URN)
Tilgjengelig fra: 2018-12-14 Laget: 2018-12-14 Sist oppdatert: 2018-12-15
Organisasjoner