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The synthesis of dendritic hydrogels and inorganic nanoparticles and their application as antibacterial and imaging materials
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Coating Technology.ORCID iD: 0000-0001-7639-1173
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abstract

The overuse and misuse of conventional antibiotics has caused increased prevalence of drug-resistant bacteria, the infections of which cause high mortality and economic losses per year. It is therefore crucial to develop new technologies and treatments for infections caused by drug-resistant bacteria. Dendritic polymer-based hydrogels and nanomaterials have shown promise as alternatives to traditional small-molecule antibiotics.

Third generation (G3) allyl-functional hyperbranched dendritic-linear-dendritic copolymers (HBDLDs) based on polyethylene glycol (PEG) and 2,2-bis(hydroxymethyl) propionic acid (bis-MPA) were synthesized, and used to form hydrogels with a dithiol-functional PEG crosslinker using thiol-ene coupling (TEC). The hydrogels were used to co-deliver both hydrophilic and hydrophobic antibiotics with the aid of dendritic nanogels (DNGs). Antibacterial hydrogel band aids were also fabricated in a facile procedure.

Amino-functional HBDLDs based on PEG and bis-MPA were synthesized, and together with a di-N-hydroxysuccinimide-functional PEG as the crosslinker, amino-functional hydrogels with inherent antibacterial properties were fabricated. The cationic hydrogels are highly effective towards a wide range of wound-isolated bacteria, and can reduce inflammation and oxidative stress.

To minimize the cytotoxicity of amino-functional dendrimers, self-assembled hydrogels based on cationic dendrimers and cellulose nanofibrils were fabricated. Cationic dendrimers and their fragments can be released from the hydrogels to kill bacteria whilst showing insignificant cytotoxicity with human cells.

Bis-MPA dendrimers with both amino and allyl functionalities were also synthesized. Allyl groups can be used to form hydrogels with a dithiol-functional PEG crosslinker via TEC, and the amino groups provide the hydrogels with antibacterial properties.

Fluorescent silicon nanoparticles (SiNPs) were synthesized and their interaction with bacteria was investigated. SiNPs exhibited strong binding to Staphylococcus aureus (S. aureus), showing promise as a potential capturing and imaging agent for S. aureus.

Abstract [sv]

Sammanfattning

Överanvändning och missbruk av konventionell antibiotika har orsakat förekomsten av läkemedelsresistenta bakterier, detta har resulterat i mer aggressiva infektioner som orsakar hög dödlighet och stora ekonomiska kostnader varje år. Det är därför viktigt att utveckla nya tekniker för att behandla infektioner orsakade av dessa läkemedelsresistenta bakterier. Hydrogeler och nanomaterial baserade på dendritiska polymerer har visat stor potential som alternativ till traditionell antibiotika.

Allyl-funktionella hyperförgrenade dendritiska-linjära-dendritiska sampolymerer (HBDLD), baserade på polyetylenglykol (PEG) och 2,2-bis (hydroximetyl) propansyra (bis-MPA) av tredje generationen (G3), syntetiserades och användes för att bilda hydrogeler med en ditiolfunktionell PEG-tvärbindare via av tiol-en-koppling (TEC). Hydrogelerna användes för att leverera både hydrofil och hydrofob antibiotika med hjälp av dendritiska nanogeler (DNG). Plåster av den antibakteriella hydrogelen tillverkades också via en enkel procedur.

Aminfunktionella HBDLD baserade på PEG och bis-MPA syntetiserades och användes tillsammans med di-N-hydroxisuccinimid-funktionell PEG för att tillverka aminfunktionella hydrogeler med antibakteriella egenskaper. De katjoniska hydrogelerna är mycket effektiva mot ett brett spektrum av bakterier isolerade från sår och kan dessutom minska inflammation och oxidativ stress.

För att minimera cytotoxiciteten hos aminfunktionella dendrimerer tillverkades hydrogeler baserade på katjoniska dendrimerer och nanofibriller av cellulosa. De katjoniska dendrimererna och fragment från dem kan frigöras från hydrogelerna i koncentrationer som dödar bakterier men inte är toxiska för humana celler.

Bis-MPA dendrimerer med både amin- och allylfunktionella grupper syntetiserades också. Allylgrupperna kan användas för att bilda hydrogeler med en ditiolfunktionell PEG tvärbindare via TEC, och aminerna ger hydrogelerna antibakteriella egenskaper.

Fluorescerande kiselnanopartiklar (SiNP) syntetiserades och deras interaktion med bakterier undersöktes. SiNP uppvisade stark bindning till Staphylococcus aureus (S. aureus), vilket visar en lovande potential för användning som kontrastmedel eller för att fånga in dessa bakterier.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology , 2021. , p. 65
Series
TRITA-CBH-FOU ; 2021:27
Keywords [en]
antibacterial hydrogels, dendritic polymers, dendrimers, silicon nanoparticles, cellulose nanofibrils, drug-resistant bacteria, wound dressings
National Category
Natural Sciences
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-295585ISBN: 978-91-7873-898-4 (print)OAI: oai:DiVA.org:kth-295585DiVA, id: diva2:1556638
Public defence
2021-06-15, https://kth-se.zoom.us/j/67880817786, 10:00 (English)
Opponent
Supervisors
Note

QC 2021-05-24

Available from: 2021-05-24 Created: 2021-05-24 Last updated: 2022-06-25Bibliographically approved
List of papers
1. UV-Cured Antibacterial Hydrogels Based on PEG and Monodisperse Heterofunctional Bis-MPA Dendrimers
Open this publication in new window or tab >>UV-Cured Antibacterial Hydrogels Based on PEG and Monodisperse Heterofunctional Bis-MPA Dendrimers
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2021 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 26, no 8, p. 2364-Article in journal (Refereed) Published
Abstract [en]

Bacterial infections are one of the major threats to human health due to the raising crisis of antibiotic resistance. Herein, second generation antibacterial heterofunctional dendrimers based on 2,2-bis(methylol)propionic acid were synthesized. The dendrimers possessed six alkenes and 12 ammonium end-groups per molecule and were used to fabricate antibacterial hydrogels together with dithiol-functional polyethylene glycol (mol wt of 2, 6 and 10 kDa) as crosslinkers via thiol-ene chemistry. The network formation can be completed within 10 s upon UV-irradiation as determined by the stabilization of the storage modulus in a rheometer. The hydrogels swelled in aqueous media and could be functionalized with the N-hydroxysuccinimide ester of the dye disperse red 13, which allowed for visually studying the degradation of the hydrogels through the hydrolysis of the ester bonds of the dendritic component. The maximum swelling ratio of the gels was recorded within 4–8 h and the swelling ratios increased with higher molecular weight of the polyethylene glycol crosslinker. The gel formed with 10 kDa polyethylene glycol crosslinker showed the highest swelling ratio of 40 and good mechanical properties, with a storage modulus of 8 kPa. In addition, the hydrogels exhibited good biocompatibility towards both human fibroblasts and mouse monocytes, while showing strong antibacterial activity against both gram-positive and gram-negative bacteria.

Place, publisher, year, edition, pages
MDPI AG, 2021
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-294787 (URN)10.3390/molecules26082364 (DOI)000644596400001 ()33921687 (PubMedID)2-s2.0-85105089320 (Scopus ID)
Note

QC 20210607

Available from: 2021-05-18 Created: 2021-05-18 Last updated: 2023-08-28
2. Self-Assembled Polyester Dendrimer/Cellulose Nanofibril Hydrogels with Extraordinary Antibacterial Activity
Open this publication in new window or tab >>Self-Assembled Polyester Dendrimer/Cellulose Nanofibril Hydrogels with Extraordinary Antibacterial Activity
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2020 (English)In: Pharmaceutics, E-ISSN 1999-4923, Vol. 12, no 12, article id 1139Article in journal (Refereed) Published
Abstract [en]

Cationic dendrimers are intriguing materials that can be used as antibacterial materials; however, they display significant cytotoxicity towards diverse cell lines at high generations or high doses, which limits their applications in biomedical fields. In order to decrease the cytotoxicity, a series of biocompatible hybrid hydrogels based on cationic dendrimers and carboxylated cellulose nanofibrils were easily synthesized by non-covalent self-assembly under physiological conditions without external stimuli. The cationic dendrimers from generation 2 (G2) to generation 4 (G4) based on trimethylolpronane (TMP) and 2,2-bis (methylol)propionic acid (bis-MPA) were synthesized through fluoride promoted esterification chemistry (FPE chemistry). FTIR was used to show the presence of the cationic dendrimers within the hybrid hydrogels, and the distribution of the cationic dendrimers was even verified using elemental analysis of nitrogen content. The hybrid hydrogels formed from G3 and G4 showed 100% killing efficiency towards Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with bacterial concentrations ranging from 10(5) CFU/mL to 10(7) CFU/mL. Remarkably, the hybrid hydrogels also showed good biocompatibility most probably due to the incorporation of the biocompatible CNFs that slowed down the release of the cationic dendrimers from the hybrid hydrogels, hence showing great promise as an antibacterial material for biomedical applications.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
cationic dendrimer, antibacterial materials, carboxylated cellulose nanofibrils, hybrid hydrogels
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-289013 (URN)10.3390/pharmaceutics12121139 (DOI)000602524100001 ()33255607 (PubMedID)2-s2.0-85096697401 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation
Note

QC 20210125

Available from: 2021-01-25 Created: 2021-01-25 Last updated: 2024-07-04Bibliographically approved
3. Scalable Dendritic Hydrogels Targeting Drug-Resistant Skin Pathogens and the Immunomodulation Activity in Keratinocytes
Open this publication in new window or tab >>Scalable Dendritic Hydrogels Targeting Drug-Resistant Skin Pathogens and the Immunomodulation Activity in Keratinocytes
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Microbial infections caused by antibiotic-resistant bacteria are a major threat to humans, associated with a high mortality and for the society increased economic burden. To address this, a series of cationic hydrogels based on amino-functional hyperbranched dendritic−linear−dendritic copolymers (HBDLDs) were formed easily within 1 min through interactions between the amino-terminated HBDLDs and di(N-hydroxysuccinimide ester) functionalized polyethylene glycol (PEG). The hydrogels exhibited excellent inherent antimicrobial activity towards a wide range of Gram-positive and Gram-negative clinical bacteria including drug-resistant strains, isolated from wounds. In vitro cell infection assays showed that the hydrogels were able to significantly reduce cell infections caused by different strains, with the highest killing efficacy of 96% towards S. aureus. The hydrogels also inhibited the initiation of E. coli biofilm formation. Remarkably, the hydrogels induced the expression of the antimicrobial peptides, RNase 7 and psoriasin, in keratinocytes (HaCaT) which suggests that the hydrogels are likely able to promote host-mediated bacterial killing. The expression of pro-inflammatory cytokine IL-1β, reactive nitrogen species (NO) and mitochondrial reactive oxygen species (ROS) in S. aureus-infected HaCaT cells were reduced after the treatment with the hydrogels. The hydrogels degraded within 24 h, showing great promise for treating skin infections and reducing inflammation.

Keywords
cationic dendritic hydrogels, antimicrobial, drug-resistant bacteria, wound dressing
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-295582 (URN)
Note

QC 20210531

Available from: 2021-05-23 Created: 2021-05-23 Last updated: 2022-06-25Bibliographically approved
4. Nanogel encapsulated hydrogels as advanced wound dressings for the controlled delivery of antibiotics
Open this publication in new window or tab >>Nanogel encapsulated hydrogels as advanced wound dressings for the controlled delivery of antibiotics
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2021 (English)In: Advanced Functional Materials, ISSN 1616-301X, Vol. 31Article in journal (Refereed) Published
Abstract [en]

Biocompatible and degradable dual-delivery gel systems based on hyperbrancheddendritic−linear−dendritic copolymers (HBDLDs) is herein conceptualizedand accomplished via thiol-ene click chemistry. The elasticity of thehydrogels is tunable by varying the lengths of PEG (2, 6, 10 kDa) or the dryweight percentages (20, 30, 40 wt%), and are found to be between 2–14.7 kPa,comparable to human skin. The co-delivery of antibiotics is achieved, wherethe hydrophilic drug novobiocin sodium salt (NB) is entrapped within thehydrophilic hydrogel, while the hydrophobic antibiotic ciprofloxacin (CIP) isencapsulated within the dendritic nanogels (DNGs) with hydrophobic cores(DNGs-CIP). The DNGs-CIP with drug loading capacity of 2.83 wt% are thenphysically entrapped within the hybrid hydrogels through UV curing. Thehybrid hydrogels enabled the quick release of NB and prolonged released ofCIP. In vitro cell infection assays showed that the antibiotic-loaded hybridhydrogels are able to treat bacterial infections with significant bacterialreduction. Hybrid hydrogel band aids are fabricated and exhibited betterantibacterial activity compared with commercial antimicrobial band aids.Remarkably, most hydrogels and hybrid hydrogels showed enhanced humandermal cell proliferation and could be degraded into non-toxic constituents,showing great promise as wound dressing materials.

National Category
Natural Sciences
Research subject
Fibre and Polymer Science; Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-293758 (URN)10.1002/adfm.202006453 (DOI)2-s2.0-85094644501 (Scopus ID)
Note

QC 20210623

Available from: 2021-05-23 Created: 2021-05-23 Last updated: 2022-06-25Bibliographically approved
5. Fluorescent silicon nanoparticles as a potential capaturing and imaging agent for Staphylococcus aureus
Open this publication in new window or tab >>Fluorescent silicon nanoparticles as a potential capaturing and imaging agent for Staphylococcus aureus
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Nanomaterials, with various shapes and specific physicochemical properties, have attracted a lot of interest in the biomedical fields. Fluorescent silicon nanoparticles (SiNPs) have shown promise as immunofluorescent cellular imaging agents. In this study, SiNPs were synthesized to explore their potential as bacterial imaging agents. Silicon nanoparticles with amino groups on the surface were prepared using microwave-assisted synthesis method using trisodium citrate as the reducing agent. The obtained SiNPs were characterized using dynamic light scattering (DLS), UV−vis absorption spectroscopy and fluorescence spectrophotometer. And SiNPs were used to study their interactions with both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). The interactions between the prepared SiNPs and bacteria were monitored by the fluorescence microscope, and SiNPs showed a strong interaction with S. aureus. SEM was used to study the morphological changes of S. aureus, and we found that the cell membranes of S. aureus became damaged after the interaction with SiNPs. The amino groups on the surfaces of SiNPs could also be functionalized with other functional groups for other applications. 

Keywords
fluorescent SiNPs, bio-imaging agent, nanoparticles, bacteria
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-295584 (URN)
Note

QC 20210531

Available from: 2021-05-23 Created: 2021-05-23 Last updated: 2022-06-25Bibliographically approved

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