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Copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate, a well-defined and efficient process for achieving functionalized polyesters for covalent binding of bioactive molecules
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.ORCID iD: 0000-0001-6044-586X
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.ORCID iD: 0000-0002-1922-128X
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
2013 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 6, 2095-2102 p.Article in journal (Refereed) Published
Abstract [en]

The understanding of cell-material interactions is important for creating personalized implants for tissue engineering. This has resulted in an interest in developing polymers with functional groups with the possibility of controlling the macromolecular surface. We have in a one-pot reaction synthesized a series of amorphous and degradable polyester-based copolymers with active functional groups by copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate. The properties of the final polymers were varied by varying the feed ratios of the monomers, and it was seen that it was possible to control the amount of active functional groups. The resulting epoxy-functionalized polyester was further modified by covalent immobilization of heparin. The heparinization was done in order, in a future aspect, to enhance the osteogenic differentiation of mesenchymal stem cells. Heparin binds directly with the growth factor bone morphogenetic protein-2 and helps to retain its activity. The molecular structure of the copolymers was characterized by nuclear magnetic resonance, size exclusion chromatography, and Fourier transform infrared spectroscopy. Differential scanning calorimetry and tensile testing showed that the monomer feed ratio had a great influence on the properties of the final polymer and that it thus was possible to control the mechanical properties to suit an intended application. The presence of heparin was verified by toluidine blue staining, and all of the films tested showed positive signals for heparin.

Place, publisher, year, edition, pages
2013. Vol. 14, no 6, 2095-2102 p.
Keyword [en]
Bioactive molecules, Bone morphogenetic protein-2, Cell-material interaction, Covalent immobilization, Functionalized polyesters, Glycidyl methacrylate, Mesenchymal stem cell, Osteogenic differentiation
National Category
Polymer Chemistry Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-134256DOI: 10.1021/bm4004783ISI: 000320356000043ScopusID: 2-s2.0-84878886126OAI: diva2:666032
EU, European Research Council, 246776

QC 20131121

Available from: 2013-11-21 Created: 2013-11-20 Last updated: 2014-05-14Bibliographically approved
In thesis
1. Functional Degradable Polymers by a Radical Chemistry approach
Open this publication in new window or tab >>Functional Degradable Polymers by a Radical Chemistry approach
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One class of polymers that is inherently of great value for many applications is the aliphatic polyesters. Such polymers are very suitable for use as temporary guides, scaffolds, for tissue formation and other biomedical applications, due to their biocompatibility, degradability and appropriate mechanical properties. A prominent way to incorporate sites that allow alterations and modifications of the polymer backbone could be by copolymerization of functional monomers. The focus in this thesis is the development of new monomers and subsequent polymers bestowed with functional groups.

Radical ring-opening polymerization (RROP) of cyclic ketene acetals through a free-radical mechanism presents an alternative route to conventional ring-opening polymerization for the synthesis of aliphatic polyesters. By RROP, it is possible to incorporate ester functionality into the backbone of non-degradable polymers by copolymerize cyclic ketene acetals with vinyl monomers.

The possibility of creating materials with high degree of functionality is achieved by copolymerization with other and possible functional monomers. Three different copolymerizations including cyclic ketene acetals were performed. First, to increase hydrophilicity of a hydrophobic polymer by copolymerization of two cyclic ketene acetals, 2-methylene-1,3,6-trioxocane (MTC) and 2-methylene-1,3-dioxepane (MDO). Second, to introduce degradability into a non-degradable backbone by copolymerize MDO and vinyl acetal (VAc). Subsequently, the acetate side-group was hydrolyzed into the more hydrophilic alcohol group. Third, to introduce reactive functionalities into the degradable backbone of poly(2-methylene-1,3-dioxepane) (PMDO), by copolymerize MDO and glycidyl methacrylate (GMA). The epoxide side-groups, originating from GMA, were subsequently used in post-polymerization reactions by coupling with the bioactive molecule heparin.

The degradability of this class of copolymers was evaluated using the MDO/GMA-based material as model, showing that the materials degrade during 133 days without a rapid release of acidic degradation products or any substantial lowering of the pH. Methylthiazol tetrazolium (MTT) assays were also performed to confirm the innocuousness of the material. The results from the degradation study together with the MTT assays showed that these materials would be interesting for use in biomedical applications.

Finally, a combination of controlled radical polymerization with controlled ring-opening polymerization was performed. α-Bromo-γ-butyrolactone (αBrγBL) together with ε-caprolactone (εCL) or L-lactide (LLA) was successfully copolymerized to achieve copolymers with active and available grafting sites for single electron transfer living radical polymerization (SET-LRP). Different acrylates, ranging from the hydrophobic n-butyl acrylate and methyl methacrylate to the hydrophilic 2-hydroxyethyl methacrylate, were subsequently grafted via SET-LRP. All designated acrylate monomers were successfully grafted onto the polymer backbone, thereby emphasizing the versatility and ability of αBrγBL to act as a bridge between SET-LRP and ROP for a wide range of monomers.

Abstract [sv]

De alifatiska polyestrarna är en klass polymerer som är av stort intresse för många applikationer. Dessa polymerer är mycket lämpade att använda som temporära guider, scaffolds, för vävnadsregenerering och andra biomedicinska applikationer, på grund av sin biokompatibilitet, nedbrytbarhet och goda mekaniska egenskaper. Ett bra sätt att introducera funktionella grupper, som tillåter ändringar och modifikationer i polymerkedjan, kan vara att sampolymerisera med funktionella monomerer. I denna avhandling har därför fokus varit på att utveckla nya funktionella monomerer och polymerer.

Radikal ringöppningspolymerisation (RROP) av cykliska ketenacetaler har visat sig vara ett bra alternativ till att syntetisera alifatiska polyestrar jämfört med vanlig traditionell ringöppningspolymerisation. Med RROP är det möjligt att inkorporera esterfunktionalitet i polymerkedjan för icke nedbrytbara polymerer genom att sampolymerisera cykliska ketenacetaler med vinylmonomerer.

Möjligheten att skapa material med hög grad av funktionalitet uppnås genom att sampolymerisera med andra funktionella monomerer. Tre olika sampolymerer syntetiserades. Den första sampolymeren tillverkades för att introducera hydrofilicitet till en hydrofob polymer genom att sampolymerisera två ketenacetaler; 2-metyl-1,3,6-trioxocan (MTC) och 2-metyl-dioxepan (MDO). Därefter sampolymeriserades MDO med vinylacetat (VAc) för att tillföra nedbrytbarhet från MDO till ett, från huvudkedjan, onedbrytbart material. Acetatgruppen hydrolyserades därefter till den mer hydrofila alkoholgruppen. Som en sista sampolymerisation gjordes en med MDO med glycidylmetakrylat (GMA) för att införa funktionalitet till en nedbrytbar polymer. Epoxidgruppen tillhörande GMA, användes därefter för att kovalent koppla på den bioaktiva molekylen heparin på sampolymeren.

Nedbrytbarheten i denna klass av sampolymerer undersöktes med hjälp av att använda det MDO/GMA-baserade materialet som modell. Som resultat visade det sig att man, efter 133 dagar, varken kunde se en snabb frisättning av sura nedbrytningsprodukter eller en stor sänkning av pH. MTT-analyser utfördes för att visa att materialet inte var giftigt. Både resultaten från nedbrytningsstudien tillsammans med MTT-analyserna visade att dessa material är potentiella material för användning i biomedicinska applikationer.

Till sist kombinerades kontrollerad radikalpolymerisation med kontrollerad ringöppningspolymerisation. För att syntetisera funktionella makroinitiatorer sampolymeriserades monomeren α-brom-γ-butyrolakton (αBrγBL) med ε-kaprolakton (εCL) eller L-laktid (LLA). Dessa makroinitiatorer har aktiva grupper längs med huvudkedjan som kan användas för ympning av olika akrylater; från de hydrofoba n-butylakrylat och metylmetakrylat till den hydrofila 2-hydroxyetylmetakrylat med hjälp av en kontrollerad radikalpolymerisationsmetod som kallas för SET-LRP. Genom att lyckas ympa ett brett spektrum av monomer med olika egenskaper på polyester-makroinitiatorerna resulterade detta i att det gick att kombinera två olika polymerisationsmetoder på ett enkelt sätt.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2014. 74 p.
TRITA-CHE-Report, ISSN 1654-1081 ; 2014:22
National Category
Polymer Technologies
Research subject
Fibre and Polymer Science
urn:nbn:se:kth:diva-145193 (URN)978-91-7595-126-3 (ISBN)
Public defence
2014-05-23, K2, Teknikringen 28, KTH, Stockholm, 10:00 (English)

QC 20140514

Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2014-05-14Bibliographically approved

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