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Functional Degradable Polymers by a Radical Chemistry approach
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.ORCID iD: 0000-0001-6044-586X
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.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2014:22
National Category
Polymer Technologies
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-145193ISBN: 978-91-7595-126-3 (print)OAI: oai:DiVA.org:kth-145193DiVA: diva2:717141
Public defence
2014-05-23, K2, Teknikringen 28, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20140514

Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2014-05-14Bibliographically approved
List of papers
1. Synthesis of Amorphous Aliphatic Polyester-Ether Homo- and Copolymers by Radical Polymerization of Ketene Acetals
Open this publication in new window or tab >>Synthesis of Amorphous Aliphatic Polyester-Ether Homo- and Copolymers by Radical Polymerization of Ketene Acetals
2010 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 48, no 22, 4965-4973 p.Article in journal (Refereed) Published
Abstract [en]

Radical ring-opening polymerization has been efficiently used to copolymerize 2-methylene-1,3,6-trioxocane (MTC) and 2-methylene-1,3-dioxepane (MDO). The cyclic ketene acetal MTC was first synthesized and homopolymerized at different temperatures using either 2,2-azobisisobutyronitrile or dicumyl peroxide as initiator. The polymerization mechanism was not temperature-dependent, and the polymerization proceeded with 100% ring-opening at all the temperatures evaluated. The structures of MTC and PMTC were verified by H-1-nuclear magnetic resonance (NMR) and C-13-NMR spectroscopies. A number-average molecular weight of 6500 was obtained after 2 days at 70 degrees C in bulk, which was somewhat higher than the theoretical molecular weight. A significant amount of branching was detected from the high polydispersity index as well as the glass-transition temperatures. The polyester-ether was then successfully obtained by copolymerization of MTC with MDO. Different feed ratios and temperatures were used to map the reaction, and the copolymers were characterized by NMR, size exclusion chromatography, and differential scanning calorimetry. The amount of MTC within the polymer was independent of the feed ratio and always higher than the amount of MDO.

Keyword
aliphatic polyesters, copolymerization, cyclic ketene acetal, free-radical ring-opening polymerization, 2-methylene-1, 3, 6-trioxocane, 2-methylene-1, 3-dioxepane
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-27069 (URN)10.1002/pola.24292 (DOI)000284109000008 ()2-s2.0-78649544332 (Scopus ID)
Note
QC 20101210Available from: 2010-12-10 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved
2. Random introduction of degradable linkages into functional vinyl polymers by radical ring-opening polymerization, tailored for soft tissue engineering
Open this publication in new window or tab >>Random introduction of degradable linkages into functional vinyl polymers by radical ring-opening polymerization, tailored for soft tissue engineering
2012 (English)In: Polymer Chemistry, ISSN 1759-9954, Vol. 3, no 5, 1260-1266 p.Article in journal (Refereed) Published
Abstract [en]

Vinyl polymers, e.g. polyvinyl acetate and polyvinyl alcohol, have properties which suit tissue engineering in many perspectives. A copolymer of 2-methylene-1,3-dioxepane (MDO) with vinyl acetate (VAc) should combine the desirable properties of vinyl polymers with the degradability of aliphatic polyesters. Our results and detailed kinetics information show that it is possible to vary the amount of MDO widely in the copolymer. Between 1 and 70% MDO was incorporated into the polymer when copolymerized with VAc at 60 degrees C using 2,2-azobisisobutyronitrile (AIBN) as an initiator. The amount of MDO in the copolymer was strictly controlled by the feed ratio, the copolymerization resulted in a high conversion, and the copolymers had high number average molar masses. The polymerization kinetics indicated that the ester units were added in a randomized manner to the vinyl backbone. This was a crucial point since the distribution of degradable bonds provides the opportunity to design the degradation profile of the polymer. The reactivity ratios for MDO and VAc were determined to be r(MDO) 0.93 and r(VAc) 1.71. The glass transition temperature and the number average molar masses increased with increasing amount of VAc in the feed. We confirmed that the copolymer degraded rapidly in alkali hydrolysis and less in enzymatic hydrolysis and it was apparent that it is possible to synthesize various degradable materials based on VAc and MDO with predetermined polymer compositions and high number average molar masses.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-90825 (URN)10.1039/C2PY20034A (DOI)000302315800021 ()2-s2.0-84859742475 (Scopus ID)
Note
QC 20120509Available from: 2012-02-29 Created: 2012-02-29 Last updated: 2014-05-14Bibliographically approved
3. 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
Open this publication in new window or tab >>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
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.

Keyword
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
Identifiers
urn:nbn:se:kth:diva-134256 (URN)10.1021/bm4004783 (DOI)000320356000043 ()2-s2.0-84878886126 (Scopus ID)
Funder
EU, European Research Council, 246776
Note

QC 20131121

Available from: 2013-11-21 Created: 2013-11-20 Last updated: 2017-12-06Bibliographically approved
4. Adjustable Degradation Properties and Biocompatibility of Amorphous and Functional Poly(ester-acrylate)-Based Materials
Open this publication in new window or tab >>Adjustable Degradation Properties and Biocompatibility of Amorphous and Functional Poly(ester-acrylate)-Based Materials
2014 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 7, 2800-2807 p.Article in journal (Refereed) Published
Abstract [en]

Tuning the properties of materials toward a special application is crucial in the area of tissue engineering. The design of materials with predetermined degradation rates and controlled release of degradation products is therefore vital. Providing a material with various functional groups is one of the best ways to address this issue because alterations and modifications of the polymer backbone can be performed easily. Two different 2-methylene-1,3-dioxepane/glycidyl methacrylate-based (MDO/GMA) copolymers were synthesized with different feed ratios and immersed into a phosphate buffer solution at pH 7.4 and in deionized water at 37 degrees C for up to 133 days. After different time intervals, the molecular weight changes, mass loss, pH, and degradation products were determined. By increasing the amount of GMA functional groups in the material, the degradation rate and the amount of acidic degradation products released from the material were decreased. As a result, the composition of the copolymers greatly affected the degradation rate. A rapid release of acidic degradation products during the degradation process could be an important issue for biomedical applications because it might affect the biocompatibility of the material. The cytotoxicity of the materials was evaluated using a MTT assay. These tests indicated that none of the materials demonstrated any obvious cytotoxicity, and the materials could therefore be considered biocompatible.

Keyword
degradation, biocompatible, functional, aliphatic polyesters, cyclic ketene acetal, 2-methylene-1, 3-dioxepane, radical ring-opening polymerization, MTT assay
National Category
Polymer Technologies
Research subject
Fibre and Polymer Science
Identifiers
urn:nbn:se:kth:diva-145186 (URN)10.1021/bm500689g (DOI)000339090500051 ()2-s2.0-84904295082 (Scopus ID)
Funder
EU, European Research Council, 246776
Note

QC 20140819. Updated from submitted to published.

Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2017-12-05Bibliographically approved
5. Establishing α-bromo-γ-butyrolactone as a platform for synthesis of functional aliphatic polyesters-bridging the gap between ROP and SET-LRP
Open this publication in new window or tab >>Establishing α-bromo-γ-butyrolactone as a platform for synthesis of functional aliphatic polyesters-bridging the gap between ROP and SET-LRP
2014 (English)In: Polymer Chemistry, ISSN 1759-9954, E-ISSN 1759-9962, Vol. 5, no 12, 3847-3854 p.Article in journal (Refereed) Published
Abstract [en]

Utilizing a-bromo-g-butyrolactone (aBrgBL) as a comonomer with 3-caprolactone (3CL) or L-lactide (LLA)produces copolymers with active and available grafting sites, e.g., for SET-LRP, where the choice of thegrafting monomers is limited only by one's imagination. This was deduced by utilizing a wide range ofdifferent acrylates of varying polarities and was realized with the aid of a fluorinated alcohol, 2,2,2-trifluoroethanol, which acts as a universal solvent for both the hydrophobic macroinitiators and thegrafting monomers. Using aBrgBL successfully provides a simple route to merge the two polymerizationmethodologies, ROP and SET-LRP. aBrgBL inherently meets all of the prerequisites to act as a platformmonomer for the synthesis of functional aliphatic polyesters, i.e., it is inexpensive, available, and able toform isolated grafting sites along the polymer chain. The copolymerization of aBrgBL together with twoof the most commonly used cyclic ester monomers, 3-CL and LLA, proceeds with a high degree ofcontrol and a linear relationship between the feed ratio of aBrgBL and its composition in the copolymer.The formation of isolated units of aBrgBL in the copolymer is visualized by the reactivity ratios of thecopolymerization reactions and confirmed by 13C-NMR spectroscopy. The incorporation of isolatedaBrgBL is the feature that makes this class of copolymers unique, and it can be considered to provide aroute to the “perfect graft copolymer” with a degradable backbone.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2014
National Category
Polymer Technologies
Research subject
Fibre and Polymer Science
Identifiers
urn:nbn:se:kth:diva-145189 (URN)10.1039/C4PY00148F (DOI)000336804800015 ()2-s2.0-84901352273 (Scopus ID)
Note

QC 20140627

Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2017-12-05Bibliographically approved

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  • modern-language-association-8th-edition
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