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Aliphatic Polyesters for Soft Tissue Engineering: Development from Conventional Organometallic to Novel Enzymatic Catalysis
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

The development of macromolecules with defined structure and properties, aimed specifically for biomedical applications, has resulted in diverse biodegradable polymers with advanced architectures. Among them, aliphatic polyesters synthesized by ring-opening polymerization (ROP) of lactones and lactides have a leading position due to their good mechanical properties, hydrolyzability and biocompatibility. To achieve tailored properties and controlled architecture, the technique for ROP of lactones and lactides has been continuously refined in the past years. Enzyme-catalyzed ROP is one of the most promising tools, which avoids the use of toxic organometallic catalysts and brings a “green-chemistry” appeal with it. In the work described in this thesis, enzyme-catalyzed ROP of 1,5-dioxepan-2-one (DXO), ε-caprolactone (CL) and lactides (L-, D- and D,L-lactide) was performed in bulk using Lipases from different sources. The effects of enzyme concentration, polymerization temperature and reaction water content on the monomer conversion and the polymer molecular weight during DXO polymerization were studied, and the role of water as initiator was confirmed. Terminal functionalized, block, comb and star polymers were synthesized using different alcohols as initiator in the enzyme-catalyzed ROP of DXO, CL or lactides under strictly anhydrous conditions. The effect of simultaneous and sequential copolymerization of DXO and CL on the micro-block structure of the copolymers was studied and the reactivity ratios of DXO and CL were determined under Lipase catalysis. High molecular weight copolymers of DXO and CL thus obtained were fabricated into porous scaffolds for tissue implant applications. Enzymatic degradation and alkaline hydrolysis of lactides was performed to study the effect of molecular branches and the stereochemistry of the monomer on the degradation profile. In another approach, cross-linked films of DXO and CL were prepared using 2,2´-bis-(ε-caprolactone-4-yl) propane (BCP) as the cross-linking agent and Sn(Oct)2 as the catalyst. The networks obtained thereof were elastomeric materials, easy to cast and remove from the mould.

Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , 125 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2007:2
Keyword [en]
aliphatic polyester, 1, 5-dioxepan-2-one, ε-caprolactone, L-lactide, D-lactide, D, L-lactide, enzyme, lipase CA, lipase PS
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4341ISBN: 978-91-7178-595-4 (print)OAI: oai:DiVA.org:kth-4341DiVA: diva2:11887
Public defence
2007-05-04, F3, KTH, Lindstedtsvägen 26, Stoclholm, 10:15
Opponent
Supervisors
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2011-02-21Bibliographically approved
List of papers
1. High molecular weight poly(1,5-dioxepan-2-one) via enzyme-catalyzed ring-opening polymerization
Open this publication in new window or tab >>High molecular weight poly(1,5-dioxepan-2-one) via enzyme-catalyzed ring-opening polymerization
2005 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 43, no 18, 4206-4216 p.Article in journal (Refereed) Published
Abstract [en]

To avoid organometallic catalysts in the synthesis of poly(1,5-dioxepan-2-one), the enzymatic ring-opening polymerization of 1,5-dioxepan-2-one (DXO) was performed with lipase CA (derived from Candida antarctica) as a biocatalyst. A linear relationship between the number-average molecular weight and monomer conversion was observed, and this suggested that the product molecular weight could be controlled by the stoichiometry of the reactants. The monomer consumption followed a first-order rate law with respect to the monomer, and no chain termination occurred. Water acted as a chain initiator, but it could cause polymer hydrolysis when it exceeded an optimum level. An initial activation via the heating of the enzyme was sufficient to start the polymerization, as the monomer conversion occurred when samples were left at room temperature after an initial heating at 60 degrees C. A high lipase content led to a high monomer conversion as well as a high molecular weight. An increase in the monomer conversion and molecular weight was observed when the polymerization temperature was increased from 40 to 80 degrees C. A further increase in the polymerization temperature led to a decrease in the monomer conversion and molecular weight because of the denaturation of the enzyme at elevated temperatures. The polymerization behavior of DXO under lipase CA catalysis was compared with that of epsilon-caprolactone (CL). The rate of monomer conversion of DXO was much faster than that of CL, and this may have been due to differences in their specificity toward lipase CA.

Keyword
1, 5-dioxepan-2-one, enzymes, lipase CA, molecular weight, ring-opening, polymerization, epsilon-caprolactone
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7005 (URN)10.1002/pola.20888 (DOI)000231524100019 ()2-s2.0-25144483563 (Scopus ID)
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
2. Enzyme-Catalyzed Ring-Opening Polymerization of Seven-Membered Ring Lactones Leading to Terminal-Functionalized and Triblock Polyesters
Open this publication in new window or tab >>Enzyme-Catalyzed Ring-Opening Polymerization of Seven-Membered Ring Lactones Leading to Terminal-Functionalized and Triblock Polyesters
2006 (English)In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 39, no 1, 46-54 p.Article in journal (Refereed) Published
Abstract [en]

Terminal-functionalized polyesters and triblock polyesters were synthesized by lipase-CA-catalyzed ring-opening polymerization of seven-membered ring lactones, i.e., 1,5-dioxepan-2-one (DXO) and epsilon-caprolactone (CL), in the bulk in the presence of an appropriate alcohol that acts as an initiator. To introduce a double bond at the chain end, 4-pentene-2-ol was used to initiate the polymerization of the lactones. The unsaturation introduced at the chain end in this way is a useful approach for synthesizing comb polymers. Two different dihydroxyl compounds, viz. poly(caprolactone diol) and poly(ethylene glycol), were used as macro-initiators. Triblock copolymers were synthesized in this way, where the macro-initiator formed the middle block. Polymers having different degrees of polymerization were synthesized by varying the molar feed ratio of monomer to initiator. DXO and CL showed significant differences in reactivity toward lipase-CA-catalyzed polymerization initiated by different alcohols as initiators. The polymers were characterized by FTIR, NMR, SEC, optical microscopy, and DSC techniques.

Keyword
Alcohols, Copolymers, Monomers, Nuclear magnetic resonance, Optical microscopy, Polyesters, Dihydroxyl compounds, DSC techniques, Ring lactones, SEC, Polymerization
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7006 (URN)10.1021/ma0518508 (DOI)000234500100012 ()2-s2.0-30944444008 (Scopus ID)
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
3. Chemo-enzymatic synthesis of comb polymers
Open this publication in new window or tab >>Chemo-enzymatic synthesis of comb polymers
2007 (English)In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 43, no 3, 808-817 p.Article in journal (Refereed) Published
Abstract [en]

The paper describes the synthesis and characterization of comb polymers by a two-step chemo-enzymatic process. In the first step macromonomers bearing unsaturation at the chain end were prepared by lipase catalyzed ring-opening polymerization (ROP) of E-caprolactone (CL) and 1,5-dioxepane-2-one (DXO). The ROP was carried out in bulk at 60 degrees C under anhydrous conditions using 2-hydroxyethyl methacrylate (HEMA) as the initiator. The DP of the macromonomers was controlled by regulating the monomer: HEMA molar feed concentration. The macromonomers were then homo- or co-polymerized in the second step with alkyl methacrylate monomers (methyl methacrylate or HEMA) using AIBN initiated free radical polymerization. Characterization of the polymers was done by H-1 NMR, SEC and DSC techniques.

Keyword
1, 5-Dioxepane-2-one; Comb polymers; Enzyme; Lipase-CA; Ring-opening polymerization; Copolymerization; Enzymes; Free radical polymerization; Macromolecules; Ring opening polymerization; Saturation (materials composition); Synthesis (chemical); 1, 5-Dioxepane-2-one; 2-hydroxyethyl methacrylate (HEMA); Caprolactone (CL); Comb polymers; Lipase-CA; Macromonomers; Organic polymers
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7007 (URN)10.1016/j.eurpolymj.2006.11.032 (DOI)000245064900014 ()2-s2.0-33847037905 (Scopus ID)
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
4. Porous scaffolds from high molecular weight polyesters synthesized via enzyme-catalyzed ring-opening polymerization
Open this publication in new window or tab >>Porous scaffolds from high molecular weight polyesters synthesized via enzyme-catalyzed ring-opening polymerization
2006 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 7, no 9, 2531-2538 p.Article in journal (Refereed) Published
Abstract [en]

Several aliphatic polyesters have been synthesized until now using enzyme-catalyzed ring-opening polymerization (ROP) of different lactones, although their molecular weight, hence mechanical strength, was not sufficient enough to fabricate porous scaffolds from them. To achieve this target, 1,5-dioxepan-2-one (DXO) and epsilon-caprolactone (CL) were polymerized in bulk with Lipase CA as catalyst at 60 degrees C, and porous scaffolds were prepared from the polymers obtained thereof using a salt leaching technique. The CL/DXO molar feed ratio was varied from 1.5 to 10, and the reactivity ratios of CL and DXO were determined using the Kelen-Tudos method under such conditions of polymerization. NMR results showed a slightly lower CL/DXO molar ratio in the copolymers than in the feed due to high reactivity of DXO toward Lipase CA catalysis. The crystallinity of the PCL segment of the copolymers was affected by the presence of soft and amorphous DXO domains. The copolymers having high CL content were thermally more stable. The porosity of the scaffolds was in the range 82-88%, and the SEM analysis showed interconnected pores in the scaffolds. Of the two parameters which could affect the mechanical properties, viz., the copolymer composition and the scaffold pore size, the pore size showed a significant effect on the mechanical properties of the scaffolds. The porous scaffolds developed in this way for tissue engineering are free from toxic organometallic catalyst residues, and they are highly suitable for biomedical applications.

Keyword
Aliphatic polyester; Enzyme-catalyzed ring-opening polymerization; Kelen-Tudos method; Salt leaching technique; Composition; Enzyme kinetics; Leaching; Molecular weight distribution; Nuclear magnetic resonance spectroscopy; Porosity; Ring opening polymerization; Scanning electron microscopy; Synthesis (chemical); Polyesters; 1, 5 dioxepan 2 one; aliphatic compound; copolymer; lactone; lipase B; organometallic compound; polycaprolactone; polyester; pyran derivative; unclassified drug; article; biomedicine; carbon nuclear magnetic resonance; catalysis; chemical composition; chemical structure; controlled study; gel permeation chromatography; leaching; mathematical computing; molecular weight; polymerization; porosity; priority journal; proton nuclear magnetic resonance; ring opening; scanning electron microscopy; synthesis; temperature measurement; tensile strength; thermogravimetry; thermostability; tissue engineering; Biocompatible Materials; Biotechnology; Catalysis; Chromatography; Lipase; Magnetic Resonance Spectroscopy; Microscopy, Electron, Scanning; Molecular Weight; Polyesters; Polymers; Salts; Tensile Strength; Thermodynamics; Thermogravimetry; Tissue Engineering
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7008 (URN)10.1021/bm060309w (DOI)000240403300011 ()2-s2.0-33749547412 (Scopus ID)
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
5. Microblock copolymers as a result of transesterification catalyzing behavior of lipase CA in sequential ROP
Open this publication in new window or tab >>Microblock copolymers as a result of transesterification catalyzing behavior of lipase CA in sequential ROP
2007 (English)In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 40, no 13, 4464-4469 p.Article in journal (Refereed) Published
Abstract [en]

The copolymerization of epsilon-caprolactone (CL) and 1,5-dioxepan-2-one (DXO) was performed by sequential addition of monomers in lipase CA catalyzed ring-opening polymerization (ROP) at 60 degrees C in bulk. CL was first polymerized up to a monomer conversion of 95%, and then DXO was added to the reaction mixture. The polymerization was stopped when the DXO conversion reached a level of more than 95%. The molar feed ratio of CL and DXO was varied from 1.5 to 10, and the copolymer composition, as determined by H-1 NMR spectroscopy, agreed well with the feed. The block lengths of PCL and PDXO segments in the structure of these high molecular weight copolymers reduced significantly due to the occurrence of extensive transesterification during ROP. The enzyme, lipase CA, in addition to acting as the catalyst for ROP also promoted transesterification reactions. The increase in number-average molecular weight (M-n) after DXO polymerization in the second step illustrated that the terminal hydroxyl group of preformed PCL chains in the first step possibly initiated the DXO polymerization. A single glass transition, in between the glass transition temperatures of corresponding homopolymers of PDXO and PCL, was observed in the DSC thermograms of all the copolymers. A composition of 15-20% DXO gave optimal balance between strength and elasticity of the copolymers.

Keyword
Catalysis; Elasticity; Homopolymerization; Lipases; Molecular weight; Monomers; Nuclear magnetic resonance spectroscopy; Ring opening polymerization; DXO; Microblock copolymers; Molar feed ratio; Thermograms; Transesterification; Copolymers
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7009 (URN)10.1021/ma0701179 (DOI)000247340700014 ()2-s2.0-34547189110 (Scopus ID)
Note
QC 20100818. Uppdaterad från Accepted till Published 20100818.Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
6. Branched poly(lactide) synthesized by enzymatic polymerization: effects of molecular branches and stereochernistry on enzymatic degradation and alkaline hydrolysis
Open this publication in new window or tab >>Branched poly(lactide) synthesized by enzymatic polymerization: effects of molecular branches and stereochernistry on enzymatic degradation and alkaline hydrolysis
Show others...
2007 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 10, 3115-3125 p.Article in journal (Refereed) Published
Abstract [en]

In this article the effects of the number of molecular branches (chain ends) and the stereochemistry of poly(lactide)s (PLAs) on the enzymatic degradation and alkaline hydrolysis are studied. Various linear and branched PLAs were synthesized using lipase PS (Pseudomonas fluorescens)-catalyzed ring-opening polymerization (ROP) of lactide monomers having different stereochemistries (L-lactide, D-lactide, and D,L-lactide). Five different alcohols were used as initiators for the ROP, and the monomer-to-initiator molar feed ratio was varied from 10 to 100 and 1000 for each branch in the polymer architecture. The properties of branched PLAs that would affect the enzymatic and alkaline degradations, i.e., the glass transition temperature, the melting temperature, the melting enthalpy, and the advancing contact angle, were determined. The PLA films were degraded using proteinase K or 1.0 M NaOH solution, and the weight loss and changes in the number average molecular weight (M-n) of the polymer were studied during 12 h of degradation. The results suggest that an increase in the number of molecular branches of branched PLAs enhances its enzymatic degradability and alkali hydrolyzability. Moreover, the change in M-n of the branched poly(L-lactide) (PLLA) by alkaline hydrolysis indicated that the decrease in M-n was in the first place dependent on the number of molecular branches and thereafter on the length of the molecular branch of branched PLA. The branched PLLA, poly(D-lactide) (PDLA), and poly(D,L-lactide) (PDLLA) differed in weight loss and change in M-n of the PLA segment during the enzymatic degradation. It is suggested that the branched PDLLA was degraded preferentially by proteinase K.

Keyword
ring-opening polymerization, stannous octoate, organic media, proteinase-k, polylactide, lactide, weight, stereocopolymers, stereochemistry, crystallinity
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-17020 (URN)10.1021/bm700537x (DOI)000250009900020 ()2-s2.0-35548976692 (Scopus ID)
Note
QC 20100818Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
7. Potential tissue implants from the networks based on 1,5-dioxepan-2-one and epsilon-caprolactone
Open this publication in new window or tab >>Potential tissue implants from the networks based on 1,5-dioxepan-2-one and epsilon-caprolactone
2005 (English)In: Polymer journal, ISSN 0032-3896, E-ISSN 1349-0540, Vol. 46, no 18, 6746-6755 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis and characterization of degradable polymeric networks for biomedical applications was performed. Cross-linked films of poly(epsilon-caprolactone) (PCL) and poly(1,5-dioxepan-2-one) (PDXO) having various mole fractions of monomers and different cross-link densities were successfully prepared using 2,2'-bis-(epsilon-caprolactone-4-yl) propane (BCP) as cross-linking agent. Reaction parameters were carefully examined to optimise, the film-formin.,, conditions. Networks obtained were elastomeric materials. easy to cast and remove from the mould. Effect of CL content and cross-link density on the final properties of the polymer network was evaluated. High CL content or degree of cross-linking led to increase in Young's modulus and decrease in elongation at break. An increase in crystalline domains in films having a higher CL content was observed by optical microscopy. A greater thermal stability was observed in films having a high CL content. The hydrophilicity of the materials could be tailored by changing the CL content. The surface of the films became rougher with higher CL content.

Keyword
Characterization, Crosslinking, Degradation, Implants (surgical), Monomers, Plastic films, Synthesis (chemical), Tissue, 1, 5-dioxepan-2-one, Biomedical applications, Cross-linking agents, Organic polymers
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-8817 (URN)10.1016/j.polymer.2005.06.038 (DOI)000231397200003 ()2-s2.0-23744514731 (Scopus ID)
Note
QC 20100629Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2017-12-14Bibliographically approved
8. Enzyme catalyzed synthesis of polyesters
Open this publication in new window or tab >>Enzyme catalyzed synthesis of polyesters
2005 (English)In: Progress in polymer science, ISSN 0079-6700, E-ISSN 1873-1619, Vol. 30, no 10, 949-981 p.Article in journal (Refereed) Published
Abstract [en]

In vitro enzyme catalyzed synthesis of polyesters is a new technique of polymer synthesis and is an eco-friendly process having several benefits over conventional chemical polymerization. In this article lipase-catalyzed ring-opening polymerization of lactones, lactides and macrolides, cyclic carbonates, cyclic phosphates, cyclic depsipeptides and copolymerization of oxiranes with dicarboxylic acid anhydrides leading to the formation of polyesters, polycarbonates, polyphosphates and poly(ester-amides) has been reviewed in detail. The effect of reaction parameters, i.e. solvent, temperature, enzyme and monomer concentration, on the rate and molecular weight of the polymers is discussed. Synthesis of polyesters by step-growth polycondensation reactions using simple diacids and diols, hydroxy acids or transesterification reaction of simple or activated diesters with diols has also been surveyed. The general mechanisms of ring-opening and step-growth polymerization have also been considered. Lipase hydrolyzes the ester bonds of polyesters in an aqueous medium and recombines the cleaved moiety in non-aqueous medium. The possibility of utilizing such reactions for the repetitive recycling of biodegradable polyesters has been highlighted.

Keyword
Hydrolase, Lactides, Lactone, Lipase, Macrolides, Ring-opening polymerization, Biodegradation, Catalysis, Enzymes, Monomers, Polymerization, Synthesis (chemical), Diacids, Eco-friendly process, Non-aqueous medium, Polyphosphates, Polyesters
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-7012 (URN)10.1016/j.progpolymsci.2005.06.010 (DOI)000232522000001 ()2-s2.0-25144492819 (Scopus ID)
Note
QC 20100818Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved

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