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Design of Functional Degradable Aliphatic Polyesters and Porous Tissue Engineering Scaffolds
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The regeneration of damaged tissues or organs using porous scaffolds which act as temporary guides for the patient’s own cells, i.e. tissue engineering, is a means to overcome the shortcomings of current standard medical treatments. The large number of tissue engineering applications and the high demands on materials make it necessary to design materials and scaffolds with innovative characteristics tailored to suit specific applications. The purpose of the work presented in this thesis was to design aliphatic polyester (co)polymers and porous scaffolds in order to tailor material and scaffold properties and to control the property changes induced by radiation sterilization.

Porous scaffolds were created, with an emphasis on tailoring the scaffolds thermal and mechanical properties. Stannous octoate was used in ring-opening polymerizations of L,L-lactide (LLA), ε-caprolactone (CL) and 1,5-dioxepane-2-one (DXO) to attain three copolymer types with a wide assortment of monomer compositions. A solvent casting and salt leaching scaffold fabrication technique was developed, and highly porous scaffolds possessing a range of predetermined properties were obtained.

Highly porous tubular scaffolds of different designs for use in nerve regeneration were developed using copolymers of LLA, CL, DXO or trimethylene carbonate (TMC) and a versatile immersion coating and porogen leaching technique.

Reactions induced by electron beam and gamma irradiation were used to finalize the scaffold properties. By changing the nature of the radiation, the radiation dose, the type of monomers, the monomer composition and the chain microstructure, it was possible to alter the susceptibility and the degradation mechanisms of the polymers. Predicted end-properties were obtainable and the sterilization procedure was incorporated as a final step in the scaffold fabrication.

The free radical ring-opening polymerization of the cyclic ketene acetal 2-methylene-1,3-dioxe-5-pene was developed, a reaction mechanism was proposed and the reaction products were characterized as a first step towards the creation of an innovative multifunctional aliphatic polyester. The reaction mechanism was shown to be temperature-dependent and propagation was inhibited by the formation of an allylic radical in the ring-opening step. The primary reaction product at higher temperatures was the cyclic ester 3-vinyl-1,4-butyrolactone. At lower temperatures, the main product was oligomers of ring-opened and ring-retained repeating units.

Abstract [sv]

Regenerering av skadade vävnader eller organ genom användning av porösa bionedbrytbara implantat som temporära byggnadsställningar för patientens egna celler är ett sätt att lösa de tillkortakommanden som finns i dagens medicinska behandlingsmetoder. De många möjliga applikationerna för vävnadsersättning och de höga krav som ställs på materialen skapar ett behov av nya material med innovativa egenskaper. I denna avhandling används design av alifatiska polyetrar och porösa strukturer för att skräddarsy deras egenskaper och för att kontrollera de förändringar i egenskaper som sker när materialet strålningssteriliseras.

Porösa strukturer tillverkades med fokus på design av deras materialegenskaper. Genom sampolymerisation av L,L-laktid (LLA), ε-kaprolakton (CL) och 1,5-dioxepan-2-on (DXO) med utvalda sammansättningar och monomerkombinationer kunde dessa skräddarsys. Porösa strukturer med hög porositet och ett stort register av förutbestämbara mekaniska och termiska egenskaper framställdes via en utvecklad saltlakningsteknik.

Porösa tuber för nervregenerering, med olika design, utvecklades genom användning av sampolymerer av LLA, CL, DXO eller trimetylenkarbonat (TMC) och en mångsidig stöpnings- och saltlakningsteknik.

Genom att utnyttja de reaktioner som uppstod i de polymera materialen vid sterilisering, med elektron- eller gammastrålning, erhölls förutbestämbara slutgiltiga egenskaper för de porösa strukturerna. Detta uppnåddes genom att skapa material som påverkas på ett specifikt sätt vid bestrålning. Genom att förändra strålningstyp, strålningsdos, monomerer och sammansättningar ändrades känsligheten mot strålning och de reaktionsmekanismer som inducerats. Steriliseringsprocessen blir härmed inkorporerad som ett sista steg i framställningen av de porösa strukturerna.

En fri radikal ringöppningspolymerisation utvecklades för monomeren 2-metylen-1,3-dioxe-5-pen. Reaktionsprodukterna bestämdes och en reaktionsmekanism föreslogs, som ett första steg i framställningen av en innovativ multifunktionell polyester. Reaktionsmekanismen är temperaturberoende och propagering är hämmad på grund av stabiliteten av den allylradikal som bildas vid ringöppning. Vid högre reaktionstemperaturer bildades den cykliska estern 3-vinyl-1,4-butyrolakton som huvudprodukt. Vid lägre temperaturer var den huvudsakliga produkten oligomerer bestående av både ringöppnade och ringslutna repeterande enheter.

Place, publisher, year, edition, pages
Stockholm: KTH , 2009. , 58 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:20
Keyword [en]
Ring-opening polymerization, Stannous octoate, 2, 2’-azoisobutyronitrile, 1, 5-dioxepane-2-one, ε-caprolactone, L-lactide, Trimethylene carbonate, 2-methylene-1, 3-dioxe-5-pene, Copolymer, Porous scaffold, Porous tubular scaffold, Electron beam, Gamma irradiation
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-10368ISBN: 978-91-7415-309-5 (print)OAI: oai:DiVA.org:kth-10368DiVA: diva2:216375
Public defence
2009-05-29, E1, KTH, Lindstedtsvägen 3, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100805Available from: 2009-05-14 Created: 2009-05-08 Last updated: 2010-08-05Bibliographically approved
List of papers
1. Elastomeric hydrolyzable porous scaffolds: Copolymers of aliphatic polyesters and a polyether-ester
Open this publication in new window or tab >>Elastomeric hydrolyzable porous scaffolds: Copolymers of aliphatic polyesters and a polyether-ester
2005 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 6, no 5, 2718-2725 p.Article in journal (Refereed) Published
Abstract [en]

Porous scaffolds of 1,5-dioxepan-2-one (DXO), L-lactide (LLA), and epsilon-caprolactone (CL) were prepared by a solvent casting, salt particulate leaching technique in which the composites were detached from their mold using a novel methanol swelling procedure. By incorporating DXO segments into polymers containing LLA or CL, an increase in hydrophilicity is achieved, and incorporating soft amorphous domains in the crystalline sections enables tailoring of the mechanical properties. The porosities of the scaffolds ranged from 89.2% to 94.6%, and the pores were shown to be interconnected. The materials were synthesized by bulk copolymerization of 1,5-dioxepan-2-one (DXO), L-lactide (LLA), and epsilon-caprolactone (CL) using stannous 2-ethylhexanoate as catalyst. The copolymers formed varied in structure; poly(DXO-co-CL) is random in its arrangement, whereas poly(DXO-co-LLA) and poly(LLA-co-CL) are more blocky in their structures.

Keyword
biodegradable polymeric scaffolds, epsilon-caprolactone, l-lactide, mechanical-properties, phase-separation, 1, 5-dioxepan-2-one, degradation, poly(epsilon-caprolactone), poly(l-lactide), polylactones
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-14414 (URN)10.1021/bm050190b (DOI)000231899200042 ()2-s2.0-25844458172 (Scopus ID)
Note
QC 20100805Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
2. Design of Resorbable Porous Tubular Copolyester Scaffolds for Use in Nerve Regeneration
Open this publication in new window or tab >>Design of Resorbable Porous Tubular Copolyester Scaffolds for Use in Nerve Regeneration
2009 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 10, no 5, 1259-1264 p.Article in journal (Refereed) Published
Abstract [en]

Copolymers of L,L-lactide (LLA), epsilon-caprolactone (CL), trimethylene carbonate (TMC), or 1,5-dioxepane-2-one (DXO) were used to design porous tubular scaffolds with various mechanical properties, porosities, and numbers of layers in the tube wall. The mechanical properties of the tubular scaffold types showed good suitability for nerve regeneration and other nonload-bearing tissue engineering applications and were easy to handle without damaging the porous structure. A low stannous 2-ethylhexanoate-to-monomer ratio of 1:10000 did not change the tensile properties of the copolymer tubes significantly compared to those of scaffolds made using a Sn(Oct)(2)-to-monomer ratio of 1:600. The adaptability of the immersion coating and porogen leaching technique was demonstrated by creating tubes with different designs. Tubes with different wall layers were created by varying the immersion solutions, and the ease of altering the porosity, pore shape, and pore size was exemplified by using sodium chloride alone or mixed with poly(ethylene glycol) as porogen.

Keyword
l-lactide; epsilon-caprolactone; trimethylene carbonate; aliphatic polyesters; molecular-weight; cyclic dimer; copolymers; 1, 5-dioxepan-2-one; polymerization; guide
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-14415 (URN)10.1021/bm900093r (DOI)000265914200031 ()2-s2.0-66149089558 (Scopus ID)
Note
QC 20100805Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
3. Finalizing the properties of porous scaffolds of aliphatic polyesters through radiation sterilization
Open this publication in new window or tab >>Finalizing the properties of porous scaffolds of aliphatic polyesters through radiation sterilization
2006 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 27, no 31, 5335-5347 p.Article in journal (Refereed) Published
Abstract [en]

Porous scaffolds made of various L,L-lactide (LLA), 1,5-dioxepane-2-one (DXO) and epsilon-caprolactone (CL) copolymers were sterilized by EB- and gamma-irradiation. Differences in the comonomers, composition and the microstructure of the starting materials were used to influence the degradation mechanism and susceptibility towards irradiation and by this means to achieve sterilized scaffolds with predicted end-properties. The chemical changes and the formation of low-molecular-weight products were determined by SEC, H-1 nuclear magnetic resonance (NMR), C-13 NMR and gas chromatography-mass spectrometry (GC-MS). The degradation mechanism changed from random chain scission to cross-linking depending on the choice of monomers, the copolymer composition and the monomer sequences. Copolymerization of LLA with small amounts of CL or DXO increased the stability compared to that of the LLA homopolymer. Changing DXO to CL in a LLA copolymer also increased the stability. The type of radiation and the microstructure of the copolymer chains determined which of the monomer sequences were more prone to degrade. The most abundant low-molecular-weight product identified after sterilization was DXO monomer. Traces of LLA and CL monomers were also identified. Modification of the copolyester microstructure changed the degradation mechanism and the susceptibility towards irradiation. This allows the use of radiation sterilization to finalize the scaffold properties.

Keyword
electron beam, gamma irradiation, scaffold, copolymer, polycaprolactone, polylactic acid
National Category
Polymer Chemistry Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-14416 (URN)10.1016/j.biomaterials.2006.06.024 (DOI)000240611000001 ()2-s2.0-33746216928 (Scopus ID)
Note

QC 20150720

Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
4. The influence of composition of porous copolyester scaffolds on reactions induced by irradiation sterilization
Open this publication in new window or tab >>The influence of composition of porous copolyester scaffolds on reactions induced by irradiation sterilization
2008 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 2, 129-140 p.Article in journal (Refereed) Published
Abstract [en]

In our previous work regarding radiation sterilization of porous scaffolds we have concluded that the composition and microstructure of the polymer chain are a key factor influencing the degradation reactions occurring upon irradiation. In this work we in contrast reported on the effects of high-energy irradiation on the thermal and mechanical properties. Electron beam (EB)- and T-irradiation sterilization were used in order to finalize the properties of a series of porous scaffolds comprised of different aliphatic polyester copolymers. The results presented here show that, for both sterilization methods, the crystallinity increased for all copolymers of 1,5-dioxepan-2-one (DXO) and L,L-lactide (LLA) at the minimum sterilization dose. The same was true of the P.-caprolactone (CL)- and LLA-containing copolymers upon EB sterilization, while a reduction in crystallinity were found upon gamma-irradiation. As was anticipated, it was shown that crystallinity also is a characteristic of the copolymer influencing the effects of the irradiation-induced reactions. Both the onset temperature and the temperature corresponding to the maximum rate of weight loss increased after irradiation and hence the thermal stability was increased. This is a result of a simultaneous lengthening of the chains by cross-linking reactions and a shortening by random chain-scissions occurring throughout the molecule, which lead to the formation of new endgroups with higher thermal stability. Scaffolds of crystalline polymers retained more of their initial tensile properties after irradiation compared to amorphous materials. The result previously published, showing that the composition was a key factor influencing the degradation reactions occurring upon irradiation, was augmented here.

Keyword
copolymer, sterilization, electron beam, gamma irradiation, POLY-EPSILON-CAPROLACTONE, ALIPHATIC POLYESTERS, THERMAL-DEGRADATION, L-LACTIDE, POLY(LACTIDE-CO-GLYCOLIDE) PLGA, STRUCTURAL INVESTIGATIONS, RADIATION STERILIZATION, POLY(L-LACTIDE) PLLA, MASS-SPECTROMETER, CYCLIC DIMER
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-13610 (URN)10.1016/j.biomaterials.2007.08.046 (DOI)000251492200001 ()2-s2.0-35548945835 (Scopus ID)
Note
QC 20100622Available from: 2010-06-22 Created: 2010-06-22 Last updated: 2017-12-12Bibliographically approved
5. Mapping the Characteristics of the Radical Ring-Opening Polymerization of a Cyclic Ketene Acetal Towards the Creation of a Functionalized Polyester
Open this publication in new window or tab >>Mapping the Characteristics of the Radical Ring-Opening Polymerization of a Cyclic Ketene Acetal Towards the Creation of a Functionalized Polyester
2009 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 47, no 18, 4587-4601 p.Article in journal (Refereed) Published
Abstract [en]

Radical ring-opening polymerization of cyclic ketene acetals is a means to achieve novel types of aliphatic polyesters. 2-methylene-1,3-dioxe-5-pene is a seven-membered cyclic ketene acetal containing an unsaturation in the 5-position in the ring structure. The double bond functionality enables further reactions subsequent to polymerization. The monomer 2-methylene-1,3-dioxe-5-pene was synthesized and polymerized in bulk by free radical polymerization at different temperatures, to determine the structure of the products and propose a reaction mechanism. The reaction mechanism is dependent on the reaction temperature. At higher temperatures, ring-opening takes place to a great extent followed by a new cyclization process to form the stable five-membered cyclic ester 3-vinyl-1,4-butyrolactone as the main reaction product. Thereby, propagation is suppressed and only small amounts of other oligomeric products are formed. At lower temperatures, the cyclic ester formation is reduced and oligomeric products containing both ring-opened and ring-retained repeating units are produced at higher yield.

Keyword
cyclic ketene acetal, polyester, radical polymerization, reaction mechanism, ring-opening polymerization
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-14418 (URN)10.1002/pola.23511 (DOI)000269632500011 ()2-s2.0-69549083370 (Scopus ID)
Note
QC 20100805Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved

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