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Controlled Degradation of Polyester-Ethers Revealed by Mass Spectrometry Techniques
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

The use of degradable biomedical materials in e.g. tissue engineering and controlled drug delivery has changed medical science during recent decades. The key question is to adapt the material with respect to mechanical properties, surface characteristics, and degradation profile to suit its intended application. Products formed during the degradation of bioresorbable materials are generally considered non-toxic and they are excreted from the human body. However, large amounts of specific degradation products such as hydroxyacids and oligomers may induce a pH decrease and a subsequent inflammatory response at the implantation site.

 

In this study, macromolecular design and a combination of cross-linking and adjusted hydrophilicity are utilized as tools to control and tailor the degradation rate and the subsequent release of degradation products from polyester-ethers. A series of different homo- and copolymers of e-caprolactone (CL) and 1,5-dioxepan-2-one (DXO) were synthesized and their hydrolytic degradation was monitored in aqueous media at 37 °C for up to 546 days. The low and medium molar mass degradation products released during hydrolysis were monitored by various mass spectrometry techniques. The materials studied included linear DXO/CL triblock and multiblock copolymers, PCL and PDXO linear homopolymers, and cross-linked homo- and random copolymers of CL/DXO where 2,2’-bis-(ε-caprolactone-4-yl) propane (BCP) was used as a cross-linking agent.

 

The results show that macromolecular engineering and controlled hydrophilicity of cross-linked networks are useful tools for customizing the release rate of acidic degradation products. Thereby, the formation of local acidic environments is prevented and the risk of inflammatory responses in the body is reduced.

Abstract [sv]

Läkarvetenskapen har under de senaste årtiondena förändrats genom användandet av nedbrytbara biomedicinska material inom t.ex. vävnadsersättning och kontrollerad läkemedelsfrisättning. Nyckeln är att anpassa materialets mekaniska egenskaper, ytegenskaper och nedbrytningsprofil för den tilltänkta tillämpningen. Produkterna som bildas under nedbrytningen av bioresorberbara material anses generellt vara icke-toxiska och utsöndras ur människokroppen, men stora mängder specifika nedbrytningsprodukter som t.ex. hydroxysyror kan orsaka en pH-sänkning och därmed en inflammatorisk reaktion vid implantationsplatsen.

 

I detta arbete används makromolekylär design och en kombination av tvärbindning och anpassad hydrofilicitet som verktyg för att kontrollera och skräddarsy nedbrytningshastigheten och den efterföljande frisättningen av nedbrytningsprodukter från polyester-etrar. En serie av olika homo- och sampolymerer av e-kaprolakton (CL) och 1,5-dioxepan-2-on (DXO) syntetiserades och deras hydrolytiska nedbrytning studerades i vattenlösning vid 37 °C i upp till 546 dagar. De låg- och medelmolekylära nedbrytningsprodukterna som frisattes under hydrolysen analyserades med olika masspektrometritekniker. Materialen som undersöktes inkluderade linjära DXO/CL triblock- och multiblocksampolymerer, linjära PCL och PDXO homopolymerer, samt tvärbundna homo- och slumpvisa sampolymerer av CL och DXO där 2,2’-bis(e-kaprolakton-4-yl)propan (BCP) användes som tvärbindare.

 

Resultaten visar att makromolekylär design och tvärbundna nätverk med kontrollerad hydrofilicitet är användbara verktyg för att skräddarsy frisättningshastigheten av sura nedbrytningsprodukter. Därmed kan bildandet av lokalt sura miljöer förhindras och risken för inflammatoriska reaktioner i kroppen minskas.

 

Place, publisher, year, edition, pages
Stockholm: KTH , 2008. , 59 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2008:57
Keyword [en]
Degradation products, biocompatibility, -caprolactone, 1, 5-dioxepan-2-one, 6-hydroxyhexanoic acid, 3-(2-hydroxyethoxy)propanoic acid, oligomers
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4898ISBN: 978-91-7415-098-8 (print)OAI: oai:DiVA.org:kth-4898DiVA: diva2:1812
Public defence
2008-09-26, F3, KTH, Lindstedtsvägen 26, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100812Available from: 2008-09-17 Created: 2008-09-17 Last updated: 2010-08-12Bibliographically approved
List of papers
1. Controllable Degradation Product Migration from Cross-Linked Biomedical Polyester-Ethers through Predetermined Alterations in Copolymer Composition
Open this publication in new window or tab >>Controllable Degradation Product Migration from Cross-Linked Biomedical Polyester-Ethers through Predetermined Alterations in Copolymer Composition
2007 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 6, 2025-2032 p.Article in journal (Refereed) Published
Abstract [en]

Uniformly degrading biomaterials with adjustable degradation product migration rates were customized by combining the advantages of cross-linked poly(epsilon-caprolactone) with the hydrophilic character of poly(1,5-dioxepan-2-one). Hydrolytic degradation of these random cross-linked networks using 2,2'-bis-(epsilon-caprolactone-4-yl) propane (BCP) as the cross-linking agent was studied for up to 546 days in phosphate buffer solution at pH 7.4 and 37 degrees C. The hydrophilicity of the materials was altered by varying the copolymer compositions. After different hydrolysis times the materials were characterized, and the degradation products were extracted from the buffer solution and analyzed. Fourier transform infrared spectroscopy, differential scanning calorimetry, atomic force microscopy, scanning electron microscopy, and gas chromatography-mass spectrometry were used to observe the changes taking place during the hydrolysis. From the results it was concluded that degradation profiles and migration of degradation products are controllable by tailoring the hydrophilicity of cross-linked polyester-ether networks.

Keyword
Biomaterials; Crosslinking; Degradation; Ethers; Hydrolysis; Hydrophilicity; Polyesters; Hydrolytic degradation; Product migration
National Category
Polymer Chemistry Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-8054 (URN)10.1021/bm070292x (DOI)000247107900035 ()2-s2.0-34347335743 (Scopus ID)
Note

QC 20100812

Available from: 2008-03-03 Created: 2008-03-03 Last updated: 2016-05-30Bibliographically approved
2. Tuning the release rate of acidic degradation products through macromolecular design of caprolactone-based copolymers
Open this publication in new window or tab >>Tuning the release rate of acidic degradation products through macromolecular design of caprolactone-based copolymers
2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 19, 6308-6312 p.Article in journal (Refereed) Published
Abstract [en]

Macromolecular engineering is presented as a tool to control the degradation rate and release rate of acidic degradation products from biomedical polyester ethers. Three different caprolactone/1,5-dioxepan-2-one (CL/DXO) copolymers were synthesized: DXO/CL/DXO triblock, CL/DXO multiblock, and random cross-linked CL/DXO copolymer. The relation of CL and DXO units in all three copolymers was 60/40 mol %. The polymer discs were immersed in phosphate buffer solution at pH 7.4 and 37 degrees C for up to 364 days. After different time periods degradation products were extracted from the buffer solution and analyzed. In addition mass loss, water absorption, molecular weight changes, and changes in thermal properties were determined. The results show that the release rate of acidic degradation products, a possible cause of acidic microclimates and inflammatory responses, is controllable through macromolecular design, i.e., different distribution of the weak linkages in the copolymers.

Keyword
epsilon-caprolactone, aliphatic polyesters, hydrolytic degradation, l-lactide, 1, 5-dioxepan-2-one, polymers, implants, polymerization, glycolide, blends
National Category
Polymer Chemistry Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-16623 (URN)10.1021/ja0702871 (DOI)000246415100047 ()2-s2.0-34249041978 (Scopus ID)
Note

QC 20150720

Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
3. Fingerprinting the degradation product patterns of different polyester-ether networks by electrospray ionization mass spectrometry
Open this publication in new window or tab >>Fingerprinting the degradation product patterns of different polyester-ether networks by electrospray ionization mass spectrometry
Show others...
2008 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 46, no 13, 4617-4629 p.Article in journal (Refereed) Published
Abstract [en]

Fingerprinting of the degradation product patterns by electrospray ionization mass spectrometry (ESI-MS) was evaluated as a tool to monitor the degree of degradation in polyester-ether networks. Four different crosslinked caprolactone (CL) and/ or 1,5-dioxepan-2-one (DXO) networks were subjected to hydrolytic degradation in aqueous solution at 37 degrees C for up to 147 days. After predetermined time periods, the water-soluble degradation products were analyzed by ESI-MS and tandem ESI-MS. In addition, changes in pH, mass loss, and copolymer composition were determined. In the case of more slowly hydrolyzed CL-rich (co)polymers, CL and/or DXO oligomers terminated by hydroxyl and carboxyl end groups were predominantly formed as degradation products. However, on prolonged hydrolysis oligomers with attached crosslinking agent dominated the degradation product patterns of more easily hydrolyzed DXO-rich (co)polymers. It was shown that in the recorded mass spectra the variation of intensities in the series of ions corresponding to DXO and CL/DXO oligomers with or without attached crosslinking agent could be utilized to monitor the extent of hydrolytic degradation in the polyester matrix and the disruption of the network structure.

Keyword
biocompatibility, crosslinking, degradation, mass spectrometry, polyesters, molecular-weight products, in-vitro degradation, epsilon-caprolactone, matrix changes, 1, 5-dioxepan-2-one, polymers, poly(epsilon-caprolactone), polyethylene, polylactide, delivery
National Category
Polymer Chemistry Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-17642 (URN)10.1002/pola.22796 (DOI)000257153500033 ()2-s2.0-46349108984 (Scopus ID)
Note

QC 20100525

Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
4. ESI-MS reveals the influence of hydrophilicity and architecture on the water-soluble degradation product patterns of biodegradable homo- and copolyesters of 1,5-dioxepan-2-one and epsilon-caprolactone
Open this publication in new window or tab >>ESI-MS reveals the influence of hydrophilicity and architecture on the water-soluble degradation product patterns of biodegradable homo- and copolyesters of 1,5-dioxepan-2-one and epsilon-caprolactone
Show others...
2008 (English)In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 41, no 10, 3547-3554 p.Article in journal (Refereed) Published
Abstract [en]

The hydrolytic degradation process and degradation product patterns of biodegradable homo- and copolyesters of 1,5-dioxepan-2-one (DXO) and epsilon-caprolactone (CL) were monitored by electrospray ionization mass spectrometry (ESI-MS). The degradation product patterns were compared to mass loss, molecular weight changes, copolymer composition, and pH changes after various hydrolysis times. Water-soluble oligomers up to heptadecamer were identified after hydrolysis of hydrophilic PDXO, while only oligomers up to hexamer were detected after hydrolysis of the more hydrophobic PCL. The product pattern of DXO-CL-DXO triblock copolymer mainly consisted of DXO-based oligomers, whereas the CL/DXO multiblock copolymer degradation product pattern contained DXO and CL oligomers as well as oligomers containing both DXO and CL units. The DXO-rich oligomers, however, dominated the product patterns. ESI-MS gave valuable insights into the hydrolysis process of hydrophobic and hydrophilic polyesters and showed that hydrophilicity of the polymer as well as copolymer architecture both greatly influenced the water-soluble degradation product patterns.

Keyword
ring-opening polymerization, molecular-weight products, mass-spectrometry, copolymers, polyesters, oligomers, acids
National Category
Polymer Chemistry Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-17545 (URN)10.1021/ma800365m (DOI)000256058000025 ()2-s2.0-45749126984 (Scopus ID)
Note

QC 20100525

Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
5. Spontaneous Crosslinking of Poly(1,5-dioxepan-2-one) Originating from Ether Bond Fragmentation
Open this publication in new window or tab >>Spontaneous Crosslinking of Poly(1,5-dioxepan-2-one) Originating from Ether Bond Fragmentation
2008 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 46, no 21, 7258-7267 p.Article in journal (Refereed) Published
Abstract [en]

The spontaneous reaction of unsaturated double bonds induced by the fragmentation of ether bonds is presented as a method to obtain a crosslinked polymer material. Poly(1,5-dioxepan-2-one) (PDXO) was synthesized using three different polymerization techniques to investigate the influence of the synthesis conditions on the ether bond fragmentation. It was found that thermal fragmentation of the ether bonds in the polymer main chain occurred when the synthesis temperature was 140 degrees C or higher. The double bonds produced reacted spontaneously to form cross-links between the polymer chains. The formation of a network structure was confirmed by Fourier transform infrared spectrometry and differential scanning calorimetry. In addition, the low molar mass species released during hydrolysis of the DXO polymers were monitored by ESI-MS and MALDI-TOF-MS. Ether bond fragmentation also occurred during the ionization in the electrospray instrument, but predominantly in the lower mass region. No fragmentation took place during MALDI ionization, but it was possible to detect water-soluble DXO oligomers with a molar mass up to approximately 5000 g/mol. The results show that ether bond fragmentation can be used to form a network structure of PDXO.

Keyword
crosslinking, degradation, mass spectrometry, polyester-ethers, ring-opening polymerization, ring-opening polymerization, collision-induced dissociation, degradation-product patterns, ionization mass-spectrometry, epsilon-caprolactone, l-lactide, block-copolymers, 1, 5-dioxepan-2-one, hydrophilicity, polyglycols
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-17940 (URN)10.1002/pola.23037 (DOI)000260587100035 ()2-s2.0-55349110646 (Scopus ID)
Note
QC 20100525Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved

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