Elastomeric networks based on trimethylene carbonate polymers for biomedical applications: physical properties and degradation behaviour
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- Tez No: 400009
- Danışmanlar: PROF. DR. D. W. GRIJPMA, PROF. DR. J. FEIJEN
- Tez Türü: Doktora
- Konular: Kimya, Chemistry
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2010
- Dil: İngilizce
- Üniversite: University of Twente
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 256
Özet
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Özet (Çeviri)
The number of applications for biomedical technologies is ever-increasing, and thereis a need to develop new materials with properties that can conform to the requirements of aspecific application. Synthetic polymers are of great importance in the biomedical field asthey can be designed to exhibit a wide range of physical- and biological properties and arange of degradation profiles. Interest in biodegradable elastomers is increasing, particularlyfor the engineering of soft and elastic tissues. These materials are also being utilized more andmore for controlled drug delivery purposes.In this thesis, the development of biodegradable elastomers based on trimethylenecarbonate polymers using different approaches is presented.A general introduction to the thesis and the relevant scientific background informationregarding this study is given in Part I. The aim of the study and the structure of the thesis arepresented in Chapter 1. General information on degradation and erosion of syntheticbiodegradable polymers and on tissue engineering is presented in Chapter 2. The need forbiodegradable elastomers in preparing scaffolds in (soft-) tissue engineering is highlighted byoutlining recent findings in the literature. In the final section of this chapter, a short literaturereview on biodegradable elastomers and trimethylene carbonate (TMC) based elastomers isprovided. In Chapter 3, the mechanical- and biological properties of poly(trimethylenecarbonate) (PTMC) crosslinked by gamma irradiation is evaluated. It was found thatcrosslinked PTMC films promote the adhesion and proliferation of neo-natal cardiomyocytes.The porous scaffolds had stiffness values close to those of human myocardium, making thismaterial interesting as a scaffolding material for cardiac tissue engineering. It was also shownthat these materials were angiogenic and eroded rapidly upon implantation on the heart ofrats.A first approach to obtain elastomeric networks with lower erosion rates was toprepare networks by crosslinking of TMC copolymers using different doses of gammairradiation (Part II). Trimethylene carbonate was copolymerised with ?-caprolactone (CL) aspoly(?-caprolactone) can also be crosslinked by gamma irradiation and erodes at a muchlower rate in vivo than PTMC. It is shown in Chapter 4 that elastomeric networks couldindeed be prepared by gamma irradiation of poly(trimethylene carbonate-co-?-caprolactone)films although their gel contents and network densities were relatively low. Nevertheless,even at low gel contents the tensile strength and elongation at break values were higher forgamma irradiated copolymers than for the non-irradiated ones. These materials degraded bysurface erosion upon incubation in aqueous lipase solutions. The enzymatic erosion rates ofthese films could be tuned by adjusting the (co)polymer composition and the irradiation dose(for homopolymers). Contrary to our expectations, however, the erosion rates increased withincreasing CL content. Although previous studies showed that aqueous lipase solutions couldbe used to predict the in vivo erosion rate of PTMC, apparently for CL containing(co)polymers this was not the case. Therefore, we then investigated the in vivo erosion ofthese networks by subcutaneous implantation in rats (Chapter 5). These studies showed thatin vivo erosion of these networks was not affected much by copolymerisation of TMC with upto 30 mol % CL or by tuning the network density by adjusting the irradiation dose. The tissueresponse to these (co)polymer networks and their erosion rates were comparable to those ofpreviously investigated non-irradiated PTMC films. These surface eroding (co)polymernetworks are more suitable for short-term biomedical applications, and it was concluded that adifferent approach need to be taken to prepare more slowly eroding elastomers.In the investigations described in Chapters 4 and 5, the CL content was limited to 30mol %, as TMC copolymers having 30 to 70 mol % CL were previously reported to have poormechanical strength. However, the results obtained in Chapter 4 suggest that relativelystrong and creep-resistant networks could be prepared by gamma irradiation of copolymerscontaining more than 30 % CL. The mechanical properties and biodegradation behaviour ofthese (co)polymer networks is presented in Appendix A.In Part III, initially an in vitro macrophage culture model was first set-up toinvestigate the erosion behaviour of networks prepared from trimethylene carbonate polymersand to assess the effect of structural parameters on this behaviour. The development of thismodel is described in Chapter 6. Using this in vitro assay, it was clearly demonstrated thatmacrophages are able to erode gamma irradiated PTMC films effectively whereas no effect ongamma irradiated PCL films (which were used as controls) was observed. This studydemonstrated that a physical contact between the macrophages and PTMC network films is aprerequisite for erosion to occur. It was shown that selected enzymes and reactive oxygenspecies that can be secreted by macrophages were likely to be involved in these erosionprocesses. Particularly, the erosion behaviour of PTMC- and PCL networks in aqueoussolutions of cholesterol esterase was shown to be similar to that observed in in vivoexperiments as well as in macrophage cultures.As the elastomeric networks prepared from TMC and CL copolymers did not havesignificantly lower erosion rates than that of linear high molecular weight PTMC polymersand PTMC networks, we evaluated new strategies to prepare relatively slowly eroding,elastomeric trimethylene carbonate-based networks. It was hypothesized that furtherincreasing the network densities and gel contents of PTMC networks would yield slowerosion rates. Chapter 7 presents a systematic investigation of the effect of gamma irradiationdose and initial polymer molecular weight on the properties of PTMC networks. By gammairradiation of PTMC films that incorporate pentaerythritol triacrylate (PETA) as acrosslinking aid, a remarkable increase in gel contents and network densities could beachieved. The gel contents and network densities could be increased by increasing (i) initialpolymer molecular weight, (ii) PETA content, and (iii) irradiation dose. The denselycrosslinked PETA containing PTMC networks were still flexible, elastomeric and non-toxicto cells. Moreover, upon incubation in aqueous cholesterol esterase solutions, PETAcontainingPTMC networks prepared by gamma irradiation eroded at lower rates whencompared to PTMC networks that did not contain PETA.This promising approach was then extended to poly(trimethylene carbonate-co-D,Llactide)(co)polymers, as presented in Chapter 8. PDLLA or (co)polymers of DLLA withTMC either degrade or crosslink very inefficiently upon sterilization by gamma irradiation.This adversely influences their strength and leads to a more rapid erosion (compared to nonirradiated (co)polymers) of implants prepared from these materials. The work showed that byincorporating PETA into these copolymer films, amorphous TMC and DLLA (co)polymernetworks with high gel contents and high network densities could be easily obtained. Thenetworks had a wide range of elastic moduli and glass transition temperatures. Moreover, theyexhibited large recoverability upon deformation, and were compatible with cells. Themacrophage-mediated erosion of TMC and DLLA (co)polymers could be tuned by adjustingthe (co)polymer composition and by crosslinking in the presence of PETA. The surfaceerosion behaviour of these materials was more pronounced with increasing TMC contents.To be able to perform these crosslinking reactions under more moderate conditions inhouse, we investigated the possibility of crosslinking trimethylene carbonate polymers byultraviolet light. This is reported in Chapter 9. Crosslinking in this manner would also permitstabilisation of the shape of any device prepared from these polymers immediately afterprocessing at much lower costs. It was shown that by UV irradiation of PTMC filmscontaining pentaerythritol triacrylate (PETA) and a photoinitiator, flexible, biodegradablenetworks with high toughness and excellent elastomeric behaviour could readily be prepared.The network characteristics, mechanical properties, wettability, and in vitro enzymatic erosionbehaviour of the networks could easily be tuned by selection of the initial molecular weight ofPTMC or by crosslinking blends of PTMC with block copolymers containing PTMC,poly(ethylene glycol) and PCL blocks. We demonstrated the advantage of this crosslinkingmethod by preparing scaffolds for tissue engineering by fused deposition modelling. PTMCand its blends with different block copolymers were thermally processed in the presence of acrystallisable solvent and subsequently crosslinked using ultraviolet light. These scaffolds hadinterconnected macropores. Due to leaching out of the solvent, micropores also formed on thefibres. Moreover, the scaffolds prepared from PTMC and blends with PCL containing blockcopolymers were shown to be suitable for the culturing of human mesenchymal stem cellsmaking them attractive for tissue engineering applications. Scaffolds prepared from blendswith PEG containing block copolymers reduced or prevented the adhesion of cells.In Chapter 10, we report on the crosslinking of high molecular weight PTMC usingonly a (relatively) biocompatible photoinitiator or a photoinitiator together with methacrylateend-functionalised PTMC oligomers as crosslinking aids. By adjusting the methacrylatecontent or the irradiation time, the preparation of resorbable networks with high gel contentsand tuneable network densities was possible. The formed flexible and elastomeric networkswere compatible with (stem-) cells. Crosslinking with a macromer and/or a photoinitiator alsoallowed the preparation of TMC-based materials with lower erosion rates than noncrosslinkedPTMC as assessed using macrophage cultures, aqueous solutions- of cholesterolesterase and potassium superoxide.In Part IV, the work presented in Chapters 4 and 5 is extended to copolymers ofTMC and CL having higher CL contents (Appendix A). Although the mechanical propertiesof the amorphous (co)polymer could be improved by gamma irradiation, increasing the CLcontent in the copolymers also did not reduce the in vivo erosion rates of amorphous(co)polymer networks very significantly. Networks prepared from semi-crystalline(co)polymers of TMC and CL did erode at lower rates than amorphous (co)polymers.However, these networks deformed plastically upon application of stress, and were thereforenot ideal for engineering of elastic (soft-) tissues. The suitability of macrophage cultures inassessing the effect of structural parameters of the materials on their erosion behaviour wasconfirmed in this study, as the results of macrophage-mediated erosion studies performedwith these networks were similar with those obtained by in vivo studies.In Appendix B, thermoresponsive hydrogels based on triblock copolymerssynthesized from TMC and polyethylene glycol (PEG) are presented. The gelation behaviourand the rheological behaviour of the gels depended on the composition and concentration ofthe copolymer in water.The work described in this thesis shows that by using a crosslinking aid, elastomericnetworks can be obtained in a very practical manner from linear trimethylene carbonatepolymers. The erosion rates and the physical- and biological properties of these networks canbe easily varied for instance by copolymerisation, blending, or by adjusting the crosslinkingaid content, initial polymer molecular weight, etc. These materials exhibited interestingbiological properties as was assessed by initial cell culturing assays performed usingmacrophages and mesenchymal stem cells. Nevertheless, these very interesting materials needto be further evaluated with regard to biological properties when a specific application in softtissue engineering or controlled drug release is envisaged.
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