Cornelissen, Maria

De Clercq, Heidi

Gasthuys, Frank

Gorski, Tomek

Jackers, Geert

Paesen, B

Schacht, Etienne

Van der Vreken, N

Verbeeck, Ronald

Vlaminck, Lieven

Ghent University Academic Bibliography

Bone regeneration scaffolds prepared fromcrosslinkable biodegradable polymersE. Schacht, T. Gorski, B. Paesen, G. Jackers, R. Cornelissen, H. DeClercq, R. Verbeeck, N. Van den Vreken, F. Gasthuys, L. VlaminckInstitute for Biomedical Technologies- IBITECHUniversiteit GentKrijgslaan, 281 – B-9000 Ghent – Belgiumetienne.schacht@Ugent.beIntroduction     Osseous  tumors, trauma, disease and birth defects can create aneed to fill bone tissue deficiencies in the skeletal system. We havedeveloped in situ crosslinkable, biodegradable,methacrylate–endcapped polymers based on glycolide, D,L-lactide,trimethylene carbonate (TMC) and e-caprolactone as well aspoly(ortho-esters) for bone tissue regeneration. Crosslinkage can beinititated by redox type or photoinitiators. By adding controlledamounts of gelatine powders of selected size, scaffolds can beobtained with controlled porosity, pore size and pore connectivity. Inaddition calcium phosphates or other osteoconductive materials likebioplant HTR or demineralised bone can be added.Experimental     Materials. Linear and branched low molecular weight copolyesterswith viscous-liquid properties were prepared using ring openingpolymerization of cyclic monomers, zinc acetate as catalyst anddifferent types of alcohol initiators. In a second step the hydroxylmoieties were derivatized into methacrylate endgroups bymethacryloyl chloride [1].Poly(ortho esters) bismethacrylates were prepared in a one-potsynthesis as shown in Figure 1.Figure 1: Synthesis of low molecular weight poly(ortho esters).The diols and HEMA were dissolved in dry tetrahydrofuran (THF).The mixture is stirred until all solids are dissolved; then 3,9-di-ethylidene-2,4,8,10-tetraoxaspiro[5,5]-undecane (DETOSU) is added.The polymerization is initiated by the addition of a trace of a 10mg/ml solution of p-toluene sulfonic acid (pTSA) in THF. Thereaction temperature rapidly rises to the boiling point of THF and thangradually decreases. After 60 min the polymers were precipitated inMeOH and triethylamine is added as stabilizer. To completeprecipitation the mixture was kept overnight in a freezer at –22°C.Afterwards the methanol was removed and the polymers were dried ina vacuum oven during two days to remove traces of solvents.The methacrylate–endcapped copolymers were converted into a solid,3-D polymer network by visible-light irradiation in the presence ofD,L-camphorquinone/N-phenylglycine initiator system [2].By mixing, before irradiation, the liquid-viscous oligomers withdifferent types of additives such as gelatin with defined particles size,a- or b-tricalcium phosphate salts or HTRTM–24 (Bioplant®)materials with pore forming and osteoconductive properties can beobtained [3].Results and discussion     Polyester-based scaffolds.  Using monomer/initiator ratio 20/1and polymer composition: 50:50(mol%) D,L-lactide/e-caprolactone(trimethylene carbonate) and 30:70(mol%) glycolide/  e-caprolactone(trimethylene carbonate) we are able to obtain viscous-liquidmethacrylate-endcapped oligomers  which can be mixed manuallywith different types of additives. To improve the viscous propertiesand decrease the Tg of the copolymers based on glycolide or D,L-lactide and TMC, triacetin was used as a plasticizer.Mechanical properties of the crosslinked polymer network can becontrolled  by using different types of alcohol initiators such as 1,6-hexanediol [HXD], trimethylolpropane [TMP], pentaerythritol[PENT] and dipentaerythritol [DPENT]:Table I. Molecular weight measured by GPC (PS standards, eluent –THF), thermal properties (DSC, 2nd run) and compressive modulus ofthe copolymers based on D,L-lactide - e-caprolactone and differenttypes of the alcohol initiators.Type oftheinitiatorMn [g/mol] Mw/Mn Tg [oC] E [MPa]HXD 2800 1.5 -26.4 27TMP 3000 1.5 -21.9 43PENT 3300 1.4 -21.9 46DPENT 2900 1.4 -21.3 91Additionally the mechanical properties of the composites can besignificantly improved using different types of additives.The gelatin particles are leached out leaving open cells with a poresize and morphology defined by the gelatin particles and providing theosteoconductive properties of the composites.Finally, by changing the polymer composition, crosslinking density,type and amount of additives we are able to control the degradationrate of the composite.     Polyorthoester-based scaffolds.  The molecular weight of thepolymers could not be controlled by varying the stoichiometry of themonomer. Therefore, a monofunctional monomer, HEMA, is added inthe beginning of the reaction.Figure 2 shows that an increase in HEMA results in a decreasedmolecular weight. In the absence of HEMA the molecular weight ismore than double as we expected.Figure 2 : Control of the molecular weight by adding an increasingamount of HEMA the reaction.3rd s tepmethacryloyl    chlorideOCOR'+Zn(OAc)2R OH( )nR O COR' O H( )m( )n1st s tepR O COR' O COC CH2CH3( )m( )n2nd s tepD,L-camphorquinone   N-phenylglycinehv    biodegradable  polymer networkn  -  2 ,  3 ,  4 ,  6OO OOHO R OH+ OOOH+OO OO OO OOOOO O R O OOOpTSA020004000600080000 1 1.25 1.5 1.75 2 2.5amount of HEMAMn (g/mol)HEMA addition allows to control the molecular weight and theendgroup functionality in the polymer chain. The physical properties,such as glass transition, hydrofibicity and viscosity, can be controlledusing different diol monomers.Polymers were characterized by NMR, GPC, DSC and FT-IR.The glass transition temperatures of the polymers can be controlled byusing different diols (Figure 3).Figure 3 : Glass transition temperatures for different homopolymersusing diols with different chain flexibility.The glass transition temperature decreases when the chain flexibilityof the polymers increases. To obtain viscous polymers flexibel diolshave to be used. The prepolymers were converted into a biodegradablenetwork, after addition of a photo initiator, by irradiation with a dentallamp. Conversion profiles of the bismethacrylate prepolymers weredetermined by real-time Fourier transform infrared spectroscopy.     Biological evaluation. In vitro biocompatibility studies, usingfibroblast or osteoblast cell lines and the MTT-method as a test forcell viability indicated that the various crosslinked polymers andcomposites were well tolerated. Studies with osteoblast cell linesclearly showed that the ingrowth of cells is strongly related to thedegree of porosity and the pore size. A porosity of minimal 70 vol% ispreferred. Preliminary implant studies in sheep thibia indicated thatthe composite materials gave no severe inflammation reactions. Thematerials degraded and bone formation occurred. In a separate study,the osteogenic property was investigated in vivo using cranial critical-sized bone defects (CSD) on beagle dogs as in vivo model.Demineralised Bone Powder was selected  as bioactive additive. Theimplants proved to be compatible. Bone formation occured from theperiphery but the amount of newly formed bone was less than thecontrol defect (autologous bone). The implant site was wellrevascularized.More details on the biological studies will be presented and discussed.Conclusions     Low molecular weight bismethacrylate endcapped polyesters andpoly(ortho-esters) are synthesized. In case of the polyesters, themolecular weight and chemical composition can be easily controlledby the selection of comonomers and the monomer tot initiator ratio.Mechanical properties can be varied by the functionality of theinitiating diol. In case of the poly(ortho-esters), the molecular weightcould be controlled using HEMA as a chain stopper in the reaction.Material properties were controlled by the choice of diols.These bismacromonomer-type prepolymers can easily be convertedinto a 3-D biodegradable network using a photo initiator andirradiation with blue light.The presented injectable, in situ polymerizable, biodegradablecomposites may serve as scaffolds for guided bone regeneration andmay provide an alternative for irregular bone defect treatment.References[1] Robson F. Storey et al, (1993), Polymer, 34,  4365-4372[2] Kucybala Z et al, (1996), Polymer, 20, 4585-4596[3] Thomson R. et al, (1995), J. Biomater. Sci.   Polymer Edn, 7, 23-38AcknowledgementsThis work is supported by the Ghent University (BOF GOA-project) ,by the Belgian Government – Belgian Science Policy (IUAP-V-03)and by the Institute for Encouragement of Science and Technology inFlandern (IWT) (GBOU-project)-40-30-20-10010203040Tg (°C)POE-CDMPOE-EG POE-BUDPOE-HXDPOE-NODPOE-DOD

Bone regeneration scaffolds prepared from crosslinkable biodegradable polymers

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Bone regeneration scaffolds prepared from crosslinkable biodegradable polymers

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