Hard scaffold

专利摘要:
Pss447ssiioo ABSTRACT The present document is directed to medical impiants in the form of titanâurn dioxidescaffolds. Disclosed Es a method for producing titanium dioxide scaffolds having anincreased mechanical strength by recoating the titanium dioxide scaffold with a lowviscosity titanium dioxide slurry in a vacuum infiitration process fotlowed by sintering of thescaffold. The document is also directed to the recoated titanium dioxide scaffoldsproduced and their uses as medical implants.
公开号:SE1251044A1
申请号:SE1251044
申请日:2012-09-18
公开日:2014-03-19
发明作者:Håvard Jostein Haugen；Ståle Petter Lyngstadaas；Hanna Tiainen
申请人:Corticalis As；
IPC主号:

专利说明:

PS54478SE00 HARD SCAFFOLD TECHNICAL FIELD The present document is direct to scaffold structures which may be used as in medicalapplications as medical prosthetic devices. The document discloses a method forproducing titanium dioxide scaffolds having an improved mechanical strength by arecoating procedure and scaffolds produced by this method. The scaffolds have a highmechanical strength while the necessary pore architecture is left basically unaffected bythe method for improving the strength.
BACKGROUND OF THE INVENTION Conditions such as trauma, tumours, cancer, periodontitis and osteoporosis may lead tobone loss, reduced bone growth and volume. For these and other reasons it is of greatimportance to find methods to improve bone growth and to regain bone anatomy.Scaffolds may be used as a framework for the celis participating in the bone regenerationprocess, but also as a framework as a substitute for the lost bone structure. lt is also ofinterest to provide a scaffold to be implanted into a subject having a surface structure thatstimulates the bone ceiis to grow allowing a coating of the impianted structure by bone after a healing process.
Orthopaedic implants are utiiized for the preservation and restoration of the function in themuscuioskeletai system, particulariyjoints and bones, including alleviation of pain in thesestructures. Orthopaedic irnpiants are commonly constructed from materiais that are stabtein biological environments and that withstand physical stress with minimal deformation.These materials must possess strength, resistance to corrosion, have a goodbiocompatibility and have good wear properties. Materials which fulfil these requirements include biocompatible materials such as titanium and coboit-chrome ailoy.
For the purposes of tissue engineering it is previously known to use scaffolds to supportgrowth of cells. lt is believed that the scaffoid pore size (pore diameter), porosity andinterconnectivity are important factors that influence the behaviour of the ceiis and thequality of the tissue regenerated. Prior art scaffolds are typically made of calcium phosphates, hydroxyl apatites and of different kinds of polymers.
PS54478SE00 One principie of tissue engineering is to harvest celts, expand the cell population in vitro, ifnecessary, and seed them onto a supporting three-dimensional scaflold, where the cellscan grow into a complete tissue or organ. For most clinical appiications, the choice ofscaffold material and structure is cruciai. ln order to achieve a high cell density within thescaffold, the materia! needs to have a high surface area to volume ratio. The pores mustbe open and large enough such that the cells can migrate into the scaffoids. When cellshave attached to the material surface there must be enough space and channeis to allowfor nutrient delivery, waste removai, exciusion of material or celis and protein transport,which is only obtainabie with an interconnected network of pores. Bioiogical responses toimplanted scaffolds are also influenced by scaffold design factors such as three-dimensional rnicroarchitecture. in addition to the structural properties of the material,physical properties of the material surface for cell attachment are essential.
Bone in-growth is known to preferentiaily occur in highly porous, open cell structures inwhich the celi size is roughly the same as that of trabecular bone (approximately 0.25-0.5mm), with struts roughly 100 pm (0.1 mm) in diameter. Materials with high porosity andpossessing a controlled microstructure are thus of interest to both orthopaedic and dentalimpiant manufacturers. For the orthopaedic market, bone in-growth and on-growth optionscurrently include the following: (a) DePuy Inc. sinters meta! beads to implant surfaces,leading to a microstructure that is controlled and of a suitabie pore diameter for bone in-growth, but with a tower than optimum porosity for bone in-growth; (b) Zimmer Inc. usesfibre metai pads produced by diffusion bonding loose fibers, wherein the pads are thendiffusion bonded to implants or insert injection moulded in composite structures, whichalso have tower than optimum density for bone in-growth; (c) Biomet Inc. uses a plasmasprayed surface that results in a roughened surface that produces on-growfth, but doesnot produce bone in-growth; and (d) lmplex Corporation produces using a chemicai vapordeposition process to produce a tantalum-coated carbon microstructure that has alsobeen called a metal foam. Research has suggested that this "trabecular metal" leads tohigh quality bone in-growth. Trabecular metal has the advantages of high porosity, anopen-cell structure and a cell size that is conducive to bone in-growth. i-lowever,trabecular metal has a chemistry and coating thickness that are difficult to control.Trabecular meta! is very expensive, due to material and process costs and longprocessing times, primarily associated with chemical vapour deposition (CVD).
PS544 8SE00 3 Furthermore, CVD requires the use of very toxic Chemicals, which is disfavoured inmanufacturing and for biomedical applications. in order to ensure viabie cell attachment, nutrient and waste product transportation,vascuiarisation, and passage of the newiy formed bone tissue throughout the entirescaffold volume, a bone scaffold is required to have a weil-interconnected pore networkwith large pore volume and an average pore connection size preferably exoeeding 100um. ln addition to the reticulated pore space, appropriate pore morphology and averagepore diameter larger than 300 pm are necessary to provide adequate space andpermeabiiity for viable bone formation in a non-resorbable scaffold structure. i-lowever,one of the most important prerequisites for the scaffold structure is that the scaffoldmateriai itseif is fuiiy biocompatibie and favours bone cell attachment and differentiationon its surface to promote the formation of a direct bone-to-scaffold interface.
Ceramic TiOg has been identified as a promising material for scaffold-based bone tissuerepair, and highiy porous TiOQ scaffoids have previously been shown to provide afavourabie microenvironment for viable bone ingrowth from surrounding bone tissue invivo. The excellent osteoconductive capacity of these Ti02 scaffolds has been attributedto the large and highly interoonnected pore volume of the TiOz foam structure. However,as the mechanical properties of a scaffoid are governed not only by the scaffold materia!but also by the pore architecture of the scaffold structure, increasing pore diameters andporosity are known to have a detrimental effect on the mechanical properties of cellularsolids, and consequently reduce the structural integrity of the scaffold construct. As one ofthe key features of a bone scaffolois is to provide mechanical support to the defect siteduring the regeneration of bone tissue, the lack of sufficient mechanical strength limits theuse of the TiOz scaffold structure to skeletal sites bearing only moderate physiologicalloading. The mechanicai properties of such ceramic TiOz foams should therefore beimproved through optimized processing so as to produce bone scatfolds with adequateload-hearing capacity for orthopaedlc applications without cornpromising the desired porearchitectural features of the highly porous TiO2 bone scaffolds.
Reticuiated ceramic foams, such as those of WO08078164, have recently attractedincreasing interest as porous scaffoids that stimulate and guide the natural boneregeneration in the repair of non-healing, or criticai size, bone defects, Since the purposeof such a bone scaffoid is to provide optimal conditions for tissue regeneration, the foam PS54478SEOO 4 structure must allow bone ceii attachment onto its surface as weli as provide sufficientspace for ceil proliferation and unobstructed tissue ingrowth. Therefore, Structure!properties, such as porosity and pore morphology, of the 3D bone scaffold construct playa crucial role in the success of scaffoid-based bone regeneration. Reticulated ceramicfoams may be produced by a so calied replication method or the polymer sponge method.This method was first described by Somers and Schwartzwalder in 1963. ln short, such amethod comprises coating a porous, combustible structure with a meta! oxide slurry, andremoving the porous structure by heating at high temperatures, which causes the removalof the porous structure and fusion of the metal oxide particles.
The mechanicai properties of reticulated ceramic foams prepared by replication methodare strongly dependent on the size and distribution of cracks and ffaws in the foamstructure, which typicaily determine the strength of the foam struts (Brezny et al. 1989).i-lowever, it has been an object in may studies to try to enhance the mechanicai strengthby optimising the various processing steps involved in the replication process.
Vogt et al. 2010 have previously described a vacuurn infiltration process in which thehollow interior the replicated foams struts is fiiied with ceramic slurry, thus resulting in anincrease in the compressive strength of these ceramic foams. However, the holiow spaceinside the ceramic struts can be considered practicaliy closed porosity and the infiltrationof the ceramic slurry into this holiow space is likely to be limited even under vacuum,particuiarly in foams with smalier strut sizes with narrower triangular voids within the strutinterior. Thus, it may be speculated that the improved mechanicai strength obtained bythe method of Vogt et al. 2010 mainly depends on a an effect of strengthening the outersurface parts of the scaffold without a concornitant strengthening of the more inner partsof the scaffold. Aiso, the method of Vogt ef al. 2010 is expected to affect the pore architecture by making the pores narrower.
As is evident from the above, there stili exists a need in the field of medical prostheticdevices for scaffoid structures having high mechanicai strength and a weil formed porenetwork. The object of the present document is to overcome or at least mitigate some of the problems associated with the prior art.
SUMMARY OF INVENTION The present document is directed to a titanium dioxide (TiOZ) scaffold having amechanicai strength making it suitabie for use as a medical prosthetic device. it is PS544 8SE00 5 therefore an object of the present disciosure to provide a titanium dioxide scaffold to be used as a medical prosthetic device for implantation into a subject that e.g. has a good biocompatibility and does not cause adverse reactions when impianted into a subject, which allow for celi growth into the S-dimensionai scaffold and which stili has a mechanical stability which ailows it to be practically useful as a stabilizing structure. in one aspect, this document is directed to a method for producing a recoated titanium dioxide scaffold, said method comprising: a) b) C) s) apptying a first siurry comprising titanium dioxide to a combustible porousstructure ailowing the first slurry to sotidify on said combustibie porous structure;removing said combustible porous structure from the solidified titanium dioxideslurry by a first sintering at about 400-550°C to produce a titanium dioxidescaffoid structure; subjecting the titanium dioxide structure to a second sintering at a temperatureof at least 1300°C for at ieast 10 hours to provide a single-coated titaniumdioxide scaffotd characterized in that said method further comprises a vacuum infiltrationprocedure, wherein said vacuum infiltration procedure comprises the steps ofapplying a second slurry comprising titanium dioxide to said single coatedtitanium dioxide scaffold by vacuum infiltration and thereafter optionallysubjecting said single-coated titanium dioxide scaffold to centrifugation;aliowing the second sturry of step e) to solidify on the single-coated titaniumdioxide scaffold; and performing a third sintering at a temperature of at least i100°C to provide a recoated titanium dioxide scaffold.
The vacuum-infittration procedure of steps e)-g) in the above method may also be preceded or followed by a double-coating procedure comprising the steps of: i) ti) applying a third slurry comprising titanium dioxide to the single-coatedtitanium dioxide scaffold of step d) or the recoated titanium dioxide scaffoldof step g) and optionaiiy subjecting the scaffold to centrifugation; allowing the third slurry of step i) to soiidify on the scaffold; and performing a further sintering at a temperature of at ieast 1100°C.
PS544 8SE00 6 The method for producing a recoated titanium dioxide scaffotd may therefore comprise orconsist of the following steps, presented in the order they are performed in the respectiveaiternative: 1. Steps a)-g) 2. Steps a)-d), steps i)-iii), steps e)-g) 3. Steps a)-g), steps i)-iii) By performing the method according to aiternatives 1, 2 or 3 above, a recoated titaniumdloxide scaffold is produced. Titanium dioxide scaffolds produced by the methodaccording to alternatives f, 2 or 3 are in the present context coiieotiveiy denoted recoatedtitanium dioxide Scaffotds. The present document is aiso directed to a recoated titaniumdioxide scaffold obtained or obtainable by performing a method according to alternatives 1, 2 or 3 above.
This document is therefore also directed to a recoated titanium dioxide scaffold obtainableby the method of a) applying a first slurry comprising titanium dioxide to a cornbustible porousstructureb) allowing the siurry to solidify on said combustible porous structure; c) removing said cornbustible porous structure from the solidtfied titanium dioxideslurry by a first sintering at about 400-550°C to produce a titanium dioxidescaffold structure; subjecting the titanium dioxide structure to a second sintering at a temperatureof at least 1300°C for at least 10 hours to provide a single-coated titaniumdioxlde scaffold characterized in that said method further comprises a vacuum infiltrationprocedure, wherein said vacuum infiltration procedure comprises the steps ofe) appiying a second slurry comprising titanium dioxide to said single coated titanium dioxide scaffold by vacuum infiltration and thereafter optionallysubjecting said singte-coated titanium dioxide scaffold to centrifugation; f) ailowing the second slurry of step e) to solidify on the single-coated titaniumclioxide scaffoid; and performing a third sintering at a temperature of at ieast 1100°C to provide arecoated titanium dioxide scaffold, 3,5 Ps5447ssišo07 _ wherein the vacuum infiltration procedure of steps e)-g) is optionaily preceded or followed by a doubte-coating procedure comprising the steps of: i) applying a third slurry comprising titanium dioxide to the single-coatedtitanium dioxide scaffold of step d) or the recoated titanium dioxide scaffoldof step g) and optionally subjecting the scaffold to centrifugation; ii) allowing the third sturry of step i) to solidify on the scaffold; and iii) performing a sintering at a temperature of at least 1100°C.This document also discloses a medicat prosthetic device comprising a recoated titanium dioxide scaffold obtainable by the above method. The document is aiso directed to thisrecoated titanium dioxide scaffold for use a medical prostnetic device.
Further, this document is directed to a method for the regeneration, repair, substitutionand/or restoration of tissue comprising the impiantation into a subject in need thereof of arecoated titanium dioxide scaffold as disciosed herein or a medical prosthetic devicecornprising it and the use of a recoated titanium dioxide scaffold or a medical prostheticdevice comprising it for the regeneration, repair, substitution and/or restoration of tissue.Also disclosed is a recoated titanium dioxide scaffold or a medical prosthetic devicecomprising it for use for the regeneration, repair, substitution and/or restoration of tissueand the use of a recoated titanium dioxide scaffold for the preparation of a medicalprosthetic device for the regeneration, repair, substitution and/or restoration of tissue.
Since the recoated titanium dioxide scaffold of this document is made of titanium dioxidewhich has a good biocompatibility, the risk for adverse reactions, such as ailergicreactions, is reduced when the scaffotds are irnpfanted into a subject. The recoatedtitanium dioxide scaffolds also have a beneficiat effect on the regeneration of tissue due tothe material they are made of and their surface structure. Due to the use of vacuurninfiltration in the recoating procedure, the recoated titanium dioxide scaffolds in additionhave a stability which is particularly suitabte for their use in medical implants havingenough stability to provide a stabilizing function while still not being too rigid.
Other features and advantages of the invention wifi be apparent from the followingdetailed description, drawings, examples, and from the claims.
PS54478SE00 DEFINITIONS “Scaffoid” in the present context relates to an open porous structure. By "titanium dioxidescaffold” is meant a scaffold comprising predominantly titaniurn dioxide (i.e. more than 50vvt°/u titanium dioxide, such as about 51 wt%, 60 wt%, 70 wt%, 80 wt%, 90 vvt%, 95 wt%,96 virt%, 97 wt%, 98 wt%, 99 wt% or 100 wt% titanium dioxide).
By “pore diameter" is in the context of the present document intended the hydrauiic diameter of a pore without its surrounding walls. The hydraulic diameter is well known tothe person skilled in the art and is defined as lir-area of a pore divided by the circumferentiai length of the pore.
“Fractal dimension strut” is a statistlcai quantity that gives an indication of how completelya fractal appears to fill space, as one zoorns down to finer and finer scales. There aremany specific definitions of fractal dimension and none of them should be treated as theuniversal one. A value of 1 pertains to a straight Eine. The higher the number the more complex is the surface structure.
“Totai porosity" or “porosity” is in the present context defined as all compartments within abody which is not a material, e.g. the space not occupied by any material. Total porosity involves both closed and open pores.
By "inner strut volume” is meant the volume of the inner lumen of the strut.
"”Vacuum infiltration” in the present refers to a process for forcing iiquid into an object by the pressure less than 100 l By "sintering", “sinter" and the iike is meant a method for making objects from powder byheating the material (beiow its melting point) until its particles adhere to each other (fuse).Sintering is traditionally used for manufacturing ceramic objects, and has also found uses in fields such as powder metailurgy.
By “reticuiated foam" is in the present context intended a porous and open soiid foam. By“reticulated ceramic foam" is intended an open porous structure made up of a ceramic PS54478SE00 9 material, such as titanium dioxide. A reticulated ceramic foam may be produced by areplication method comprising the steps of coating a porous, cornbustible structure with ametal oxide slurry, and removing the porous, combustible structure by heating at hightemperatures, which causes the removal of the porous, cornbustibie structure and fusionof the meta! oxide particles, thus forming a ceramic porous structure.
A ”medical prosthetic device, “medical impiant”, "implant" and the like in the presentcontext relates to a device intended to be implanted into the body of a vertebrate animal,such as a rnammai, eg. a human mammal. implants in the present context may be usedto replace anatomy and/or restore any function oi the body. Examples of such devicesinciude, but are not limited to, dentai implants and orthopaedio implants. ln the presentcontext, orthopaedic implants includes within its scope any device intended to beimplanted into the body of a vertebrate animal, in particular a mammal such as a human,for preservation and restoration of the function of the muscuioskeletal system, particularlyjoints and bones, inciuding the alieviation of pain in these structures. ln the presentcontext, dental impiant includes within its scope any device intended to be irnplanted intothe orai cavity of a vertebrate animal, in particular a mamma! such as a human, in toothrestoration procedures. Generally, a dental implant is composed of one or several implantparts. For instance, a dentai implant usually comprises a dentai fixture coupled tosecondary implant parts, such as an abutment and/or a dental restoration such as acrown, bridge or denture. However, any device, such as a dental fixture, intended forimplantation may aione be referred to as an implant even if other parts are to beconnected thereto. Orthopaedic and dental implants may also be denoted as orthopaedicand dentai prosthetic devices as is clear from the above. ln the present context, "subject" relates to any vertebrate animal, such as a bird, reptile, mammal, primate and human.
By “ceramics” are in the present context meant objects of inorganic powder materialtreated with heat to form a solidified structure.
BRiEF DESCRIPTiON OF DRAWENGS Fig. 'I shows the effect of sintering time at 1500 °C on the microscopic appearance oftheTiOz scaffolds (Fig. ia) and their compressive strength (Fig. 1b). Statistically significant PS54478SE00 difference in comparison to foams sintered for 2 h (*,**) and 10 h (tränat). *p < 0.05 and**,fit#p < 0.01, n =10.
Fig. 2 shows the viscosity as a function of shear rate for the TiOz slurries used in thescaffold production. (a) The difference in viscosity between the slurries used for differencecoating procedures, (b-c) effect of soiid content on the rheological properties of the TiOz slurry.
Fig. 3 shows the that the double coating procedure was found to reduce the flaw size andnumber by filling the micropores and folds remaining in the TiOz foam struts after therepiication process. Vacuum infiltration with low viscosity slurry further improved theuniformity of the strut structure without blocking the rnacropore windows. (A) Single-coated, (B) double-coated prior to sintering, (C) double-coated after sintering, and (D)doubie-coated and vacuum intiltrated TiO2 foam after sintering at 1500 °C.
Fig. 4 shows how the soiid content of the third siurry used for doubie coating infiuencedthe uniformity of the TiOz foam structure: low solid content slurry had Eow viscosity whichresulted in less reproducibility in comparison to slurries with 35-40 g TiOZ powder,whereas higher solid contents (45 g TiOz powder) resulted in too viscous siurry that didnot infiltrate uniformly throughout the scaffold interior. Circle in 40 g TiOg powder imagedepicts the VOI selection for 3D analysis.
Fig. 5 shows that: (a) The recoating procedure led to significant increase in thecompressive strength of the prepared ceramic TiO2 scaffoids. Statistically significantdifference in comparison to SC (*,**) and DC (fait), *p < 0.05 and **,##p < 0.01, n == 10. (b)Effect of the DC and VI procedures on the interconnectivity of the pore network. SC =single-coated, DC = double-coated, VI = vacuum infiltration.
DETAILED DESCRIPTION OF THE INVENTION The present document relates to recoated titanium ciioxide scaffolds having a highbiocompatibiiity and a mechanical stability which makes them useful in medical implants.The document aiso relates to methods for producing such recoated titanium dioxide scaffolds and uses thereof.
PS54478SEOO 11 Fiaws and irregularities in the strut structure are known have a strong influence on thernechanical properties of reticulated ceramic foarns, and the strut strength may thereforebe optimised by improving the processing method. in the present document, processparameters were optimized to improve the mechanical properties of titanium dioxiclescaffolds. lt was demonstrated that long sinterihg times at high temperatures led to aninvvard collapse of one walls of the triangular voids typicaily found in the strut interior offoams prepared using the replication method. This strut fotding Eed to increasedcompressive strength, while the pore architectural features were not significantly affected.Furthermore, the majority of the internal porosity of the foam struts was partiallyeliminated and became accessible for infiltration with Ti02 siurry. The reooating proceduredisciosed herein was found to markedly reduce the flaw size and number in the TiOZ foamstruts, which led to significant strengthening of the cerarnic structure by improvedstructural uniformity and slightiy increased strut diameter. ih one aspect, this document is therefore directed to a method for producing a recoatedtitanium dioxide soaffold, said method comprising: a) applying a first slurry comprising titanium dioxide to a combustibie porous structure b) altowing the first siurry to solidify on said cornbustible porous structure; c) removing said combustible porous structure from the solidified titanium dioxidesiurry by a first sintering at about 400-550°C to produce a titanium dioxidescaffoid structure;subjecting the titanium dioxide structure to a second sintering at a temperatureof at least 1300°C for at least 10 hours to provide a single-coated titanium d) dioxicte soaffold characterized in that said method further comprises a vacuum infiltration procedure, wherein said vacuum infiltration procedure comprises the steps of applying a second slurry comprising titanium dioxide to said single coated titanium dioxide soaffold by vacuum infiitratiori and thereafter optionally subjectihg said single-coated titanium dioxide scaffold to centrifugation; f) ailowing the second siurry of step e) to solidify on the single-coated titaniumdioxide soaffold; and g) performing a third sihtering at a temperature of at least 1100°C to provide arecoated titanium dioxide soaffold.
PS54478SEOÛ 12 The vacuum infiltration procedure of steps e)-g) may aiso be preceded or foltowed by adouble coating procedure comprising the steps ofi) applying a third siurry comprising titanium dioxide to the single-coatedtitanium dioxide scaffoid of step d) or the recoated titanium dioxide soaffoldof step g) and optionally subjecting the soaffold to centrifugetion;ii) allowing the third slurry of step i) to solidify on the soaffold; and iii) performing a further sinteririg at a temperature of at least 1100°C.The structure resulting by performing steps a)-c) in the above method may in the presentdocument be referred to as a titanium dioxide scaffoid structure. The scaffolds producedafter steps a)-d) may in the present document be referred to as “stngle-coated” (SC)scaffolds or sintered titanium dioxide scaffolds. Steps i)-iii) are in the present contextreferred to as a double coating (DC) and result in a double-coated (DC) soaffold whenpreceded by at teast steps a)~d). The process of steps e)-g) is in the present referred to asa vacuum infiltration (VI) process. A soaffold subjected to steps e)-g) may therefore bedenoted a vacuum infiltrated (Vi) soaffold. By performing step a)-d) and then steps e)-g), aSC+Vl soaffold or recoated titanium dioxide scaffoid is produced. By performing steps a)-d), then steps e)-g) before steps i)-iii), a Vl+DC soaffold or recoated titanium dioxidesoaffold is produced. By performing steps a)-d) before steps i)-iii) and then performingsteps e)~g), a DC+Vi soaffold or recoated titanium dioxide soaffold is produced. Theabove abiareviations denoting different kinds of scaffolds and how they are produced maybe referred to in other parts of this document. However, the term “recoated titaniumdioxide scaffoid(s)” or “recoated scaffold(s)”, as used in this document, coltectively refersto titanium dioxide scaffolds which have been produced by performing steps a)-d) directlyfollowed by steps e)-g), titanium dioxide scaffolds which have been produced byperforming steps i)-iii) after steps a)-d) but before steps e)-g) and titanium dioxidescaffolds produced by performing steps a)-g) before steps i)-iii). The present document istherefore also directed to a recoated titanium dioxide soaffold obtainabie by or obtained byperforming steps a)-d) directly followed by steps e)-g), a recoated titanium dioxide soaffoldwherein steps i)-iii) have been performed after steps a)-d) but before steps e)-g) and arecoated titanium dioxide scaffoid wherein steps a)-g) have been performed before steps n-fii). lt was surprisingly found that the order of the doubte coating (steps i)-iii)) and vacuuminfiltration (steps e)-g)), resulting in DC+VI or Vi+DC scaffolds did not cause any PS54478SEO0 13 significant alterations in either the pore architectural Characteristics or the com pressivestrength of the resulting recoated scaffolds.
The first stage of the method for producing a recoated titanium dioxide scaffold involvesthe provision of a titanium dioxide scaffold. This may be provided e.g. by the performingmethod steps a)-ct) or by performing the methods disciosed in WO 081078164, such as bythe hot piate moulding process or polymer sponge method (aiso ctenoted polymer spongerepiicatâon method) disciosed therein. Even though preferred, it is therefore not necessaryto provide the titanium dioxide scaffold to be subjected to DC (steps i)-iii) and/or VI (stepse)-g) by the method of steps a)-d) but other methods also providing a titanium dioxidescaffotd may be used. The present document is therefore also directed to a method forincreasing the mechanical strength of a titanium dioxide scaffold, which methodcomprises providing a titanium dioxide scaffold (such as the single-coated scaffoldprovided by steps a)-d)) and subjecting the titanium dioxide scaffold to at least one of thevacuum infiltration steps e)-f) or the double-coating of steps i)-iii). This document isconsequently also directed to a recoated or double-coated titanium dioxide scaffoldobtainabie by or obtained by the method of providing a titanium dioxide scaffold (such asby performing steps a)-d) and subjecting said titanium dioxide scaffold to at teast one ofthe vacuum infiltration steps e)-g) or the doubte-coating steps i)-iii).
As mentioned above, the titanium dioxide scaffoid is typically provided by performingsteps a)~d). in these steps, a first sturry comprising titanium dioxide is applied to acombustible porous structure and allowed to solictify thereon before performing a firstsintering at about 400-550°C for at teast 30 min and a second sintering at a temperatureof at least 1200°C for at least 10 h to produce a single~coated titanium dioxide scaffotd(sintered titanium dioxide scaffold). Steps a)-d) may be performed as disclosed in WO081078164.
The combustibte porous structure may e.g. be a sponge structure, such as a syntheticsponge. The material the combustible porous structure is made of is preferabiy an organicmaterial in order to facilitate the removal of the combustible porous structure from thescaffold by combustion. The combustibte porous structure may therefore be an organicsponge structure, such as an organic porous polymer sponge, e.g. a polyethylene,silicone, celluioses or polyvinytchloride sponge. One example of a combustible porousstructure is a 45 or 60 ppi Bulbren poiyurethane foam (Bulbren S, Eurofoam GmbH, PS54478SE00 14 Wiesbaden, Germany). The combustible porous structure may be washed with waterbefore providing the first siurry comprising titanium dioxide (herein also denoted firsttitanium dioxide sturry or first siurry) thereto in order to remove residuals and/oroontaminations. The first siurry may be provided to the combustible porous structure byimmersing the combusttble porous structure in the first siurry. After the immersion, excesssiurry may be removed by squeezing and/or cehtrifuging the combustible porous structureimmersed in the first siurry. The first siurry is then allowed to solidify on the porouspolymer structure, e.g. by drying the combustibie porous structure immersed in the firstsiurry for at Eeast 5 hours, such as for about 5-24 hours, such as about 10-24 or 15-14hours, e.g. about 5, 10, 15, 16, 20 or 24 hours.
The size and shape of the recoated titanium oxide scaffold may be adjusted by adjustingthe size and shape of the combustible porous structure used. Thereby it Es possible toproduce a scaffold that is tailor-made for a specific intended implantation site of a specificsubject. Further, it is possible to use techniques, such as CAD (computer assisted design)camera techniques, to tailor-make recoated titanium oxide scaffolds for specificapptications, such as implants specifically made to fit a certain defect. CAD couid beperformed both on the combustibie porous structure or on the titanium dioxide scaffold(before or after the recoating procedure in order to provide a scaffold with the desiredshape. The CAD of a titanium dioxide scaffold which has been subjected to at least onesintering wouid provide higher accuracy than by performing the CAIJ on the combustibleporous structure. The CAD could e.g. be performed with Nd:YAG laser (J Pascual-Cospet al.) or by milltng.
After solidification of the first siurry on the combustibte porous structure, the combustibleporous structure is removed from the thereon soliditied siurry to obtain a titanium dioxidescaffold structure. This step may be performed as disclosed in WO 081078164.
The combustible porous structure may be a porous polymer structure and thus removedfrom the solidified first siurry by heating. Thereby step c) ih the above method may e.g. beperformed by burning off the combustible porous structure from the soiidtfied first siurry ina siow sintering step. The temperature and time necessary to perform this process will, asthe skilled person readily understands, depend on the material that the combustibleporous structure is made of. importahtly, the temperature and time should be selected to allow for more or iess complete removal of the combustible porous structure. The skilled 538544785 E00 person will know how to select the necessary time and temperature for a specificcornbustibie porous structure and scaffold to achieve this. The temperature is slowlyraised to the desired temperature, such as at 02-08 °Clrnin, e.g. 04-06 °Clmin or 0.5°C/min. Typically, a temperature of about 400-550°C, such as about 440-510°C, 490-510°C or 440-460°C, e.g. about 400, 450, 500 or 550°C, is used. This temperature is heldfor at least 30 min, such as 30-90 min or 45-75 min, e.g. 45, 60, 75 or 90 min. A titaniumdioxide structure is thereby obtained.
This titanium dioxide structure is then subjected to a second sintering (step d)) by raisingthe temperature after the desired holding time in the first sintering step. ln this step, thetitanium dioxide scaffold structure is subjected to a fast sintering at a higher temperature.This is typically performed at a temperature of at least 1200°C or at ieast 1300°C, such as1200-1800°C or 1700-1800°C, e.g. about 1750°C. Typically, the temperature in thissecond sintering step Es raised more rapidly than ih the first sintering step, such as at ca2-5 °C/min, e.g. 3 °C/min. The desired temperature is then held for at least 2 hours, suchas 2-45 hours, 5-40, 10-40, 20-40 or 10-30 hours. The single-coated titanium oxidescaffoid obtained is then ailowed to cooE to room temperature. This cooiing may e.g. beperformed at rate of about 2-8°C/min, such as 2-5 °C/min, e.g. 5 °Clmin After providing a titanium dioxide scaffold such as by performing steps a)-d), the titaniumdioxide scaffold may either directiy be subjected to the vacuum infiltration of steps e)-g) ordouble-coated by performing method steps i)-iit).
Steps e)-g) are performed by apptying a second slurry comprising titanium dioxide (alsodenoted second titanium dioxide slurry or second sturry) to the single-coated titaniumdioxide scaffoid obtained by steps a)-d) or othervvise provided. The second titaniumdioxide slurry is then forced into the scaffold by use of vacuum, dried so that the secondsiurry solidifies and subjected to a third sintering step. The second slurry may be appliedto the titanium dioxide scaffold by immersion into the second slurry. The scaffold to whichthe second slurry has been applied is then suhjected to vacuum to force the slurry furtherinto the scaffoid structure. This may be performed by placing the scaffold in a vacuumtight glass container and applying a vacuum of at least 0.1 mbar, e.g. about 01-05 mbar,such as 01-03 mbar, e.g. 0.1, 0.2, 0.3, 0.4 or 0.5 mbar for at Eeast 1 min, such as 1-10min, 1-7 min, 3-6 min, 4-6 min or 5 min. Any excess second sturry may then be removede.g. by careful centrifugation for a few minutes (such as 0.5-5 min, 1-5 or 1-3 min) at a PS54478SE00 16 speed such as 500-1500 rpm (based on a rotor size suitable for a Biofuge 22R, HeraeusSepatec centrifuge). Centrifugation after immersion may improve the fina! result as thisresults in a more uniform covering of the struts without blocking pore windows. Thesecond sturry is then allowed to solidify on the scaffotd for at least 5 hours, such as forabout 5-24 hours, such as about 10-24 or 15-24 hours, e.g. about 5, 10, 15, 16, 20 or 24hours. The scaffotd is then subjected to a third sintering at a temperature of at Eeast1100°C, such as about 1100-1800°C, 1200-1600°C, 1400-1600°C, e.g. at 1400°C, 1500°Cor 1600°C. The time for the third sintering is typically about at ieast 2 hours, such as about245, 2-10, 2-8, 3-5 or about 3 or 4 hours. The temperature is raised at ca 2-5 °C/min, e.g.3 °Clmin, while the cooling rate for cooling down to room temperature is about 2-8°Clmin,such as 2-5 °C/min, e.g. 5 °C/min.
As mentioned above, double coating steps i)-iii) may be performed before steps e)-g) orthereafter. For double coating, a third slurry comprising titanium dioxide (also dehoted athird titanium dioxide slurry or third slurry) applied to the scaffotd e.g. by immersion intothe third slurry. Any excess third sturry may then be removed e.g. by careful centrifugiationfor a few minutes (such as 0.5-5 min, 1-5 or 1-3 min) at a speed such as 500-1500 rpm(based oh a rotor size suitable for a Biofuge 22R, Heraeus Sepatec centrifuge).Centrifugation after immersion may improve the fina! result as this results in a moreuniform covering of the struts without btocking pore windows. The third slurry is thenattowed to sotidify on the scaffold for at Eeast 5 hours, such as for about 5-24 hours, suchas about 10-24 or 15-14 hours, e.g. about 5, 10, 15, 16, 20 or 24 hours. The scaffold isthen subjected to a further sintering at a temperature of at least 1100°C, such as about1100-1800°C, 1200-1600°C, 1400-1600°C, e.g. at 1400°C, 1500°C or 1600°C. The timefor this further sintering is typically at least 2 hours or at ieast 10 hours, such as 2-50hours, 5-40, 10-50, 10-30, 20-50, or 20-40 hours, e.g. 10, 20, 25, 30, 35, 40, or 45 hours.The temperature is raised at ca 2-5 °C/min, e.g. 3 °C/min, while the cooling rate forcooling down to room temperature is about 2-8°C/min, such as 2-5 °C/min, e.g. 5 °C/min.
The titanium oxide powder used for preparing the first, second and third titanium dioxideslurries may be in the amorphous, anatase, brookit or rutile crystal phase. The titaniumdioxide powder may be precieaned with NaOH (e.g. 1 M NaOH) to removecontaminations, such as contaminations of secondary and tertiary phosphates.Alternativeiy, if titanium dioxide powder free of contaminations of secondary and/or tertiary phosphates is desirable, titanium dioxide powder free of such contaminations is PS54478SE00 17 commerciaiiy avaiiabie (e.g. the titanium oxide from Sachtleben). lt may be advantageousto use a titanium dioxide powder having at the most 10 ppm of contaminations ofsecondary and tertiary phosphates, By using titanium oxide containing less than about 10ppm of contaminations of secondary and/or tertiary phosphates when preparing the slurry,the titanium oxide particies are small enough to aliow a proper sintering without theaddition of organic antiagglomerating compounds and/or surfactants. The titanium dioxideslurries typically have a pH value of about 1.0 to 4.0, preferably about 15-20, in order toavoid coagulation and to control the viscosity. The pH of the slurry is preferably kept atthis pH for the entire duration of dispersion of the titanium dioxide powder in soivent withsmall additions of HCl (such as 1 M HCl). lt is preferable to reduce the size of the titaniumoxide particles as close as possible to the pH value which gives the theoretical isoelectricpoint of titanium oxide. For TiOg this pH value is 1.7. The mean particle size of thetitanium oxide particles may be 10 um or less, such as 1.4 um or less. The titanium oxideparticles may be monodispersed. The titanium dioxide powder is typically dispersed inwater (under stirring and the pH readjusted by the addition of an acid, such as HCl) toprepare a titanium dioxide slurry. The stirring may be continued after all titanium dioxidepowder is dispersed, such as for about 2-8 hours. The slurry is e.g. dispersed with arotatioriat dispermat with metai blades, preferably titanium blades. For example the stirringmay be performed at a speed of at ieast 4000 rpm and for at least 4 hours, such as at5000 rpm for 5 hours or longer. The pH of the slurry is regularly adjusted to the chosen pHvalue for adequate zeta potential of the suspension.
The titanium dioxide slurries typically have different conceritrations of titanium dioxide inorder to have different viscosities. The first siurry typically has a concentration of about2000-5000 mg/ml of titanium dioxide, such as about 2500-4000 mg/ml, 3000-3500 mg/mior about 3250 mglml. The concentration of titanium dioxide in the second slurry Es typicatiyabout 200-1000 mglml, such as about 300-900 mglmi, 400-800 mg/ml, 500-600 ing/ml,e.g. about 400, 500, 600, 700 or 800 mg/mi. The concentration oftitanium dioxide in thethird siurry is typicaily about 1200-1800 mglml, such as about 1300-1700 mg/ml, 1500-1700 mg/ml, e.g. 1400 mg/ml, 1500 mg/ml, 1600 mg/mior 1700 mg/ml.
As is demonstrated in Example 1, the sintering time used in step d) has a iarge impact onthe scaffold structure and compressive strength. With increasing sintering times, thehoilow appearance of the struts was changed due to partiai eiimination of the trianguiarvoids with the struts. This eiimination of internal strut porosity appeared to occur by inward PS54478SE00 18 coilapse of one of the three titanium dioxide strut walls. This coliapse led to the formationof cracks and voids at the points where three or more struts join together. Furtherincreasing the sintering time resulted in a reduction of flaw size and number, the strutsthereby taking a solid triangular structure with rounded corners. No statistical difference inthe pore architectural pararneter so the scaffolds occurred during increasing sinteringtimes. However, the compressive strength was markedly increased by the use of longersintering times. Therefore, by increasing the sintering time of the first sintering (step d)),the strength of the scaffolds can be increased.
Also as demonstrated in Example 1, doubie coating and vacuum infiitration furtherincreased the compressive strength of the scaffolds. Vacuum infiltration was for exampledemonstrated to aimost double the compressive strength of a double-coated scaffold.
Although not wishing to be bound by theory, this increase in compressive strength appearto be the result of the double coating and/or vacuum infiltration procedures improving thestrut uniformity by the second and third siurries depositing in the voids and folds of thestruts.
Curiousiy, reversing the order of the doubie coating and vacuum infiltration processescaused no significant alterations in the pore architectural Characteristics of the recoatedtitanium dioxide scaffolds or their compressive strength. lt appears that the low viscositysecond titaniurn dioxide slurry, used in the vacuum infiltration process, is deposited mainlyin the micropores and small voids of the struts, whiie the optional centrifugation processeffectively removes the excess slurry from scaffold, leaving oniy a very thin coating on thestrut surface. Due to the low viscosity of the second slurry it can be forced into theremaining smail flaws in the strut structure with the aid of vacuum, while the thicker thirdslurry, used for double coating, is deposited in the larger folds of the struts. A negligibieincrease in strut size due to the vacuum infiltrated coating is likely to arise from blockageof some of the srnailest pore windows and accumulation of the second slurry at the strutjunctures, which also caused the slight drop in the interconnectivity of the foam structure(see Fig. 5b). This reduction in the interconnectivity of the pore network was morepronounced when the vacuum infiltrated scaffoids were double-coated with the thickerthird slurry, indicating that a DC+Vi process results in less blocked pore openings thanapplying the same procedures in reversed order (VH-DC). Nonetheless, the additionaivacuum infiitrated low viscosity coating (the second slurry) appears to be an effective PS54478SEOO 19 method for improving the structural uniformity of a titanium dioxide scaffold, and thussignificantly enhancing the mechanical strength of the scaffolds while still maintaining appropriate pore architectural features.
Since the low viscosity second slurry used for the vacuum infiltration in steps e)-g)appears to only have a negiigible effect on the scaffold structure, the pore architecturalCharacteristics are mainly dependent on the higher viscosity third slurry used in steps i)-iii). As the interconnectivity of the pore volume has been identified as one of the mostimportant characteristics for a bone scaffold, the number of blocked pore windows ispreferably minimized in the scaffold by optimization of the procedure. /iscosity of the thirdsturry used for double-coating the scaffoids (DC) had a notable influence on the uniformityof the “fiOz foam structure with both low (30 g) and high (45 g) solid contents causingblockage ofthe pore windows (Fig. 4), and thereby influencing the interconnectivity ofthepore network (Fig 5b). Since the poor infiltration of the more viscous third slurry resulted inbiocked pore openings mainly at the outer edges of the TiOz foam, the effect of thisbiockage was not manifested in the 3D interconnectivity analysis as the selected VOIexciuded the outermost region of the scaffold cylinder. However, the blockage of the outerpore windows is likely to significantly hinder the celi and tissue penetration towards thescaffoid interior and is therefore particuiariy undesirable. Controlling the viscosity of thethird slurry was therefore identified as one of the most important processing parametersgoverning the uniformity and interconnectivity of the pore network when the mechanlcalintegrity of titanium dioxide scaffolds is improved by a recoating procedure.
The mechanical strength (compression strength) of the recoated titanium dioxide scaffoldsproduced in accordance with the present document is typically about 1-5 MPa, such as 3-5 MPa. However, as is clear to a person skilled in the art, the compression strength of arecoated titanium dioxide scaffold depends on its porosity. The above mentionedcompression strength values are given for a recoated titanium dioxide scaffold havingabout 90% porosity. independently on the porosity of a titanium dioxide scaffold, bysubjecting the scaffold to the recoating procedure disclosed herein, the compressionstrength is rnarkedly increased. The compression strength of a scaffoid may bedetermined by performing compression tests in accordance with DIN EN ISO 3386 (e.g. as disciosed in Exarnple 1).
PS544 8SEO0 The recoated titanium dioxide scaffoid may be used for implantation into a subject, te.used as a medical implant. The recoated titanium dioxide scaffold comprises a porousstructure with improved surface properties which enhances its biocompatibility andstimuiates the growth of cetts and attachment of the implant. The porous structure altowsingrowth of cells into the scaffold, which thereby allows for the regeneration of tissue. Thelarge surface area of the recoated titanium dioxide scaffold also facilitates the growth ofcells into the structure and thereby the attachment of the scaffold and regeneration oftissue. As the recoated titanium dioxide scaffold is made of a materia! which in itself has agood biocompatibility, adverse reactions to the scaffotd when implanted into a subject arereduced.
The recoated titanium dioxide scaffoloi is macroporous and comprises macropores andinterconnections. The macropores have a pore diameter in the range of betweenapproximately 10-3000 pm, such as about 20-2000 pm, 30-1500 pm or 30-700 pm. Themaoropore diameter may be above about 100 pm or about 30-700 pm. For bone, the porediameter is optimaiiy 30-100 pm. However, it is important that the scaffotd atso allows forthe ingrowth of larger structures such as blood vesseis and trabecular bone, Le. also haspores of about 100 pm or more. lt is important that at least some of the pores of the scaffolds are interconnected.
The pore diameter (pore size) may be adjusted by the choice of structure used forproducing the scaffold, e.g. the choice of sponge and the number ottimes this structure isdipped into the first slurry comprising titanium dioxide. By altering the pore diameter onemay affect the rate and extent of growth of celts into the recoated titanium dioxide scaffoid and therefore the constitution of the resuiting tissue. tt may be preferable that the pores are interconnective or partially interconnective. Thismeans that the pores are not pores with a “dead end” or closed pores, but that they haveat least two open ends altowing for the passage of nutrients and waste products in morethan one direction. Thereby, the risk that necrotic tissue forms is reduced. Themacroporous system preferably occupies at Eeast 50% volume of the scaffold. The volumeof the macro» and rnicropores in the recoated titanium dioxide scaffotds may varydepending on the function of the scaffold. lf the aim with a treatment is to replace muchbone structure and the recoated titanium dioxide scaffold can be kept unâoaded during the PS54478SEOO 21 heating time, the recoated titanium dioxide scaffold may be made with a macroporous system occupying up to 90% of the total scaffold volume. lt may be preferred that a recoated titanium dioxide scaffold has a total porosity of about40-99%, preferably 70-90°/°.
The tractal dimension strut of the recoated titahium dioxide scaffold is typicaliy about 2.0-3.0, such as about 2.2-2.3. The strut thickness affects the strength of the scaffotds, thethicker the struts in the scaffold are, the stronger Es the scaffotd.
The recoated titanium dioxide scaffotds essentially lack an inner strut voturne, which canbe observed by the filled up cross section in SEM. lt will be understood by those of skill in the art that the surface of the recoated titaniumdioxide scaffotd also has a structure on the microlevel and the nanolevel. This micro andnano structure may be modified due to the manufacturing conditions. The pores createdby the manufacturing process are on the rnicrotevei in the range of 1-10 um. The pores onthe nanolevel are less than 1 um in diameter.
A recoated titanium dioxide scaffotd typicaliy has a combined micro and macro porediameter of approximately 10 - 3000 um, such as 20-2000 um, 30-1500 um or 30-700um. The pore diameter may be above 40 um, with interconnective pores of at least 20 pm.
The recoated titanâum dioxide scaffolds have a structure of hoilow tubules in which thebone wii! grow and create the interconnecting bone trabeculae. Ceils witl grow both on the inside and the outside of these tubules.
Atso, biomolecules may be provided to the surface of the recoated titaniurn dioxidescaffolds. lt biomolecules are to be provided to the recoated titahium dioxide scaffold,these may be provided after atl recoating steps are finalized. The presence ofbiomolecules may further increase the biocompatibility of the recoated titanium dioxidescaffoids and rate of celt growth and attachment. Biornoiecules comprise in the presentcontext a wide variety of biologically active moleoules including natural biomolecutes (i.e.naturally occurring molecules derived from naturat sources), synthetic biomotecules (i.e. naturelly occurrihg biomolecules that are synthetically prepared and non-naturatly PS54478SE00 22 occurring moiecules or forms of molecules prepared synthetically) or recombinantbiomolecules (prepared through the use of recornbinant techniques). Examples ofbiomolecuies of interest include, but are not limited to biomolecules disclosed in US2006/0155384, such as bioadhesives, cell attachment factors, biopolymers, bloodproteins, enzymes, extraceliular matrix proteins and biomolecules, growth factors andhorrnones, nucleic acids (DNA and RNA), receptors, synthetic biomolecules, vitamins,drugs biologicaliy active ions marker biomolecules etc., including proteins and peptidessuch as statins and proteins or peptides that stimuiate biomineralization and boneformation. Other examples of biomoiecules include inorganic, bioiogically active ions,such as caicium, chromiurn, fiuorlde, gold, iociine, iron, potassium, magnesium,manganese, selenium, sulphur, stannum, silver, sodium, zinc, strontium, nitrate, nitrite,phosphate, chioride, suiphate, carbonate, carboxyl or oxide. The biomolecules may e.g.be attached to the surface of the titanium dioxide scafiold via dipping into a solutioncomprising the biomolecule or via an eiectrochemical process, such processes beingknown by the skilled person and e.g. disciosed in VV002/45764 or WOOIš/086495.
The present document is aiso dlrected to a medical prosthetic device comprislng arecoated titanium dioxide scaffold as defined herein. A medicai prosthetic device may bea recoated titanium dioxide scaffoid in itself. Alternatively, the medical prosthetic devicemay comprise a recoated titanium dioxide scaffold in combination with another structure,such as orthopaedic, dental or any other fixating devices or implants. This document istherefore aiso directed to a recoated titanium dioxide scaffoid or a medical prostheticdevice comprising a recoated titanium dioxide scaffoid for the regeneration, repair, substitution and/or restoration of tlssue, in particuiar bone tissue.
The recoated titanium dioxide scafloid may be impianted into a subject wherein cells willgrow into the scaffold structure. it is also possibie to seed and grow cells on the scaffoldprior to implantation. The interconnected macroporous structure of the recoated titaniumdioxide scaffold is especially suitable for tissue engineering, and notably bone tissueengineering, an intriguing alternative to currently available bone repair therapies. in thisregard, bone marrow-derived cell seeding of the recoated titanium dioxide scaffold isperformed using conventional methods, which are well known to those of skiii in the art(see e.g. Maniatopoulos et al. 1988). Cells are seeded onto the recoated titanium dioxidescaffold and cultured under suitable grovvth conditions. The cultures are fecl with media appropriate to establish the growth thereof.
PS54478SEOÜ 23 As set out above, ceils of various types can be grown throughout the present recoated titanium dioxide scaffotd. More precisely, cell types include hematopoietic ormesenchymal stem cells, and also include cells yielding cardiovascular, muscular, or anyconnective tissue. Cells may be of human or other animal origin. However, the recoatedtitanium dioxide scaffold is particularly suited for the growth of osteogenic cells, especiallycells that elaborate bone matrix. For tissue engineering, the cells may be of any origin.The cells are advantageously of human origin. A method of growing cells in a threedimensionat recoated tttanlum dioxide scaffold allows seeded osteogenlc cells, forexample, to penetrate the metal oxide scaffold to elaborate bone matrix, during the in vitrostage, with pervasive distribution En the structure of the recoated titanium dioxide scaffold.Osteogenic cell penetration and, as a result, bone matrix elaboration can be enhanced by mechanical, ultrascnlc, electric field or electronic means The recoated titanium dioxide scaffold is useful whenever one is in need of a structure toact as a framework for growth of celts, such as for regeneration, repair, substitution and/orrestoration of a tissue. The recoated titanium dioxide scaffold is particularly useful for theregeneration, repair, substitutlon and/or restoration of bone and/or cartilage Structures.Examples of situations where the regeneration of such structures may be necessaryinclude trauma, Surgical removal of bone or teeth or in connection to cancer therapy.
Examples of structures in a subject which wholly or partially may be replaced include, butare not limited to, cranio-facial bones, including arcus zygomaticus, bones of the inner ear(in particular the rnalieus, stapes and incus, maxitlar and mandibular dentoatveolar ridge,walls and floor of eye sockets, walls and floor of sinuses, skull bones and defects in skullbones, socket ot hip joint (Fossa acetabulf), eg. in the case of hip joint dysplasias, complicatect fractures of long bones including (but not restricted to) humerus, radius, ulna,femur, tibia and fibula, vertebrae, bones of the hands and feet, finger and toe bones, fillingof extraction sockets (from tooth extractions), repair of periodontal defects and repair of periimplant defects. ln addition, the recoated titanium dioxide scaffold is useful for the fiiling of alt types ofbone defects resulting from (the removal of) tumors, cancer, infections, trauma, surgery,congenital matformations, hereditary conditions, metabolic diseases (e.g. osteoporosis and diabetes).
PS54478SE00 24 This document is therefore also directed to a recoated titanium dioxide scaffold as definedherein for use as a medical prosthetic device.
The present document is further directed to a method for the regeneration, repair,substitution and/or restoration of tissue, such as bone, comprising the tmpiantation into asubject in need there-of of a recoated titanium dioxide scaffold or a medicai prostheticdevice comprising a recoated titaniurn dioxide scaffold.
The recoated titanium dioxide scaffold may also be used for the regeneration, repair,substitution and/or restoration of tissue. This document is therefore also directed to theuse of a recoated titanium dioxide scaffold or a medicat prosthetâo device comprising arecoated titaniurn dtoxide scaffoid for the regeneration, repair, substitution and/orrestoration of tissue. Further disclosed is a recoated titanlum dioxide or a medicalprosthetic device comprising a recoated titanium dtoxide scaffold for use for theregeneration, repair, substitution and/or restoration of tissue. Also, this document isdirected to the use of a recoated titanium dioxide scaffold for the preparation of a medicalprosthetic device for the regeneration, repair, substitution and/or restoration of tissue.
The high compression strength of the recoated titanium dioxide scaffold also enabies newuses of the scaffold in load bearing bone Structures. Previously available scaffoldsgenerally are too weak to be used in such applications. However, due to the highercompression strength of the recoated titanium dioxide scaffotd disctosed herein, it is nowpossible to implant the scaffold into bone structures, such as spine, femur, tibia, with highload bearing. lt also attows for placement in iarger defects than today's bone graftsubstitutes. Also, the number of surgical operations may be reduced and bone healing increased. lt is to be understood that while the invention has been described in conjunction with thedetailed description thereof, the foregoing description is intended to iilustrate and not limitthe scope of the invention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of the foilowing claims.
PS54478SE00 Untess expressly described to the contrary, each of the preferred features describedherein can be used in combination with any and atl of the other herein described preferred features.
The invention will be further described in the following examptes, which do not limit the scope of the invention described in the claims.
EXPERIMENTAL SECTION Example 1 Materiats and methods Sample preparationPolymer sponge reptication method was used to produce the retšcutated ceramic foam scaffolds. Ceramic slurry was prepared by gradual addition of 65 g of the ceramic TiOzpowder (Kronos 1171, Kronos Titan GmbH, Leverkusen, Germany; precleaned with 1 MNaOH) in total to 25 ml of sterilízed water. En order to avoid coagutation and to control theviscosity, the pH of the slurry was kept at 1.5 for the entire duration of stirring with smalladditions of 1 M HCi. After dispersing the TiOQ powder in water, stirring was continued for2.5 h at 5000 rpm (Dispermat Ca-40, VMA-Getzmann GmbH, Reiohshof, Germany). Formore details ofthe polymer sponge reptication method, see Tiainen H et al. 2010.
Cylindrical polyurethane foam templates (60 ppi, Butbren S, Eurofoam GmbH,Wiesbaden, Germany), 10 mm in both diameter and height, were coated with theprepared slurry. Excess slurry was squeezed out of the foam templates between twopolymer foam sheets. The samples were then placed on a porous ceramic plate andatiowed to dry at room temperature for at ieast 16 h before sinterlng. For the burnout ofthe polymer, the scaffotds were slowly heated to 450 °C at a heating rate of 0.5 °C/min.After 1 h holding time at 450 °C, the temperature was raised to 1500 °C at a rate of 3°Clmin and the sintering time at this temperature was set to 2-40 h (HTC-08/16,Nabertherm GmbH, Lilienthal, Germany). The sintered scaffolds were then cooled back toroom temperature at the cooting rate of 5 °Clmin providing a single-coated titanlumdioxide scaffotd (SC scaffold). 98544788500 26 Some of the single-coated titanium dioxide scaffolds produced by the above replicationmethod (sintered for 40 h) were double-coated (DC) with TEOQ slurry containing 40 g ofpowder dispersed in 25 ml of sterilized water and prepared as described above. The pHwas adjusted to 1.5 for the entire duration of stirring. The SC scaffoids were immersed inthe prepared slurry and excess slurry was removed from the foam structure bycentrifugation (1 min @ 1000 rpm; Biofuge 22R Heraeus Sepatech, Osterode, Germany)to ensure that the TiOg slurry covered the surface of the foam struts uniformly withoutblocking the pore windows. After 16 h of drying, sintering of the foams was performed byraising the temperature to 1500 °C at a rate of 3 °Clmin and the setting the sintering timeat this temperature to 40 h. The sintered scaffolds were then cooled back to room temperature at the cooling rate of 5 “iC/min.
Some of the double-coated scaffold samples were then further coated with a low viscosityslurry containing 10-20 g of the cleaned Ti02 powder dispersed in 25 ml of sterilized waterand prepared as described above. The scaffold samples were immersed in the slurry andsupjected to a vacuum infiltration (VI) process. The slurry infiltrated scaffolds were placedin a vacuum tight glass container and vacuum of 0.2 mbar was applied for 5 minutes.Following the vacuum infiltration, the removal of the excess slurry was performed withcentrifugation as described above. After 16 h drying period in room temperature, thecoated scaffolds were sintered at 1500 °C for 4 h before being cooleci back to roomtemperature at 5 °Clmin cooling rate, while the heating rate was set to 3 °Clmin. The orderof the two procedures (DC and VI) was reversed for some of the scaffold samples.
Slurry rheologvThe rheoiogical properties of the prepared TiOz slurries were evaiuated using a Bohlin Visco 88 viscometer (Malvern Instruments Ltd, lvlalvern, UK) using cup and bob geometry(C 25) at 20 °C. Viscosity of the TiO2 slurry was measured at shear rate interval 25-100 s-1 with both increasing and decreasing shear rates.
Pore architectural Characterization The initial visualization and optical observation of the microstructure of the preparedscaffolcls was performed using a scanning electron microscope (TM-1000, Hitachi High-Technologies, Japan). The samples were mounted on aluminum stubs with conductivecarbon tape and viewed with backscattered electrons at 15 kV accelerating voltage.
PS54478SE00 27 Micro-computed tomography was used to determine the three-dimensional mlcrostructureof the scafiolds. The samples were mounted on a plastic sample holder and scanned withdesktop 1172 micro-CT imaging system (SkyScan, Aartseiaar, Beigium) at 6 um voxelresolution using source voltage of 100 kV and current of 100 uA with 0.5 mm aluminumfilter. The sampies were rotated 180° around their vertical axis and three absorptionimages were recorded every 0.4° of rotation. These raw images of the samples werereconstructed with the standard SKyScan reconstruction software (NRecon) to serialcoronal-oriented tomograms using 3D cone beam reconstructlon algorithm. For thereconstruction, bearn hardening was set to 20 % and ring artifact reduction to 12. Theimage analysis of the reconstructed axial bitmap images was performed using thestandard SkyScan software (CTan and CTvol) and included thresholding and despeckling(removing objects smaller than 500 voxels and not connected to the 3D body). ln order toeliminate potential edge effects, a cylindrlcal volume of interest (VOi) with a diameter of 8mm and a height of 3 mm was seiected in the center of the scaffold. The porosity wasthen caiculated as 100 % - vol. % of binarised object in the VOI.
All images underwent 3D analysis, foilowed by the quantification of interconnectivity usingthe 'shrink-wrap' function, which allows measuring the fractlon of pore volume in ascaffoid that is accessibie from the outside through openings of a certain minimum size(Moore et al. 2004). A shrink-wrap process was performed between two 3Dmeasurements to shrink the outside boundary of the V0! in a scaffold through anyopenings the size of which is equal to or larger than a threshold value (0 - 160 um were used in this study). interconnectivity was calculated as follows: V - V. .i w ,Inlerconnectívíry = :ÅIïÜÜffÄ-ïï >< 100% , HI where V is the total volume of VOI, Vshn-flkqpæp is the VOl volume after shrink-wrap processing, and Vm is the volume of scaffold materiai.
The mean strut and pore diameter distributions for each scaffold sampie were found bymeasuring the material thickness and material separation on reconstructed binariseddataset, respectively. Additional noise was again removed using the 'despeckllngfunction, which removed atl objects smaller than 500 voxels and not connected to the 3Dbody.
PS54478SEOO 28 Compressive strengthThe mechanical strength was investigated in a compressive test (Zwicki, ZwickRoell, Utm, Germany). The compression tests were performed in accordance with DIN EN ISO 3386at room temperature using a load cell of 1 kN with preloading force set to be 0.5 N. Thesoaffolds were compressed along their long axes at a compression speed of 100 mm/rninuntil failure. The force and dispiacement were recorded throughout the compression andconverted to stress and strain based on the initial scaffold dimensions.
Statistical analysisNormality and equal variance tests were performed prior to further statistical testing.
Statisticai comparison of different data groups was performed using Students t-test orone-way analysis of variance (ANOVA) test followed by post hoc tests for pairwisecornparisons performed using Holm-Sidak method. Statistical significance was consideredat a probability p < 0.05 and n = 10 unless othenlvise specified. A correlation study wasperformed with a bivariate regression analysis, Spearman Rank Order correlation. Theresults were interpreted as follows: small correlation if 0.1 < ip] < 0.3; medium correlationif 0.3 < |p1 < 0.5; strong correlation if 0.5 < lpl < 1 and p < 0.05 [22]. A negative p indicateda negative correlation, whereas a positive p indicated a positive correlation (p =Spearrnans rank correlation coefficient). All statistical analysis was performed usingsoftware SigmaPlot 12 (Systat Software lnc, San Jose, USA).
Results Effect of sinterinq time on scaffold structure and compressive strength The typical microscopic appearances and compressive strengths of the SC TiOg scaffoldsafter various sintering times are presented in Fig. 1. After a sintering time of 2 h at 1500°C, the Ti02 foam struts had the typical hoilow appearance of foams prepared using thereplication process. Finer~scale microporosity was also apparent as small iongitudinalruptures on some of the strut walls and occasionai laterai cracks on the strut edges. Asthe sintering time was increased to 5 hours, the trianguiar voids within the ceramic strutswere partialiy eliminated from approximately 50% of the foams struts. This etimination ofthe internal porosity occurred by inward collapse of one of the three TiOz strut wallsresulting in a folded strut appearance with a V-shaped cross-section of thin TiOz edges(Fig. 1; 5 h - 10 h). The collapse of the hollow strut structure also led to appearance of PS54478SE00 29 iarge cracks and voids at the stems of the foams where three or more struts join together.Such iarge fiaws were also found in rnajority of collapsed struts present in the TiOz foarnssintered for 10 h. After 10 h of sintering at 1500 °C almost ail of the struts had undergonestrut folding, while further increase in sintering time at the same temperature resulted inmarked reduction in the fiaw size and number. ln both 20 h and 40 h groups, majority ofthe foided struts had deveioped a solid triangular structure with rounded corners and theeartier rather distinct V-shaped structure of the folded struts disappeared (Fig 1; 40 h).The large voids at the junctures of TiOg struts as well as longitudinal cracks along the strutedges were markedly less frequent observation in the TiOz scaffolds that werecontinuously sintered for .>. 20 hours in comparison to the scaffolds prepared with shorter sintering times.
As illustrated in Fig. 1, the overall superficial grain size of TiO2 dici not alter markedlyduring the long sintering times, although the amount of the smallest grains appeared toreduce noticeabiy as the sintering time increased resulting in more uniform grain size. TheTiOz grains were well~integrated via uniform grain boundaries and the overaii grain sizewas relatively iarge in all samples. Preferential grain growth of few large grains was alsoevident in alt of the sample groups, particutarly close to the strut junctures, while theaverage grain size in the struts themselves remained rnarkedly smaller. The features ofthe of the folded TiOg struts became observably more rounded as the sintering time wasprolonged from 5 h to 20 h, and the outer edges of the superficial TiOz grains becamemore three-dirnensionai resulting in an increased height difference at superficiai grainboundary regions in comparison to the more planar strut microstructure that underwentshorter sintering procedure in 1500 °C. No apparent changes occurred in the scaffoldmicrostructure as the sintering time was further increased to 40 h. increasing sintering time had no significant infiuence on the pore architectural parametersof the SC TiOZ scaffolds, although the porosity appeared somewhat reduced fotlowing 40h sintering while a shift towards larger average strut size values was observed due tolonger sintering times at 1500 °C. However, no statisticaiiy significant difference wasobserveci it the pore architectural parameters of the TiOz scaffoid groups, whereas thecom pressive strength of the TiOz scaffolds was found to strongly correlated withincreasing sintering time (p = 0.592, p < 0.01). in addition, the overall dimensions of theTiOz scaffold cyiinders were found to diminish siightly as the sintering time increased.
PS54478SEO0 Effect of DC and/or VI procedures on scaffold structure and compressive strengthViscosities of the TiO2 siurries used for the ccating of the sintereci TiOz foams are plottedas a function of shear rate in Fig. 2. All prepared slurries demonstrated pseudoplasticrheoiogical behaviour. The viscosities of the slurries used in different coating proceduresas well as the different slurries prepared for either doubte~coating (DC) or vacuum-infiitration (VI) with low viscosity slurry showed a marked increase at low shear rates asthe solid content increased, while the difference in viscosity became considerably smaller with increasing shear rate.
Double coating (DC) was found to reduce the flaw size and number in the TiO2 foamstruts by partially fiiiing the micropores, voids, and foids remaining in the foided strutstructure on the single-coated scaffoids (SC) as iliustrated in Fig. 3. DC slurry wasdeposited to the voids and folds of the struts, while only a thin layer of TiOg particlescovered the rest of the strut surface (Fig. 3b), resuiting in only slight increase in the strutthickness and, consequently, somewhat reduced pore size (pore diameter) and overall porosity (Table 1).
Procedure Porosity Pore size Strut size% pm pmDC 30g 89.1 i 1.6 429 i 22 62.7 i 7.4DC 35g 89.8 i 1.2 453 i 8 64.1 i 3.7DC 40g 89.8 i 1.7 441 i 14 63.9 i 6.6DC 45g 90.0 i 1.0 443 i 10 64.9 i 4.7DC+V|10g 89.1 i1.0 443i9 7041:53DC + VI 15g 89.5 i 0.9 439 i 12 68.0 i 3.6DC + Vi 209 88. i 1.4 430 i 13 69.3 i 6.7 Table 1. Selected pore architectural parameters of the scaffolds prepared using variousprocedures (mean i SD). Statistically significant difference was found between aliparameters for recoated groups in comparison to single-coated scaffolds, whereas nodifference was observeci between the different recoated groups. DC = double-coating, Vi = vacuum infiltration.
Vacuum infiltrating the DC scaffolds with low viscosity slurry led to further improvement inthe strut uniforrnity without significant changes in the strut thickness as most of the TiOgsiurry was deposited in the remaining micropores of the foam struts. No significantchanges were observed in any of the measured pore architectural parameters between PS54478SE00 31 the different groups (DC, DC+Vl, or /|+DC). l-iowever, the viscosity of the double-coatingslurry was found to have an effect on the uniformlty of the overall foam structure asillustrated in Fig. 4. While the foams coated with sturry containing 35-40 g of TiOz powderhad a uniform structure throughout the scaffoid votume with only a limited number ofblocked pore windows, both higher (45 g) and tower (30 g) solid content resuited in areduction in structurai uniformity. Slurries with low solid contents, and thereby reducedviscosity, resutted in increased number of biocked pore windows, whereas high viscosityof the slurry containing 45 g of TiOz led to poor infittration of the slurry into the interiorregions of the scaffolci structure, while the many pores at the outer edges of the scaffoldsremained blocked following removal of excess slurry by centrifugation.
The compressive strength of the porous TiO2 scaffolds was found to increase significantlydue to the different procedures (Fig. Sa). The titanium dioxide slurry applied by thevacuum infiltration process was shown to further enhance the compressive strength of thescaffolds as the average strength values increased from 1.78 i 0.52 MPa for double-coated scaffolds to 3.39 i 0.77 MPa when the vacuum infiltrated TiOg coating wasapplied. However, the interconnectivity of the pore network was slightly reduced due tothe low viscosity siurry, although this reduction was only noticeabte at interconnect sizedabove 100 um (Fig. 519), Furthermore, also the sotict content of the slurry used for doubte-coating the ceramic foams influenced the interconnectivity of the pore network with lowestsolid content resulting in a reduction in interconnectivity while only small differences were observabie between the three other DC groups.
Discussion The presence of pre-existing flaws in the ceramic foam structure may have detrlmentateffect on the strut strength, and therefore can severely restrict their use in appticatlonswhere mechanicai loading is expected. One crucial factor timiting the compressivestrength of reticulated ceramic foams prepared using the polyrner sponge repiicationmethod is the presence of trianguiar void within the ceramic foam sketeton. This hollowspace within the foam struts is a common feature in foams prepared with this method andcorresponds to the space formerly occupied by the sponge template. ln addition, thereplication process typically results in several lateral cracks alongside the highly curvededges of the foams struts due to the poor sturry coverage at such location and the low PS54478SE00 32 resistance of these narrow strut edges to stresses induced by the therrnal expansionmismatch of the polymer template and the ceramic coating.
Long sintering times have been previously been shown to result in partiai elimination ofthe triangular pores within the struts of highly porous ceramic TiOz scaffold structures(Fostad et ai. 2009 and Tiainen et ai. 2010). Fostad et al. 2009 reported strut folding inTiO2 scaftolds prepared using 45 ppi polymer foam template following 30 h sintering in1500 °C but they oniy observed a small correlation between the strength and increasingsintering time. Nevertheiess, they recommended exceeding 30 h as such heatingscheduie ied to strut foiding in TiOQ foams with pore diameters between 400 um and 600pm. However, the mechanism and evolution of the strut folding and subsequentconsoiidation of the strut structure during the sintering process has not previously been described in detaii in the relevant iiterature.
Typicaliy, the strut walls of replicated ceramic foams appear to be composed of threeindividual lath-like segments, and often the sintered struts also have longitudinal cracksseparating the three strut segments from each other. However, even after 2 h of sinteringat 1500 °C, the three walls of the struts of prepared TiOz foams formed a uniformstructure and the typical longitudinal cracks at the edges of them were a relatively rarefinding. This was due to the high sintering rate of the TiOz particles, manifested by thelarge overall grain size of the strut walls observed even after the shorter holding times (2-5 h), at the applied sintering temperature of 1500 °C. The densification induced by thehigh sinterability of TiOz led to reduction in the initial volume of the hollow strut interior asthe corners of the strut walls sintered together, causing one of the three walls to bend inwards.
As the sintering time was increased, the strut foiding evoived as an inward collapse of oneof the three strut walls, which was typicaliy preceded by a longitudinal rupture of thinconcave strut wail (Fig.1; 2-5 h). By 10 h holding time, virtuaily all of the foam struts hadaiready underwent fuii strut folding, thus practicaliy eliminating the hollow space within thestrut columns but creating large voids in the junctures where three or more strut columnsjoin together. ln combination with the thin V-shaped strut geometry, these iarge folds andvoids at the stem of the struts are iikeiy to have caused the small drop in the strengthvalues of these foams in comparison to those sintered for only 5 hours. Furtherconsolidation of the strut structure during long sintering times (20-40 h) ied to solid and PS54478SEOO 33 round-edged triangular struts as the outer edges of the folded V-shaped struts mergecttogether (Fig. 1), resutting in improved compressive strength due reduced flaw size andenhanced structure! uniformity. Enteresttngly, the strut foiding and the subsequentconsoiidatioh of the ceramic struts did not result in a reduction En the mean strut thlcknessas one might have expected. instead, a siight but not statistically significant increase wasobserved as the sintering time was increased, whereas the overall porosity appeared tobe somewhat reduced (Tabie 2).
Sintering Porosity Pore size Strut size% pm pm2h 94.1 :13 45019 4681:415 h 93.0 i 0.8 434 i 5 48.1 i 1.710 h 93.7: 1.5 4381:11 47314320 h 93.5: 1.3 45016 49614840h 9252204 436116 51.1 3:16 Table 2. Seiected pore architectural parameters of the scaffolds prepared using varioussintering times (mean d: SD). No stattstically significant differences were observedbetween the different scaffoid groups. n = 10. Pore size is the pore diameter.
This apparent increase in the strut diameter may be linked to the consolidation of theoverall rnicrostructure with the increasing degree of sintering also resulting in slightlyreduced porosity and the overail dimensions of the TiOz foam cyiinders. White the overallsize of the superficlal grains appeared not to grow markedly during the prolongedsintering, the votume of the TiOz grains increased drastically as the fraction of smallestgrains was consumed by the larger grains, thus facilitating the consotidation of the strutstructure. Nonetheiess, the further densification in the microstructure that occurred atter20 h of sintering did not appear to have an effect on the mechanicai properties of the TiOz scaffold foams.
Although most of internal void volume was eiiminated by the strut folciing occurring duringprolonged sintering of the TiOz foams, some inaccessible ciosed porosity stiti remainswithin the strut structure, particuiariy at the juhcture of the foam struts where the volumeof the initial hoiiow void volume had been the largest. However, the increased radius ofcurvature at the corners of this remaining internal porosity resuits in lower degree of localstress amplification at the flaw site, which also contributes to the increased cornpressive ZÛ PS54478SE00 34 strength of the scaffold structure. ln addition, the thickness of the ceramic coating istypicaily iarger at the stern of the strut in comparison to the strut columns, and thus theceramic wall surrounding the blunted edge of the internal void space is more resistant tofracture than the thin walls of the hollow struts in samples sintered for < 10 h, which alsocontributes to the increased strength of the sarnpies sintered from 20-40 h. The use ofsintering times of about 20-40 hours may therefore preferably be used in the method forproviding a recoated titanium dioxide scafiold of the present document. Furthermore,applying a thicker ceramic coating on the polymer template ought to result in thicker, andthereby stronger, foldeci struts.
Nevertheless, it was surprisingly found that the major advantage of the inward collapse ofthe walls of the hollow struts is the fact that the formerly nearly inaccessible pore volumewithin the ceramic foam skeleton is for most part eiiminated or made accessible forrecoating procedure. While the strut folding itself ied to significant enhancement in thecompressive strength of the prepared TiO2 scaffolds, the strength of these single-coatedscaffolds remained well lower limit of the strength of heaithy trabecular bone (<< 2 MPa).But as the scaffolds with folded strut structure were coated with TiOz slurry, the numberand size of flaws was efficiently reduced as the slurry was deposited in the large voidsand folds present on the strut surface (Fig 3). This enhancement in the microstructuraluniformity of the strut structure is considered to cause the observed dramatic improvement in compressive strength of the prepareci TiOz foams (Fig. Sa).
Previous studies have shown that muitipie coatings can lead to further improvement in thestrength of reticulated ceramic foams. i-iowever, this improvement is usualiy achieved atthe expense of porosity and interconnectivity of the pore network, which may uitimateiyrestrict the use of such foams in their intended applications. ln contrast, by the use of therecoating method presented herein, the number of the remaining defects in the ceramicstruts was reduced by recoating the double-coated TiOz foarns with very iow viscosityTiOz slurry under vacuum conditions in order to avoid the increase in the strut thickness.Such vacuum infiltration process was found to lead in cirastic improvement in themechanical integrity of the TiOg foams due to further improved strut strength of the moreuniform ceramic structure (Figs. 3 and 5a). Vogt et al. 2010 have previously described avacuum infiltration process in which the hollow interior the replicated foams struts is fiiledwith ceramic slurry, thus resulting in an increase in the compressive strength of theseceramic foams. l-iowever, the holiow space inside the ceramic struts can be considered PS54478SE00 practically closed porosity and the infiltration of the ceramic slurry into this holiow space islikely to be limited even under vacuum, particularly in foams with smaller strut sizes withnarrower triangular volds within the strut interior. ln addition, the viscosity of the siurryused in the vacuum infiltration procedure ought to be kept low in order to reach majority ofthe tortuous pore space inside the ceramic strut network through the few accessibieopenings, such as fractured struts and narrow cracks at the strut edges.
Curiousiy, reversing the order of the two applied processes (DC and VI) caused nosignificant alterations in either the pore architectural characteristics of the prepared TiOgfoams or their compressive strength. it appears that the tow viscosity siurry used in the Viprocess is deposited mainly in the micropores and small voids of the struts, whiie thecentrifugaticn process effectively removes the excess slurry from foam structure, leavingoniy a very thin coating on the strut surface. Due to the low viscosity of the used TiOzslurry even at iow shear stresses, the slurry can be force into the remaining small flaws inthe strut structure with the aid of vacuum, while the thicker DC slurry is deposited in thelarger foids of the struts. The negligibie increase in strut size due to the vacuum infiitratedcoating is likely to arise from blockage of some of the smailest pore windows andaccumulation of TIO; slurry at the strutjunctures, which also caused the slight drop in theinterconnectivity of the foam structure at (Fig. 5b). This reduction in the interconnectivity ofthe pore network was more pronounced when the vacuum infiltrated scaffolds weredoubie-coated with thicker siurry, indicating that DC+V| process results in less biockedpore openings than appiying the same procedures in reversed order (VHDC).Nonetheiess, the additional vacuum infiltrated low viscosity coating appears to be aneffective method for improving the structural uniformity of the TiOz foam structure, andthus significantiy enhancing the mechanical strength of the TiOz scaffolds while still w maintaining appropriate pore architectural features of the TiOz scaffold structure.
Since the low viscosity coating used in the VI process appears to only have a negligibleeffect on the scaffold structure, the pore architectural characteristics are mainlyciependent on the higher viscosity double coating procedure. As the interconnectivity ofthe pore volume has been identified as one of the most important characteristics for abone scaffold, the number of blocked pore windows should be minimized in the scaffoldstructure by optimization of the double coating procedure. Viscosity of the slurry used fordoubie coating the scaffolds (DC) had a notable infiuence on the uniformity of the TiOzfoam structure with both low (30 g) and high (45 g) solid contents causing biockage of the PS54478S E00 36 pore windows (Fig. 4), and thereby influencing the interconnectivity of the pore network(Fig 5b). Since the poor infiltration of the more viscous slurry resulted in blocked poreopenings mainiy at the outer edges of the TiOZ foam, the effect of this biockage was notmanifested in the 3D interconnectivity anaiysis as the selected V01 (voiume of interest)excluded the outermost region of the scaffoid cylinder. However, the blockage of the outerpore windows is likety to significantly hinder the ceti and tissue penetration towards thescaffoid interior and is therefore particularty undesirabte. Controiling the viscosity of thethird sturry was therefore identified as one of the most important processing parametersgoverning the uniformity and interconnectivity of the pore network when the mechanicalintegrity of ceramic foams is improved with the recoating procedure.
The method disclosed in the present document for providing a recoated titaniutn dioxidescatfold thus provides a scatfold with improved mechanical strength while not negatively affecting the pore architecture and interconnectivšty of the pore network. lt is to be understood that while the invention has been described in conjunction with thedetaiied description thereof, the foregoing description is intended to illustrate and not limitthe scope of the invention, which is defined by the scope of the appended ctaims. Otheraspects, advantages, and modifications are within the scope of the following ciaims.
Uniess expressly described to the contrary, each of the preferred features describedherein can be used in combination with any and all of the other herein described preferred features.
PS54478SEOO 37 REFERENCES Brezny R, Green DJ, Dam CQ. Evaluation of strut strength in open-cell ceramics. J AmCeram Soc 1989722885-889.
Postad G, Hafeil B, Førde A, Dittmann R, Sabetrasekh R, Will J, Ellingsen JE,Lyngstadaas SP, Haugen HJ. Loadable TlOz scaffolds - A correlation study betweenprocessing parameters, micro CT analysis and rnechanical strength. J Eur Ceram Soc2009;29:2773-2781.
Manlatopoulos et al., in Cell Tissue Res 254, 317-330, 1988 Moore MJ, Jabbari E, Ritman EL, Lu L, Currier Bl., Windebank AJ, Yaszemski MJ.Quantitative analysis of interconnectivity of porous biodegradable scaffolds with micro~computed tomography. J Blomed Mater Res Part A 2004;71A:258 - 267.
Tiainen H, Lyngstadaas SP, Ellingsen JE, Haugen HJ. Uitra-porous tltanium oxidescaffold with high compresslve strength. J Mater Sci: Mater Med 2010;21:2783-2792.
Vogt UF, Gorbar M, Dimopoulos-Eggenschwiler P, Broenstrup A, Wagner G, Colombo P.lmproving the properties of ceramic foams by a vacuum infiltration process. J Eur CeramSoc 2010;30:3005-3011.
J Pascuai-Cosp, A.J Ramirez del Valle, J García-Fortea, P.J Sánchez-Soto, Laser cuttingof high-vitrlfled ceramic materials: development of a method using a Ndñ/AG laser toavoid catastrophic breakdown, Materials Letters, Volume 55, Issue 4, August 2002, Pages274280, ISSN 0167-577X, 10.1016/S0167-577X(02)OO377-4.(httoillwtywscienoedirect.com/sciencefartlcle/piš/SO1675 7X02003774).
Schwartzwalder, K., and Somers, A. V., Method of Making a Porous Shape of SinteredRefractory Ceramic Articles. United States Patent No. 3090094, 1963.

权利要求:
Claims (12)
[1] 1. PS54478SEOO CLAiMS 1. 38 A method for producing a recoated titanium dioxide scaffotd, said method comprising: o) applying a first slurry comprising titanium dioxide to a combustible porousstructure allowing the first siurry to solidify on said cornbustible porous structure;removing said combustlbie porous structure from the solidified titanium dioxideslurry by a first sintering at about 400-550°C to produce a titaniurn dioxidescaffold structure; subjecting the titanium dioxide structure to a second sintering at a temperatureof at least 1300°C for at least 10 hours to provide a single-coated titaniurndioxide scaffold characterized in that said method further comprises a vacuum infiltrationprocedure, wherein said vacuum infiitration procedure comprises the steps ofapplying a second slurry comprising titanium dioxide to said single coatedtitanium dioxide scaffotd by vacuum infiltration and thereafter optionallysubjecting said single-coated titanium dioxide scaffotd to centrifugation;aiiowing the second slurry of step e) to solidify on the single-coated titaniumdioxide scaffold; and performing a third sintering at a temperature of at least 'lt00°C to provide a recoated titanium dioxide scaffold. A method according to ciairn 1 wherein said vacuum infiltration procedure is preceded or followed by a double-coatihg procedure comprising the steps of i) ir) m) applying a third slurry comprising titanium dloxide to the single coated titaniumdioxide scaffold of step d) or the recoated titanium dioxide scaffcld of step g)and optionally subjecting the scaffold to centrifugatioh; ailowing the third slurry of step i) to soiidify on the scaffold; and performing a further sintering at a temperature of at least 1100°C. The method of ctaim 2, wherein said further sintering of step iii) is performed for at least 10 hours, such as 20-50 hours.The method according to any one of the precedâng claims, wherein said third sintering of step g) is performed for about 2-15 hours, such as 3 hours. The method according to any one of the precedlng claims, wherein the concentration of titanium dioxide in said second slurry is 300-900 mg/ml, such as400-800 mglml. PS54478SE00 10. 11. 12. 39 The method according to any one of ciaims 2-5, whereân the concentration oftitaniurn dioxide in said third slurry is about 1300-1700 mg/ml, such as 1500-1700mglrnl. The method according to any one of the preoeding ctaims, wherein said vacuuminfiltration is performed at least 0.1 mbar, such as 01-03 mbar. A method for increasing the mechanical strength of a titanium dioxide scaffoid,said method comprising providing a titanium dioxide scaffoid and subiecting saidtitanium dioxide scaffold to at least one of the vacuum infiltration steps e)~f) ordouble coating steps i)-iii) as defined in ciaim t and 2, respectively. A recoated titanium dioxide scaffold obtaânable by the method of any one of claims1-7. A medical prosthetic device comprising a recoated titanium dioxide scaffoldaccording to claim 9. A recoated titanium dioxide scaffold according to oiaim 9 for use as a medicalprosthetic device. A recoated titanium dioxide scaffold according to claim 9 or a medical prostheticdevice according to claim 10 for use for the regeneration, repair, substitution and/or restoration of tissue.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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WO2008078164A2|2006-12-21|2008-07-03|Numat As|Metal oxide scaffolds|SE537637C2|2012-09-18|2015-09-01|Corticalis As|Titanium dioxide scaffold, method of producing this scaffolding medical implant including it|

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US9498337B2|2013-12-23|2016-11-22|Metal Industries Research & Development Centre|Intervertebral implant|

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KR101576052B1|2014-03-27|2015-12-09|연세대학교 산학협력단|carbon dioxide separation membrane comprising porous hollow titanium dioxide nanoparticle and manufacturing method thereof|

法律状态:
2018-05-02| NUG| Patent has lapsed|

优先权:

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SE1251044A|SE537634C2|2012-09-18|2012-09-18|Titandioxidscaffold|SE1251044A| SE537634C2|2012-09-18|2012-09-18|Titandioxidscaffold|

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PCT/EP2013/069250| WO2014044666A1|2012-09-18|2013-09-17|Hard scaffold|

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US14/427,901| US9889011B2|2012-09-18|2013-09-17|Hard scaffold|

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KR1020157006903A| KR20150058233A|2012-09-18|2013-09-17|Hard scaffold|

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CA2884215A| CA2884215A1|2012-09-18|2013-09-17|Hard scaffold|

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EP13770414.4A| EP2897657B1|2012-09-18|2013-09-17|Hard scaffold|

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PL13770414T| PL2897657T3|2012-09-18|2013-09-17|Hard scaffold|

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ES13770414.4T| ES2608630T3|2012-09-18|2013-09-17|Hard scaffolding|

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JP2015531599A| JP2015531270A|2012-09-18|2013-09-17|hard scaffold|