Patent Application
20090209717
The invention relates to a shape memory polymer that, in addition to a permanent shape, can memorize at least two temporary shapes, a process for its preparation and a process for programming its shape, as well as its use.
So-called shape memory polymers or SMPs that, upon induction by an appropriate stimulus, display a shape transition from a temporary shape to a permanent shape consistent with previous programming, have been known from prior art. Most frequently, this shape memory effect is thermally stimulated, i.e., when the polymer material is heated to above the defined transition temperature, resetting triggered by entropic elasticity occurs. As a rule, shape memory polymers are polymer networks where chemical (covalent) or physical (non-covalent) cross-linking sites define the permanent shape. Programming is achieved in that the polymer material is deformed above the transition temperature of a switch segment and subsequently cooled to below this temperature while the deformation forces are maintained in order to fix the temporary shape. Renewed heating above the transition temperature results in a phase transition and the restoration of the original permanent shape.
Furthermore, in recent times, polymer networks have been described, said networks having two switch segments with different transition temperatures.
For example, document EP 1 362 879 A describes shape memory polymers (in this case interpenetrating networks—IPNs) that consist of a covalently cross-linked polymer component, in particular on the basis of caprolactone units, lactid units, glycolid units or p-dioxano units, and of a non-covalently cross-linked polyester urethane component. The polymer is capable of storing two temporary shapes, whereby the transition temperatures are said to be about 50 and 90° C.
Also, Liu et al (Macromol. Rap. Comm. 26, 2005, 649 ff) discloses an SMP (semi-interpenetrating network—SIPN) consisting of polymethyl methacrylate units (PMMA) and polyethylene glycol units (PEG) that also has two transition temperatures (40 and 86° C.). The programming process described there, however, permits only the memory of one temporary shape.
An important field of use of shape memory polymers is medical technology where such materials can be used, for example, as self-knotting suture material or as implant material. In many such applications resorbable polymers that are hydrolytically degraded in the body after some time are desirable. The disadvantage of the known shape memory polymers is that their switch temperatures are outside a physiologically tolerable range and/or that they are not resorbable or that they, or their decomposition products, are not biocompatible.
The object of the invention is to provide a new biocompatible shape memory polymer that is capable of memorizing at least two temporary shapes. The corresponding switch temperatures of the polymer should be within a physiologically acceptable range, i.e., the stimulation of the shape memory should be possible without damaging the surrounding cells. Furthermore, a method for programming at least two temporary shapes of the shape memory polymer is to be provided.
This object is achieved by a shape memory polymer displaying the features of claim 1. The shape memory polymer in accordance with the invention comprises at least two switch segments with different transition temperatures so that the polymer material may—as a function of temperature—take at least two temporary shapes in addition to one permanent shape. The polymer system in accordance with the invention comprises a first switch segment that is essentially based on a polymer having the general Formula I where n=1 . . . 6, or on a derivative thereof, or on a copolyester having the general Formula I where n=1 . . . 6, wherein at least two ester units having different chain lengths n are present, or on a derivative thereof.
Furthermore, the polymer system comprises a second switch segment that is essentially based on a polyether having the general Formula II where m=1 . . . 4, or on a copolyether having the general Formula II where m=1 . . . 4, wherein at least two ether units having different chain lengths m are present, or on a derivative thereof.
In conjunction with this, the term switch segment is understood to mean an oligomer or polymer in accordance with the given Formula I or II, said oligomer or polymer having a chain length p or q, that permits the formation of a separate phase due to phase segregation in the solid and thus provides the basis for the formation of typical material properties of the corresponding compound. In this manner, it is achieved that the polymer system as a whole displays material properties that can be associated with the respective switch segments, in particular, two or more different switch temperatures for the thermally induced effect, said temperatures potentially representing—independent of each other—glass transition temperatures or melting temperatures. From the viewpoint of the structure, the switch segments may be covalently or non-covalently cross-linked and terminal, linked to each other on one side or on both sides, and/or linked to a polymer spine. Furthermore, within the limitations of the present invention, derivatives of the polyester in accordance with Formula I and/or derivatives of the polyether in accordance with Formula II comprise structures, wherein one or more hydrogen radicals of the methylene units (—CH2—) are substituted by unbranched or branched, saturated or unsaturated C1 through C6 radicals. Considering the present limitations, the selection of the substituents should be such that the formation of a separate phase of the switch segments is not prevented.
As a result of the inventive composition, a material is made available that, following appropriate programming, is able to fix at least two deformations at the same time, whereby said deformations can be restored after being activated by appropriate thermal stimuli. A particularly advantageous property of the inventive polymer system has been found to be switch temperatures that are within a physiologically acceptable range. In particular, the two switch temperatures of the switch segments in accordance with Formulae I and II are below 85° C. Preferably, the monomer units, their substituents, as well as the chain lengths of the switch segments, are selected such that the switch temperatures are below 80° C., preferably below 75° C. A further advantage consists in that both switch segment polymers are physiologically resorbable and that their decomposition products are physiologically compatible.
Referring to a preferred embodiment of the invention, the first switch segment comprises a poly(ε-caprolactone) segment where n=5, or a derivative thereof, wherein the aliphatic carbon atoms, independently of each other, may be substituted by one or two, unbranched or branched, saturated or unsaturated C1 through C6 radicals. Particularly preferred, however, is the non-derivatized poly(ε-caprolactone) where n=5 in accordance with Formula I, i.e., without substituents.
Referring to another advantageous embodiment of the invention, the second switch segment comprises a polyethylene glycol segment where m=2, or a derivative thereof, wherein the aliphatic carbon atoms, independently of each other, may be substituted with one or two, unbranched or branched, saturated or unsaturated C1 through C6 radicals. However, particularly preferred is again the non-derivatized polyethylene glycol where m=2 in accordance with Formula II.
The molecular weights of the segments as well as their mass fractions in the polymer and their relative mass ratios (first switch segment:second switch segment) are adjusted in such a manner that the above-described switch temperatures are not exceeded and that distinct shape changes are achieved at least during the two phase transitions. Advantageously, the first switch segment (polyester) has a mean molecular weight in the range of from 2 000 to 100 000 g/mol, in particular of from 5 000 to 40 000 g/mol, preferably of approximately 10 000 g/mol. Independently thereof, the mean molecular weights of the second switch segment (polyether) in the range of from 100 to 10 000 g/mol, in particular of from 500 to 5 000 g/mol, preferably of approximately 1 000 g/mol, have proved to be successful. Preferably a mass fraction of the polyester segment in the shape memory polymer is in the range of from 25 to 65%, in particular in the range of from 30 to 60%. Correspondingly, the polyether segment is present in a mass fraction in the range of from 35 to 75%, in particular in the range of from 40 to 70%.
The polymer system in accordance with the invention may be a polymer network, wherein the polymer chains comprising the switch segments may exist cross-linked with each other, or may be an interpenetrating network (IPN) or a semi-interpenetrating network (SIPN). Preferably, the system exists as a polymer network, wherein one of the switch segments, in particular the polyester exists cross-linked and the other switch segment, in particular the polyether, is bound in the form of free side chains to the cross-linked switch segment or to a polymer spine structure. In so doing, in accordance with a special embodiment of the invention, the spine structure may be formed by the cross-linking units of both polymer components themselves, in particular, by acrylate and methacrylate groups.
The shape memory polymer in accordance with the invention can be advantageously prepared in that
a polyester macromer having the general Formula Ia where n=1 . . . 6 and Y representing any connecting radical, or a copolyester having the general Formula Ia (where n and Y have the above meaning) having at least two ester units with different n, or a derivative thereof, and
a polyether macromer having the general Formula IIa where m=1 . . . 4, or a copolyether having the general Formula IIa having at least two ether units with different m, or a derivative thereof
are copolymerized with each other. Preferred embodiments of the polyester and the polyether are selected in accordance with the above description. In so doing, p1 and p2, i.e., the chain lengths of the polyester or the copolyester, in Formula Ia may be the same or different. The radical Y is used exclusively for connecting the two polyester units to each other while reversing the chain direction, so that polymerizable terminal groups may be added to both sides, said groups being used for cross-linking (see below).
A suitable macromer of the polyester component, for example, has the general Formula Ib with r=2 . . . 8 and X=O or NH. Particularly preferred is a component with r=2, p3=2, and X=O, i.e., the polyester macromer is obtained by the polymerization of diethylene glycol HO-CH2-CH2-O-CH2-CH2-OH with the appropriate ester monomers.
Preferably, the first terminal group R1 and/or the second terminal group R2 of the first switch segment represent, independently of each other, a polymerizable radical. Preferably, each of R1 as well as R2 represents a polymerizable radical. Particularly preferably used for R1 and/or R2 are acryl or methacryl radicals, in particular one methacryl radical, respectively. In this manner, if both components are copolymerized, a network is obtained in which the polyester segments are linked on both sides, whereby, due to the polymerization of the polyester components among each other, poly(meth)acrylate chains are formed, said chains forming a polymer spine that is cross-linked by the polyester chains.
Likewise, the first terminal group R3 and/or the second terminal group R4 of the second switch segment may represent, independently of each other, a polymerizable radical. Preferably, only one of the terminal groups R3 or R4 is a polymerizable radical, and the other group is a non-reactive radical. This measure results in a linking (grafting) on only one side of the corresponding switch segment, either to the other switch segment or to the optionally existing spine structure. In accordance with a particularly preferred embodiment, the first terminal group R3 or the second terminal R4 is an acryl or a methacryl radical, and the other terminal group is an alkoxy radical, wherein, in particular the first terminal group R3 is a methyl ether radical and the second terminal group R4 is a methacrylate radical.
Furthermore, the copolymerization may be performed in the presence of at least one additional monomer, in particular in the presence of an acryl or methacryl monomer. Consequently, a poly(meth)acrylate is formed that forms an additional component having the aforementioned spine structure.
Consequently, referring to a particularly preferred embodiment, the first macromer, poly(ε-caprolactone)-dimethacrylate (PCLDMA), having Formula Ic is copolymerized with the second macromer, poly(ethylene glycol) methyl ether methacrylate (PEGMMA) having Formula IIc. As a result of this, a spine structure is created that consists of linearly polymerized methacrylate units of PCLDMA macromers and PEGMMA macromers. This spine is linked by PCL chains (bound on both sides) and has PEG chains in the form of free side chains (bound on one side).
Another important aspect of the invention relates to a method for programming at least two temporary shapes in a shape memory polymer in accordance with the invention. The method in accordance with the invention comprises the following steps:
In so doing, the cooling occurring in step (b) may be selectively achieved by cooling to an intermediate temperature below the upper transition temperature and above the lower transition temperature, or to a temperature below the lower transition temperature. For fixing the first temporary shape it is decisive for cooling to occur below the upper transition temperature. If the shape memory polymer is a polymer that can memorize two temporary shapes, i.e., it comprises at least three switch segments, additional temporary shapes are programmed analogously in that, respectively above the appropriate transition temperature, a deforming force is applied, and the temporary shape is fixed by cooling to below this transition temperature while maintaining the deforming force.
The shape memory polymer in accordance with the invention is particularly suitable for medical applications, in particular as implant material. For example, it can be used as an intelligent implant material, whereby thermal stimulation can be used to retrieve the memorized shapes and, as a result of this, an adaptation to existing anatomical situations becomes possible. In so doing, physiologically safe transition temperatures, as well as good bioresorption, are advantageously and effectively attained.
Additional preferred embodiments of the invention result from the remaining features disclosed in the subordinate claims.
Hereinafter, exemplary embodiments are used to explain the invention with reference being made to associate drawings. They show in
500 g (50 mmol) of poly(c-caprolactone) diol (Aldrich) having a mean molecular weight of 10 000 g/mol (PCL10k diol) are placed in 5 L of dichloromethane in a dry 3-neck flask in a nitrogen atmosphere. While cooling with ice, 20.0 mL (0.14 mol) of triethylamine are added dropwise. After stirring for 10 min at 0° C., 17.4 mL (0.18 mol) of methacryloyl chloride are added dropwise. The solution is heated to room temperature and stirred for another 24 hours. The precipitated salt is removed by filtration. The filtrate is concentrated and dissolved in ethyl acetate. This solution is precipitated in a 10 times excess of a mixture of hexane/diethyl ether/methanol (18:1:1 parts by volume) at −20° C. After vacuum drying, 475 g (47 mmol of poly(ε-caprolactone) dimethacrylate PCLMDA having a mean molecular weight of 10 kD (PCL10 kDMA) having the Formula Ic (see above) are obtained (yield, 95%). The degree of functionalization of the PCL diols having methacrylate terminal groups was determined with 1H-NMR spectroscopy to be approximately 85%. This means that 72% of the macromers are functionalized on both sides (dimethacrylate), 26% are functionalized on one side (monomethacrylate), and 2% are present as diol and not functionalized.
PCL10kDMA prepared in accordance with Example 1 and polyethylene glycol methyl ether methacrylate (PEG1kMMA) (Polyscience) having Formula IIc (see above) and having a mean molecular weight of 1 000 g/mol are weighed in various mixing ratios in accordance with Table 1. (The degree of functionalization with methyl methacrylate (MMA) terminal groups of PEG1kMMA was determined to be 100% with MALDI-TOF mass spectrometry.) The mixtures of PCL10kDMA and PEG1kMMA are melted in a vacuum furnace at 80° C. in order to achieve a good mixture. This prepolymer mixture is poured on a glass plate (10×10 cm) and again placed in the furnace. After a bubble-free homogenous melt is obtained, the mould is closed with another glass plate placed thereon, with the lateral arrangement of PTFE spacers (thickness, 0.55 cm). The structure that is fixed by clamps is irradiated for 80 min with UV radiation (Fe-doped mercury vapor lamp) in order to trigger cross-linking. Pure PCL10kDMA and pure PEG1kMMA as reference materials are treated accordingly in order to obtain a homopolymer network of PCL10kDMA (PCL(100) in Table 1) or linear homopolymers of PEG1kMMA (P[PEGMMA] in Table 1).
The thermal properties of the polymer networks of PCL10kDMA macromers and PEG1kMMA macromers having different compositions and being prepared in accordance with Example 2 are examined by dynamic difference calorimetry (DSC) and by dynamic mechanical thermo analysis (DMTA). The DSC measurements are performed on a Netzsch DSC 204 Phoenix apparatus. To do so, 5 to 10 mg of the samples are placed in an aluminum vessel and the measurements are performed in a nitrogen atmosphere at a cooling and heating rate of 1 K·min−1 within a temperature range of −100 and +100° C. The results are summarized in Table 2. DMTA measurements are performed on an Explexor 5 N (Gabo) which is equipped with a 25N force absorber. The static load is 0.50%, the dynamic load 20%, the frequency 10 Hz, and the heating rate 2 K·min−1 within a temperature range of −100 and +100° C. The results are also summarized in Table 2.
It is obvious that the inventive polymer network containing PCL and PEG segments displays two well-differentiated phase transitions within the range of 0 and 80° C. that can be attributed to the melting of PEG and PCL crystallites. In so doing, the lower melting temperature Tm is clearly associated with the melting or the crystallization of the PEG segments, said temperature being observed at 39° C. in the case of the homopolymer P[PEGMMA] and between 38 and 32° C. in the copolymer with a PCL mass fraction between 20 and 60%. In contrast, the upper melting temperature Tm can be clearly associated with the melting or the crystallization of PCL segments, said temperature being observed at approximately 55° C. in the case of the homopolymer PCL(100) and at 53 to 54° C. in the case of all copolymers. These results show that the graft polymer network in accordance with the invention displays a phase-segregated morphology, whereby the PCL segments and the PEG segments form their own domains with their own transition temperatures that are suitable for temperature-controlled fixing of two temporary shapes.
The observation, based on which the melting temperature of the PEG segments drops significantly starting with a PCL content of 70%, demonstrates that a critical PEG mass fraction of 40% in the polymer network is required in order to obtain a suitable PEG crystal size. As opposed to this, it is possible to conclude, based on the constant melting temperature of the PCL segments, that, with a PCL mass fraction of 20%, the required critical crystal size of the PCL segments has already been achieved.
A graft polymer network PCL(40)PEG prepared in accordance with Example 2 and based on 40 wt. % of PCL10kDMA and 60 wt. % of PEG1kMMA is programmed in a cyclic thermomechanical experiment in such a manner that, in addition to the preparation-specific permanent shape, two temporary shapes are stored in the “shape memory” of the polymer. Basically, this is achieved by fixing a first temporary shape at a temperature below the melting temperature of PCL (Tm(PCL)) or at a temperature below the melting temperature of PEG (Tm(PEG)), and by subsequently fixing a second temporary shape at a temperature below the melting temperature of PEG (Tm(PEG).
This principle is explained with reference to
Starting with the shape shown in
During the next step, programming of the second temporary shape TF2 occurs analogously to the first temporary shape TF1. In particular, a second mechanical stimulus is used to convert the polymer 10 into the second temporary shape TF2, which, for example, may be achieved by an additional elongation at a temperature above Tm(PEG) (
Starting with a polymer network 10 programmed in this manner, said network being present in its second temporary shape TF2, the first temporary shape TP1 and the permanent shape PF can be retrieved in succession when the polymer 10 is first heated to an intermediate temperature Tm(PEG)<T<Tm(PCL) and, subsequently, to a temperature above Tm(PCL). The restoration of previously fixed shapes is referred to as the shape memory effect (SM effect).
The programming cycle starts at a temperature Th,1 of 70° C. above Tm(PCL) (approximately 53° C.). This is followed by an elongation of the polymer to 50% (εm,1), consistent with the first temporary shape TF1. Subsequently, while continuing the application of the mechanical load, cooling takes place at a temperature gradient of 4 K·min−1 to an intermediate temperature of 40° C. (Th,2) below Tm(PCL) and above Tm(PEG) (approximately 37° C.). After a holding time of three hours the polymer is relaxed, indicating a slight reversal of the elongation. Subsequently, the sample is held another 10 min without the application of a mechanical load in order to then elongate the sample to the 100% of total elongation (εm,2), cool it under constant mechanical load to 0° C. (T1), and maintain the mechanical load for another 10 min, whereby the elongation decreases slightly.
Upon completion of the programming cycle, the memorized shapes are retrieved in succession in that (without application of a mechanical load) a heating rate of 1 K·min−1 is used to re-heat the sample from 0 to 70° C. In so doing, first the melting of the PEG crystallites and the restoration of the second temporary shape at Tm(PEG) are observed. If the temperature is held for one hour at 40° C., the second temporary shape remains stable and there is no transformation into the permanent shape (not illustrated). Continued heating above Tm(PCL) causes the PCL crystallites to melt and to achieve an almost quantitative restoration of the permanent shape. This programming and restoring cycle was performed four more times with the same result.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2006 012 169.4 | Mar 2006 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2007/052345 | 3/13/2007 | WO | 00 | 9/29/2008 |
