EA036376B1 - Shape memory polymer composite for 3d printing of medical items - Google Patents

Abstract

The invention relates to a medical purpose composite material based on a thermoplastic polymer with a bioactive shape memory ceramic, wherein a "hard" phase comprises a crystalline phase of a polymer matrix, chemical and physical crosslinking agents and a bioactive component, and a "soft" phase comprises an amorphous phase of a polymer matrix and a plasticizer. The provided composite material comprises the bioresorbable polyactide polymer matrix and hydroxyapatite bioactive filler with 100 to 1000 nm sized particles. The hydroxyapatite filling percentage is 15 to 35 wt.%. For reducing the shape memory effect activation temperature the composite material comprises a plasticizer, i.e., 4.6 to 15 wt.% polyethylene glycol. For stabilizing the mechanical properties the composite material has a crosslinked structure. The crosslinked structure of the polymer and the presence of the "hard" fixed phase, i.e. hydroxyapatite nanoparticles, provide for the development of recovery stresses of 3 MPa at a 98% shape recovery. Furthermore, the addition of the polyethylene glycol reduces the materials glass transition temperature which is the shape memory effect activation point. The shape memory effect is activated in the 35 to 45ºC range. Young's modulus and elastic modulus in compression of the polymer composite material are 4 and 11 GPa, respectively. The melt of the polymer composite material exhibits a higher viscosity at a temperature above the melting point (170ºC) providing for a higher layerwise application accuracy in the 3D printing of medical items. The technical result of this invention is providing a polymer composite material suitable for the layerwise 3D printing of shape memory medical items.

Description

Shape memory polymers have a number of advantages over shape memory metal alloys due to their much higher recoverable strains. The initial shape of the shape memory polymer article can be transformed into a temporary shape by deformation at a fixed temperature below the transition temperature (activation of the shape memory effect), which can be the glass transition temperature Tg or the melting temperature T _m when the mobility of the polymer chain segments is limited.

For the shape memory effect to exist in the polymer, a rigid fixed phase and a soft deformable phase must exist. The driving force for shape recovery is the change in the mobility of the polymer chain and transformation from a more ordered temporal configuration after deformation to a more thermodynamically favorable configuration with higher entropy and lower internal energy. This transformation can be activated by external stimulation under the influence of heat, electric or magnetic field, light, moisture, etc. The most common and convenient temperature for activating shape memory from the point of view of practical application is the glass transition temperature Tg, which is characterized by an increase in the mobility of the chain segments, as a result of which shape recovery occurs.

The shape memory effect in medical devices has potential applications in self-aligning and self-locking bone implants.

Polylactide (PLA) is a thermoplastic polymer that is of particular interest for use in bone implants because of its high modulus of elasticity, relatively low glass transition temperature Tg, and its potential for use in 3D printing. The physical links of long PLA chains can act as a rigid phase, while the polymer chains between the links can be stretched during deformation into a temporary shape. PLA properties, such as restoring stress and recoverable strains, can be improved by creating cross-links, adding dispersed high-modulus inorganic particles that can act as an additional rigid phase. From this point of view, calcium phosphate particles are of particular interest for bone tissue reconstruction.

The invention relates to a composite material for medical use based on a thermoplastic polymer with the addition of a bioactive ceramic component with a shape memory effect, which can be used to form medical products during 3D printing by layer-by-layer fusion of filaments (Fused Filament Fabrication, FFF).

Known invention US 2013/0030122 A1 (Elastomers crosslinked by polylactic acid), which is a method of creating polymer compositions based on crosslinked L-polylactide or Dpolylactide.

The disadvantage of the aforementioned invention is that the glass transition temperature Tg = -26 ° C and the melting point T _m = 224 ° C of the polymer composite, which could be the activation temperatures of the shape memory effect, are not close to the temperature of the human body.

Known invention WO 2015110981 A1 (Use of polylactide and method of manufacturing a heat sealed paper or board container or package), which is a method of creating polymer composites based on polylactide and polybutylene succinate (PBS) with the addition of a polyfunctional cross-linking agent such as trialkylsilyl isocyanurate (TAIC ).

The disadvantage of the aforementioned invention is that this polymer composite does not exhibit the shape memory effect.

Known invention US 20150123314 A1 (Process for the manufacture of shape memory polymer material), which is a method of obtaining a polymer material with a shape memory effect. The material is made from a bioresorbable polymer (polylactide, polyglycolide, polycaprolactone, polydioxanone, polyurethane, polyacrylate, polymethyl methacrylate, polybutyl methacrylate or polyetheretherketone), bioceramics (calcium phosphate, tricalcium phosphate, hydroxycolyde, a calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium carbonate, calcium sulfate)

The disadvantage of the aforementioned invention is incomplete restoration of the shape (90% in the optimal mode).

Known invention WO 2013050775 A1 (Medical devices containing shape memory polymer compositions), which is a medical device made of a polymer material with a shape memory effect. The polymeric material is made from a bioresorbable polymer (polylactide, polyglycolide, polycaprolactone, polydioxanone, polyurethane, polyacrylate, polymethyl methacrylate, polybutyl methacrylate or polyether ether ketone), as well as a plasticizer (polyethylene glycol).

The disadvantage of the aforementioned invention is the absence of a crosslinked structure and a fixed rigid phase, which would provide restoring voltages higher than in pure unfilled polylactide.

Known inventions US 2011/0144751 A1 (Multimodal shape memory polymers), US 9308293 B2 (Multimodal shape memory polymers), which are a polymer composite based on two polymers with different molecular weights and calcium phosphate ceramics.

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The disadvantage of the above inventions is that the glass transition temperature Tg of the polymer composite, which could be the activation temperature of the shape memory effect, is not close to the temperature of the human body. Also, the composite lacks a crosslinked structure that provides mechanical rigidity.

Known invention US 2014/0236226 A1 (Tailored polymers), US 2015/0073476 A1, which is a polymer composite based on polylactide and a water-soluble plasticizer.

The disadvantage of the aforementioned invention is incomplete (90% in the optimal mode) and slow (within 24 hours) restoration of the shape, as well as the absence of a bioactive component (calcium phosphate ceramics).

Known invention US 2015/0073476 Al (Shape memory polymer compositions), which is a polymer composite based on polylactide.

The disadvantage of the aforementioned invention is incomplete (up to 90%) and slow (within> 24 h) shape recovery.

All of the above inventions also lack the ability to use them for layer-by-layer 3D printing of medical devices.

The prototype is the invention patent RU No. 2215542 (Biodegradable polymers capable of recovering the shape), which is a biodegradable and biocompatible polymer composition with shape memory for use in medical products and as carriers of therapeutic or diagnostic agents.

The disadvantage of the aforementioned invention is the absence of a bioactive component - calcium phosphate ceramics, the lack of the possibility of providing layer-by-layer fusion when forming medical products by 3D printing. Another disadvantage is low mechanical properties (modulus of elasticity less than 100 MPa, ultimate strength less than 20 MPa).

The technical result of the claimed invention is to create a polymer composite that can be used to form medical products with a shape memory effect by layer-by-layer 3D-printing, which can be used for layer-by-layer 3D printing of medical products;

cross-linked structure to maintain mechanical properties;

the temperature of activation of the shape memory effect from 35 to 45 ° C;

the presence of a bioactive component with a particle size of 100 to 1000 nm;

the presence of restoring voltages of 3 MPa during shape recovery at the level of 98% upon activation of the shape memory effect;

high mechanical tensile properties: Young's modulus 4 GPa, tensile strength 43 MPa;

high mechanical properties in compression: Young's modulus 11 GPa, ultimate strength 96 MPa.

The technical result is achieved as follows: a composite material is formed based on a thermoplastic polymer with the addition of a bioactive ceramic component with a shape memory effect, in which the hard phase is represented by the crystalline phase of the polymer matrix, chemical and physical crosslinks and a bioactive component, and the soft phase is represented by the amorphous phase of the polymer matrix and a plasticizer.

In the proposed in this application, the composite material has as a polymer matrix bioresorbable polylactide, and as a bioactive filler - hydroxyapatite with an average particle size of 100 to 1000 nm. The degree of filling with hydroxyapatite is from 15 to 35 wt%. To reduce the activation temperature of the shape memory effect, the composite material contains polyethylene glycol plasticizer, from 5 to 15 wt%.

To stabilize the mechanical properties, the composite material has a crosslinked structure. The crosslinked structure of the polymer and the presence of a rigid fixed phase — hydroxyapatite nanoparticles — lead to the development of restoring stresses of 3 MPa at 98% shape recovery. At the same time, due to the introduction of a plasticizer (polyethylene glycol), the glass transition temperature of the material, which plays the role of the activation temperature of the shape memory effect, decreases. The shape memory effect is activated in the temperature range from 35 to 45 ° C. Young's modulus for tension and compression of the polymer composite is 4 and 11 GPa, respectively. The polymer composite melt has an increased viscosity at a temperature above the melting point (170 ° C) to ensure an increase in the accuracy of layer-by-layer fusion in the manufacture of medical devices using 3D printing.

The polylactide content in the polylactide composite from 80 to 47 wt% is required for the presence of both soft and hard phases with an optimal content of additional added components. When a plasticizer (polyethylene glycol, PEG) is added over 15 wt%, the strength and elastic modulus of the composite material decrease below 40 MPa and 4 GPa, respectively. When adding less than 4.6 wt.%, The effect of plasticization is not achieved, the activation temperature of the shape memory effect becomes higher than 45-50 ° C. When adding particles of hydroxyapatite (HAP) less than 15 wt.%, The bioactivity of the material is not ensured, and the content of the hard phase becomes too low to ensure the development of restoring stresses of more than 1.5 MPa and recovery of the shape of more than 95%. Slish

- 2 036376 lump same high content of HAP (more than 35 wt.%) Leads to increased fragility of the composite material. The introduction of a chemical agent for crosslinking in an amount of less than 0.4 wt% leads to insignificant crosslinking of the structure and does not create a rigid phase for the realization of the shape memory effect when heated above the activation temperature. The introduction of more than 3 wt% of a chemical agent for crosslinking leads to the formation of an excessively rigid structure with a glass transition temperature above 45 ° C. Such a composite with an overly crosslinked structure cannot be used for layer-by-layer 3D printing.

The possibility of industrial applicability of the proposed polymer composite and its use in medicine is confirmed by the following implementation example.

The invention is illustrated by drawings, where Fig. 1 shows an example of a differential scanning calorimetry (DSC) curve for a polymer composite containing 8 wt% polyethylene glycol (PEG). The first phase transformation occurs at the glass transition temperature of the material 40.9 ° C, i.e. the activation temperature of the shape memory effect is reduced to a temperature close to that of the human body. FIG. 2 shows an example of the growth of the returning voltages above the activation temperature of the shape memory effect. Deformation was carried out with fixation of the temporary shape of the sample obtained by 3D printing from a polymer composite at room temperature, followed by heating above the temperature of activation of the shape memory effect and restoration of the original shape. The maximum restoring stress is 3 MPa. FIG. 3 shows an example of a compression deformation diagram of a polymer composite with a hydroxyapatite content of 30 wt%. The ultimate strength was more than 80 MPa, and the Young's modulus was more than 10.8 GPa. FIG. 4 shows an example of a tensile strain diagram of a polymer composite with a hydroxyapatite content of 30 wt%. The ultimate strength was more than 60 MPa, and Young's modulus was more than 4.0 GPa.

Example 1.

The starting materials were polylactide (PLA) brand Ingeo 4032D (manufactured by Natureworks LLC, USA), hydroxyapatite powder (HAP) HAP 85-D (manufactured by NPO Polistom) with an average particle size of 1000 nm, polyethylene glycol (PEG) by Isomer LLC with molecular weight 4000 g / mol. Formed a polymer composite containing PLA 47 wt.%, HAP - 35 wt.%, PEG 15 wt.%. The PLA structure was chemically crosslinked using the TAIK Evonik triallyl isocyanurate (3 wt%). The glass transition temperature is 35 ° C, the restoring stresses are 2.5 MPa, the shape recovery is 98%, the compressive strength of the 3D-printed polymer composite samples is 70 MPa, the Young's modulus in compression is 9 GPa.

Example 2.

The starting materials were polylactide (PLA) brand Ingeo 4032D (manufactured by Natureworks LLC, USA), hydroxyapatite powder (HAP) GAP 85-UD (produced by NPO Polistom) with an average particle size of 100 nm, polyethylene glycol (PEG) LLC Isomer with molecular weight 4000 g / mol. Formed polymer composite containing PLA - 80 wt.%, HAP - 15 wt.%, PEG - 4.6 wt.%. The PLA structure was chemically cross-linked using PERKADOX BC-FF decumyl peroxide (0.4 wt%). The glass transition temperature is 45 ° C, the restoring stresses are 1.7 MPa, the shape recovery is 96%, the compressive strength of the samples from the polymer composite printed on the 3D-πringer is 80 MPa, and the Young's modulus in compression is 7 GPa.

Composite compositions and achieved results

Composition, wt% D, NM T _g , ° C RS, MPa ε „,% σ, MPa E, GPa PLA PEG GAP Stitching agent 47 15 35 3 1000 35 2.0 98 70 nine 80 4.6 15 0,4 one hundred 45 2.5 96 80 7 D - HAP particle size, nm T _g - glass transition temperature, which is the activation temperature of the shape memory effect (SME), ° C RS - restoring stresses upon SME activation, MPa £ _rs - shape recovery upon SME activation,% а - compressive strength , MPa E- modulus of elasticity in compression, GPa

Claims (2)

CLAIM 1. Polymer composite with shape memory, consisting of hard and soft phases based on biodegradable and biocompatible polymer compositions, characterized in that the hard phase in the polymer composite is represented by the crystalline phase of the polymer matrix, chemical and physical crosslinks and a bioactive component in the form of hydroxyapatite with a particle size from 100 to 1000 nm, and the soft phase is represented by the amorphous phase of the polymer matrix and the plasticizer in the form of polyethylene glycol, with the following ratio of components (wt%): polylactide - from 80 to 47; hydroxyapatite - 15 to 35; polyethylene glycol - from 4.6 to 15; chemical agent for crosslinking - from 0.4 to 3.0. 2. The polymer composite of claim 1, wherein the chemical crosslinking agent is triallyl isocyanurate or dicumyl peroxide.