WO2018117907A1

WO2018117907A1 - Shape memory polymer composite for 3d printing of medical items

Info

Publication number: WO2018117907A1
Application number: PCT/RU2017/000929
Authority: WO
Inventors: Fedor Svyatoslavovich SENATOV; Kirill Vyacheslavovich NIAZA; Viktor Viktorovich TCHERDYNTSEV; Sergey Dmitrievich KALOSHKIN; Juri Zaharovich ESTRIN
Original assignee: National University Of Science And Technology "Misis"
Priority date: 2016-12-19
Filing date: 2017-12-11
Publication date: 2018-06-28
Also published as: EA036376B1; CN110087702A; EA201900311A1; DE112017006358T5; RU2631890C1

Abstract

This invention describes s medical purpose composite material based on a thermoplastic polymer with a bioactive shape memory ceramic, wherein the "hard" phase comprises the crystalline phase of the polymer matrix, chemical and physical crosslinking agents and a bioactive component, and the "soft" phase comprises the amorphous phase of the polymer matrix and a plasticizer. The 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 said composite material comprises a plasticizer, i.e., 4.6 to 15 wt.% polyethylene glycol. For stabilizing the mechanical properties said composite material has a crosslinked structure. The crosslinked structure of said polymer material and the presence of a hard phase, i.e. hydroxyapatite particles, provide for the development of recovery stresses of 3 MPa at a 98% shape recovery. Furthermore, the addition of the polyethylene glycol plasticizer reduces the materials glass transition temperature which is the shape memory effect activation point. Shape memory effect is activated in the 35 to 45ºC range. Youngs modulus and elastic modulus in compression of the composite material are 4 and 11 GPa, respectively. The melt of said composite material exhibits a high viscosity at 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 3D printing of shape memory medical items.

Description

Shape Memory Polymer Composite for 3D Printing of Medical Items

Field of the Invention. Shape memory polymers have a number of advantages over shape memory metallic alloys due to higher recoverable deformations. The initial shape of a shape memory polymer product can be transformed to a temporary shape by deformation at a specific temperature below the transition point (the shape memory effect activation temperature) which may be the glass transition temperature T_g or the melting temperature T_m at which the polymer chain segment mobility is limited.

To exhibit the shape memory effect a polymer must have a "hard" fixed phase and a "soft" deformable phase. The driving force of shape recovery is a change in the mobility of the polymer shape and a transformation from a more ordered temporary as-deformed configuration to a more thermodynamically favorable configuration, having higher entropy and a lower internal energy. This transformation can be activated by external stimulation e.g. heat, electrical or magnetic fields, light, moisture etc.. The most widely used and suitable temperature for shape memory effect activation, from the viewpoint of its practical application, is the glass transition temperature T_g which is manifested by an increase in the mobility of the polymer chain segments resulting in shape recovery.

In medical items, the shape memory effect may have potential applications in self-fitting and self-anchoring bone implants.

Polylactide is a thermoplastic polymer which is of special interest for bone implant applications due to its high elastic modulus, relatively low glass transition temperature T_g and the suitability for 3D printing applications. Physical entanglements of long polyactide chains may act as the "hard" phase while the polymer chains between the entanglements can be stretched during deformation to a temporary shape. The properties of polyactide, e.g. the recovery stress and the recovery strain, can be improved by crosslinking or adding fine inorganic particles having a high elastic modulus and acting as an additional "hard" phase. From this viewpoint calcium phosphate particles are of special interest for bone tissue recovery.

This invention relates to a medical purpose composite material based on a thermoplastic polymer with a shape memory bioactive ceramic component addition which can be used for the fabrication of medical items by fused filament fabrication, FFF, implemented through 3D printing.

Prior Art. Known is an invention (US 2013/0030122 Al "Elastomers crosslinked by polylactic acid") which described a method of providing polymer compositions on the basis of crosslinked L-polylactide or D-polylactide.

Disadvantage of said invention is that the glass transition point T_g = -26 °C and the melting point T_m = 224 °C of the polymer composite material which could be the shape memory effect activation temperatures are far from the human body temperature.

Known is an invention (WO 20151 10981 Al "Use of polylactide and method of manufacturing a heat sealed paper or board container or package") describing a method of providing polylactide and polybutylene succinate (PBS) based polymer composite materials with an addition of a polyfunctional crosslinking element, e.g. triallyl isocyanurate (TAIC).

Disadvantage of said invention is that said polymer composite material does not exhibit the shape memory effect.

Known is an invention (US 20150123314 Al "Process for the manufacture of shape memory polymer material") describing a method of providing a shape memory polymer material. Said material is produced from a bioresorbable polymer (polyactide, polyglycolyde, polycaprolactone, polyurethane, polyacrylate, polymethylacrylate, polybutylmethylacrylate or polyetheretherketone), bioceramics (calcium phosphate, tricalcuim phosphate, hydroxyapatiite, calcium carbonate, calcium sulfate, bioglass or glycolide) and polyethylene glycol.

Disadvantage of said invention is an incomplete shape recovery (90% under the optimum conditions).

Known is an invention (WO 2013050775 Al "Medical devices containing shape memory polymer compositions") disclosing a medical device based on a shape memory polymer material. Said polymer material is produced from a bioresorbable polymer (polyactide, polyglycolyde, polycaprolactone, polydioxanone, polyurethane, polyacrylate, polymethylacrylate, polybutylmethylacrylate or polyetheretherketone) and a plasticizer (polyethylene glycol).

Disadvantage of said invention is the absence of a crosslinked structure and a stable hard phase to provide for a higher recovering stress compared to unfilled polyactide.

Known are inventions (US 201 1/0144751 Al "Multimodal shape memory polymers" and US 9308293 B2 "Multimodal shape memory polymers") disclosing a polymer composite material based on two polymers with different molecular weights and calcium phosphate ceramics.

Disadvantage of said inventions is that the glass transition point T_g = -26 °C of the polymer composite material which could be the shape memory effect activation temperature is far from the human body temperature. Furthermore the material does not have a crosslinked structure to provide for mechanical rigidity.

Known is an invention (US 2014/0236226 Al "Tailored polymers", US 2015/0073476 Al) disclosing a polymer composite material based on polyactide and a water-soluble plasticizer.

Disadvantage of said invention is an incomplete (90% under the optimum conditions) and slow (during 24 h) shape recovery as well as the absence of a bioactive component (calcium phosphate ceramics). Known is an invention (US 2015/0073476 Al "Shape memory polymer compositions") describing a polylactide base polymer composite material.

Disadvantage of said invention is an incomplete (90%) and slow (during 24 h) shape recovery.

Furthermore, the abovementioned inventions do not allow medical item 3D printing applications.

The closest counterpart of this invention is RU Patent 2215542 "Biodegradable shape memory polymers" describing biodegradable and biocompatible shape memory polymer compositions suitable for medical applications and as carriers of therapy or diagnostic agents.

Disadvantage of said invention is the absence of a biocompatible agent, i.e. calcium phosphate ceramics, and the impossibility of layerwise fusion in the 3D printing of medical items. Another disadvantage of said invention is related to poor mechanical properties (elastic modulus below 100 MPa and ultimate strength below 20 MPa).

Disclosure of the Invention. The technical result of this invention is providing a polymer composite material suitable for the 3D printing of shape memory medical items, distinguished by the following:

- medical item 3D printing compatibility;

- crosslinked structure retaining mechanical properties;

- 35 to 45 °C shape memory effect activation temperature;

- bioactive component with 100 to 1000 nm sized particles;

- 3 MPa recovery stress for 98% shape recovery upon shape memory effect activation;

- good tensile mechanical properties: 4 GPa Yung's modulus and 43 MPa limit strength;

- good compression mechanical properties: 1 1 GPa Yung's modulus and 96 MPa limit strength. The technical result of this invention is achieved as follows. A composite material is provided on the basis of a thermoplastic polymer with an addition of a bioactive shape memory ceramic component wherein the "hard" phase comprises the crystalline phase of the polymer matrix, chemical and physical crosslinking agents and a bioactive component, and the "soft" phase comprises the amorphous phase of the polymer matrix and a plasticizer.

In the invention described herein, the composite material comprises a 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 said composite material comprises a plasticizer, i.e., 4.6 to 15 wt.% polyethylene glycol.

Embodiments of the Invention. For stabilizing the mechanical properties said composite material has a crosslinked structure. The crosslinked structure of said polymer material and the presence of a hard 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 plasticizer reduces the material glass transition temperature which is the shape memory effect activation point. Shape memory effect is activated in the 35 to 45 °C range. Young's modulus and elastic modulus in compression of the composite material are 4 and 1 1 GPa, respectively. The melt of said composite material exhibits a high viscosity at above the melting point (170 °C) providing for a higher layerwise application accuracy in the 3D printing of medical items.

The 80 to 47 wt.% polylactide content in the composite is required for the coexistence of the "hard" and "soft" phases with the optimum concentration of the additional polymers. If the polyethylene glycol plasticizer addition is above 15 wt.% the strength and the elastic modulus of the composite material decrease to below 40 MPa and 4 GPa, respectively. However, if the plasticizer addition is below 4.6 wt.% the plasticization effect is not achieved and the shape memory effect activation temperature is above 45-50 °C. Addition of hydroxyapatite particles to less than 15 wt.% does not provide for the biological activity of the material and reduces the content of the "hard" phase to below the level sufficient for the development of recovering stresses of above 1.5 MPa and for a greater than 95% shape recovery. Meanwhile, excessive hydroxyapatite contents (higher than 35 wt.%) increase the brittleness of the composite material. Introducing a crosslinking agent at below 0.4 wt.% provides for insignificant structure crosslinking and does ensure a sufficient "hard" phase content for shape memory effect implementation at above the shape memory effect activation temperature. On the other hand, introducing a crosslinking agent to above 3 wt.% produces an excessively hard structure with a glass transition temperature of above 45 °C. This composite cannot be used for layerwise 3D printing due to its excessively crosslinked structure.

The industrial and medical applicability of the polymer composite material provided herein is confirmed by the following embodiment.

The invention is illustrated with reference to Figures where Fig. 1 shows an example of a differential scanning calorimetry (DSC) curve for the polymer material of this invention with 8 wt.% polyethylene glycol. The first phase transition occurs at the material's glass transition point, i.e., 40.9 °C, testifying that the shape memory effect activation temperature is lowered to a point close to human body temperature. Figure 2 exemplifies the growth of recovering stress at above the shape memory effect activation temperature. We deformed and stabilized the temporary shape of a specimen obtained by 3D printing of the polymer composite material at room temperature followed by heating to above the shape memory effect activation temperature and initial shape recovery. The highest recovery stress is 3 MPa. Figure 3 shows an example of a compression diagram for the polymer composite containing 30 wt.% hydroxyapatite. The ultimate strength is above 80 MPa, and Young's modulus is in excess of 10.8 GPa. Figure 4 illustrates a tensile diagram for the polymer composite containing 30 wt.% hydroxyapatite. The tensile strength is above 60 MPa, and Young's modulus exceeds 4.0 GPa.

Example 1.

The initial materials were Ingeo 4032D polylactide (Natureworks LLC, USA), GAP 85-D hydroxyapatite powder (NPO Polystom) with an average particle size of 1000 nm and polyethylene glycol (OOO Polymer) with a 4000 g/mole molecular weight. The final polymer product contained 47 wt.% polylactide, 35 wt.% hydroxyapatite and 15 wt.% polyethylene glycol. The polylactide structure is crosslinked with Evonik TAIC triallyl isocyanurate (3 wt.%). The glass transition temperature of the material is 35 °C, the recovery stress is 2.5 MPa, the shape recovery is 98%, the compression strength of the 3D printed polymer composite specimens is 70 MPa, and elastic modulus in compression is 9 GPa.

Example 2.

The initial materials were Ingeo 4032D polylactide (Natureworks LLC, USA), GAP 85-D hydroxyapatite powder (NPO Polystom) with an average particle size of 100 nm and polyethylene glycol (OOO Polymer) with a 4000 g/mole molecular weight. The final polymer product contained 80 wt.% polylactide, 15 wt.% hydroxyapatite and 4.6 wt.% polyethylene glycol. The polylactide structure is crosslinked with PERKADOX BC-FF decumyl peroxide (0.4 wt.%). The glass transition temperature of the material is 45 °C, the recovery stress is 1.7 MPa, the shape recovery is 96%, the compression strength of the 3D printed polymer composite specimens is 80 MPa, and elastic modulus in compression is 7 GPa. Table 1. Results of mechanical tests in compression

D is the hydroxyapatite (HA) particle size, nm

T_g is the glass transition temperature which is the shape memory effect activation temperature, °C

RS is the recovery stress, MPa

e_rs is the recovery strain, %

σ is the ultimate strength in compression, MPa

E is elastic modulus in compression, GPa

Claims

What is claimed is a

1. Shape memory polymer composite comprising a "hard" and a "soft" phases based on biodegradable and biocompatible polymer composites wherein said "hard" phase of said polymer composite comprises the crystalline phase of the polymer matrix, chemical and physical crosslinking agents and hydroxyapatite as a bioactive component with a particle size of 100 to 1000 nm, and said "soft" phase comprises the amorphous phase of the polymer matrix and polyethylene glycol as a plasticizer, with the following component ratio (wt.%):

80 to 47 polylactide,

15 to 35 hydroxyapatite,

4.6 to 15 polyethylene glycol,

0.4 to 3.0 crosslinking agent.

2. Polymer composite of Claim 1 wherein said chemical crosslinking agent is triallyl isocyanurate or decumyl peroxide.