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EP-4740972-A1 - METHOD FOR PRODUCING A 3D PRINTED BONE GRAFT AND 3D PRINTED BONE GRAFT

EP4740972A1EP 4740972 A1EP4740972 A1EP 4740972A1EP-4740972-A1

Abstract

A method for producing a 3D printed bone graft and a 3D printed bone graft are proposed. The method comprises a) preparing a photocurable composite resin composition by mixing a photocurable biocompatible polymeric resin, comprising one or more monomers/oligomers and a photoinitiator, with a hydrolysable calcium phosphate-based ceramic material; b) manufacturing a 3D printed bone graft using the photocurable resin composition through 3D printing with a light-based 3D printing system; c) cleaning and removing uncured resin or particles from the 3D printed bone graft by ultrasonic rinsing in a solvent; d) providing consolidation to the 3D printed bone graft by: d1) sublimating liquid contained in the resin by freeze-drying the manufactured 3D printed bone graft; and/or d2) hydrolyzing the hydrolysable calcium phosphate-based ceramic material to calcium deficient hydroxyapatite (CDHA).

Inventors

  • GINEBRA MOLINS, MARIA PAU
  • FAGOTTO CLAVIJO, Roberto
  • LODOSO TORRECILLA, Irene
  • DÍEZ ESCUDERO, Anna

Assignees

  • Universitat Politècnica De Catalunya

Dates

Publication Date
20260513
Application Date
20241107

Claims (15)

  1. A method for producing a 3D printed bone graft, the method comprising the following steps: a) preparing a photocurable composite resin composition by mixing a photocurable biocompatible polymeric resin, comprising one or more monomers/oligomers and a photoinitiator, with a hydrolysable calcium phosphate-based ceramic material; b) manufacturing a 3D printed bone graft using the photocurable resin composition through 3D printing with a light-based 3D printing system; c) cleaning and removing uncured resin or particles from the 3D printed bone graft by ultrasonic rinsing in a solvent; d) providing consolidation to the 3D printed bone graft by: d1) sublimating liquid contained in the resin by freeze-drying the manufactured 3D printed bone graft; and/or d2) hydrolyzing the hydrolysable calcium phosphate-based ceramic material to calcium deficient hydroxyapatite, CDHA.
  2. The method of claim 1, wherein step b) comprises irradiating the photocurable composite resin composition using a light source having a light wavelength of 280 nm to 460 nm.
  3. The method of claim 1, wherein step a) further comprises using a photoabsorber in a wavelength range between 280 nm to 460 nm.
  4. The method of claim 1, wherein step a) further comprises using a dispersant in a range between 0.5 and 5 wt% relative to the hydrolysable calcium phosphate-based ceramic material.
  5. The method of any one of the previous claims, wherein step d2) comprises immersing the 3D printed bone graft in distilled water or an aqueous solution at a given temperature and pressure.
  6. The method of claim 5, wherein the given temperature is comprised in the range between 20°C and 150°C and the pressure is comprised in the range between 0.5 and 2 atm.
  7. The method of claim 5 or 6, wherein the 3D printed bone graft is immersed for a period of time comprised between 10 minutes and 15 days.
  8. The method of any one of the previous claims, wherein the hydrolysable calcium phosphate-based ceramic material comprises α-tricalcium phosphate, β-tricalcium phosphate, or a mixture thereof.
  9. The method of any one of the previous claims, wherein the one or more monomers/oligomers comprise an acrylated monomer/oligomer including poly (ethylene glycol) diacrylate, PEGDA; Poly(ethylene glycol) dimethacrylate, PEGMA; methacrylated gelatin GelMA monomer; and/or a combination thereof, in a concentration ranging between 5 and 90 wt%.
  10. The method of any one of the previous claims, wherein the photoinitiator comprises a single material or a mixture of two or more materials selected from: Lithium phenyl-2,4,6-trimethylbenzoylphosphinate, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2-hydroxy-2-methylpropiophenone, (benzene)tricarbonylchromium,4,4'-bis(diethylamino)benzophenone, phenanthrenequinone, bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide,2,4,6 trimethylbenzoyl-diphenyl-phosphineoxide, 2-benzyl-2-dimethylamino-1-(4-orpholinophenyl)-butanone-1,bis(eta5-2,4-cyclopentadien-1-yl)-bis(2,5-difluoro-3-(1H-yrrol-1-yl)-henyl)titanium, and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide, tris(2,20-bipyridyl)ruthenium (II) chloride hexahydrate (Ru) / sodium persulfate (SPS).
  11. The method of any one of the previous claims, wherein the photoinitiator is comprised in an amount between 0.25 to 2 wt.% with respect to the total weight of the photocurable polymeric resin.
  12. The method of any one of the previous claims, wherein the hydrolysable calcium phosphate-based ceramic material is comprised in a range between 30 and 70 wt. % with respect to the total weight of the photocurable composite resin composition.
  13. The method of any one of the previous claims, wherein the 3D printed bone graft comprises a bone regeneration product including a scaffold.
  14. A 3D printed bone graft produced by a method for producing a bone graft, the method comprising the steps of: a) preparing a photocurable composite resin composition by mixing a photocurable biocompatible polymeric resin, comprising one or more monomers and a photoinitiator, with a hydrolysable calcium phosphate-based ceramic material; b) manufacturing a 3D printed bone graft using the photocurable resin composition through 3D printing with a light-based 3D printing system; c) cleaning and removing uncured resin or particles from the 3D printed bone graft by ultrasonic rinsing in a solvent; d) providing consolidation to the 3D printed bone graft by: d1) sublimating liquid contained in the resin by freeze-drying the manufactured 3D printed bone graft; and/or d2) hydrolyzing the hydrolysable calcium phosphate-based ceramic material to calcium deficient hydroxyapatite, CDHA.
  15. The bone graft of claim 14, comprising a bone regeneration product including a scaffold.

Description

TECHNICAL FIELD The present invention relates to 3D printing compositions comprising ceramic and polymeric materials and to methods for printing 3D ceramic and polymeric objects. Specifically, the present invention relates to a method for producing a 3D printed bone graft and a 3D printed bone graft manufactured using the method. BACKGROUND OF THE INVENTION Bone defects caused by trauma, osteoporotic fractures, infection and tumor resection pose a great clinical and socio-economic problem. The field of bone grafting is gradually shifting from autologous or allogeneic grafts to synthetic substitutes. Among them, calcium phosphate-based materials, particularly hydroxyapatite, are extensively utilized due to their biocompatibility and osteogenic potential. Bone grafts should exhibit excellent osteoconductivity, hence the ability to lead a rapid colonization by cells, which adhere, migrate, grow, and divide. Consequently, interconnected macroporosity (>100 µm) is highly desired to promote osteoconduction. These macroporous grafts are commonly referred to as scaffolds, which are a temporary mechanical structure designed to create an optimal environment for bone remodeling with minimal complications. These structures are widely employed in bone repair due to their ability to fill the defective area, provide mechanical support, and guide the growth of new tissue. Scaffolds ought to facilitate the resorption of the synthetic material, and its replacement with newly formed natural bone. Additionally, it is highly desired for scaffolds to actively influence the formation of new bone, accelerating the healing process, which is known as osteoinductivity, being the ability to favor the differentiation of mesenchymal stem cells into bone cells. With the advent of 3D-printing technologies, the field of bone grafting has seen remarkable advancements. 3D printing has enabled the development of highly personalized and high-performing bone grafts. Extrusion-based techniques such as Direct Ink Writing (DIW) or Fused Filament Fabrication (FFF) are widely used for printing high-loaded ceramic bone grafts. Extrusion-based techniques involve the layer-by-layer extrusion of an ink through a nozzle to build an implant. Despite the significant progress in this area, certain limitations still hinder the widespread application of extrusion-based technology, such as precision in structural integrity and scalability. To address these limitations, light-based technologies have been increasingly applied. Light-based printing techniques use various optical arrays and devices to direct light precisely onto specific areas containing photocurable resins, which are then photocrosslinked. These techniques encompass a wide range of systems, including Digital Light Processing (DLP) with Digital Micromirror Devices (DMD-DLP) or Liquid Crystal Displays (LCD-DLP), Stereolithography (SLA), masked SLA (mSLA), Continuous Liquid Interface Production (CLIP), Two-Photon Polymerization (2PP), and Volumetric 3D Printing (V3DP). Each of these methods employs light to cure resin, with higher resolution compared to extrusion-based techniques, enabling the creation of highly detailed structures.. In this context, patent US10835390-B2 introduces a method for manufacturing a bone graft material using 3D printing of a DLP system. The method includes dispersing a powder material including calcium phosphate-based ceramics in a solvent; recovering the calcium phosphate-based ceramics by removing the solvent from a solution in which the calcium phosphate-based ceramic material is dispersed; producing a photocurable resin composition by adding a binder resin including a crosslinking agent and a photoinitiator to the calcium phosphate-based ceramics; performing 3D rapid prototyping on a bone graft material molded body from the composition for a bone graft material by 3D printing of a DLP system; and debinding and sintering the materials remaining in the bone graft material molded body subjected to prototyping. In this method, unlike the present invention, to induce growth of the particles and improve strength, the materials have to be subjected to additional debinding and sintering steps. Other methods utilizing DLP to manufacture 3D-printed objects for bone defect regeneration and repair are known by scientific articles [1-3]. In view of the foregoing, it is an object of the present invention to enhance the disadvantages of the prior art, or to provide a useful alternative. References: [1] DLP printing of hydrogel/calcium phosphate composites for the treatment of bone defects. I.I. Preobrazhenskiy et al. Open Ceramics. Volume 6, June 2021.[2] Hydroxyapatite-Resin Composites Produced by Vat Photopolymerization and Post-Processing via In Situ Hydrolysis of Alpha Tricalcium Phosphate. Carolina Oliver-Urrutia et al. Ceramics 2023, 6(4), 2282-2294.[3] Customized bioceramic scaffolds and metal meshes for challenging large-size mandibular bone defect regeneration and repair. B