Patent Application
20230285151
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
This application is a National Stage application under 35 U.S.C. §371 of International Application No. PCT/US2021/045384, having an International Filing Date of Aug. 10, 2021, which, claims priority to U.S. Provisional Application No. 63/063,483, filed on Aug. 10, 2020, and U.S. Provisional Application No. 63/063/485, filed on Aug. 10, 2020, all of which are considered part of the disclosure of this application, and are incorporated in their entireties herein.
Tissue engineering is an interdisciplinary field that applies the principles of engineering, medicine, basic sciences to develop tissue substitutes - implants that restore, maintain or improve the function of human tissues. Large-scale cultivation of human, animal or artificial origin cells can provide materials to replace damaged components in humans.
Natural or synthetic materials when implanted into the human body as temporary structures provide a framework that allows the body’s own cells to migrate, differentiate, grow and form new tissues, while the framework itself is gradually absorbed by the body.
The requirements for a polymer implant must meet the following criteria: it must be an open interconnective network to stimulate cell growth and transfer of nutrients and metabolic waste. The biocompatibility and bioresorbability with controlled rates of decomposition and resorption have to match the rate of tissue replacement in the body. There must be a suitable surface composition for cell attachment, proliferation and differentiation. And it must offer high mechanical properties corresponding to the tissues at the site of implantation.
Furthermore, the structure of the implant must protect the interior of the proliferating cells of the pore network and their extracellular matrix from mechanical overload for a sufficient period of time. This is especially important for supporting tissues such as bones and cartilage.
Layer-by-layer fusion deposition modeling (FDM) is a well-known additive manufacturing process that forms three-dimensional objects by extrusion and deposition of individual layers of thermoplastic materials.
Generally, before any printing, one would first start with a generated model of the implant on a computer. The model is imported into specialized software which enables the use of this model for 3D printing.
The FDM method involves extrusion of a melted material through a heated nozzle, followed by a deposition in the form of thin solid layers on the substrate. The thermoplastic polymer material is fed to a temperature-controlled FDM extrusion printing head, where it is heated to a semi-fluid state. The printing head spreads the material through a nozzle in ultra-thin layers with high accuracy.
After printing the material returns from melted to solid state. Layer-by-layer fabrication allows one to design porous, interconnected structures for general applications in medicine, and the pore morphology can vary according to the implant structure.
BJP, binder-jet printing, is also a well-known method for printing polymer-based materials. Here, BJP is not suitable due to the fact that it uses powder bases and a liquid binder to bind particles.
In the case of polycaprolactone, which is usually used in granular form, it will be difficult to use it as a powder, since it will not sufficiently bind with water- or glycerin-based binders during the printing stage. It would present a further challenge in the post-processing of the product using high-temperature sintering, as is the traditional approach in the binder-jet printing, due to the fact that the chemical composition of polycaprolactone degrades at temperatures higher than 300° C.
Hydroxyapatite is an artificial bioresorbable material which is neutral for the human body. It is well-known to use hydroxyapatite to make implants. Hydroxyapatite is the chemical compound of Calcium and Phosphorus with chemical formula Ca10 (PO4)6 (OH)2 and particle size up to 100 nanometers.
Hydroxyapatite particles are utilized to stimulate the vascularization and differentiation of macrophages and mesenchymal stem cells to osteogenic cells. In addition, the main products of hydroxyapatite resorption help to buffer the by-products of the acidic resorption of aliphatic polyester and thereby help avoid the formation of an unfavorable environment for the cells due to the low pH.
In addition, polycaprolactone (PCL) is a semi-crystalline, bioresorbable polymer belonging to the family of aliphatic polyesters. It has favorable properties for thermoplastic processing.
It has a low glass transition temperature of -60° C., a melting point of 60° C., and a high decomposition temperature of 350° C., with a wide range of temperatures that allow extrusion. PCL is currently considered to be a biodegradable material compatible with soft and hard human tissue.
FDM printing technology allows us to use a modified polymer in 3D printing to give it the desired individual shape with high accuracy, printing speed and the ability to control the printing process. Also, the FDM technology allows us to optimize the range of temperatures to use the inventive polymers without the danger of damaging their chemical structure, which can lead to the loss of the desired properties of the implant.
The present embodiments are illustrated by way of example and are not intended to be limited by the figures of the accompanying drawings.
Since polycaprolactone and hydroxyapatite are chosen for the implant composition, this leads to limitations in the choice of printing technology. Generally speaking, the FDM process offers the following benefits: it enables the use of a wide range of biomaterials; it enables the ability to make bio-composites with the necessary mechanical and biological properties; it enables the flexibility to make objects of the desired shape, which can be specified in the 3D model; it offers a quick and affordable way to print products; the resultant implant meets the necessary compliance with aseptic conditions, and the subsequent sterilization of products allows their use for medical purposes.
The present invention method utilizes a FDM printing method to process a bioresorbable composite of two biomaterials to make a novel bone implant, wherein a biodegradable polymer (polycaprolactone, PCL) is mixed with a calcium-based powder (hydroxyapatite, HA) to make a compound that meets all the criteria for use in general tissue engineering applications.
Furthermore, we propose a design of the implant which mimics the structure of a tubular bone with a solid outer layer and a lattice inside to imitate a spongy bone. The inner part of the implant is made in the form of a lattice with a bar diameter of 200-500 µm and a spacing of 200-500 µm between the rods.
This structure increases the surface area of the implant, creates controlled macroporosity to stimulate angiogenesis and it attracts the mesenchymal differentiation of stem cells into osteogenic and bone tissue cells at the site of the implant.
The three-dimensional polymer matrix of the implant of the present invention has the kinetics of degradation and resorption from 6 to 18 months and the ability to maintain a given shape under the action of the biomechanical load.
The inclusion of calcium-based material in the bioresorbable polymer provides support for the composite material that improves the rates of degradation and resorption. This composite material improves the biocompatibility and integration of solid tissues.
Hydroxyapatite particles that are embedded in the matrix of a synthetic polymer provide increased osteogenic differentiation and connective tissue growth compared to the more hydrophobic surface of the polymer. In addition, the main products of hydroxyapatite resorption help to buffer the by-products of the acidic resorption of aliphatic polyester and thereby help avoid the formation of an unfavorable environment for the cells of hard tissues due to the low pH.
Since the polycaprolactone-hydroxyapatite composition itself is not porous, the inventive process enables a novel lattice structure inside the implant to provide the implant body with conditions for the growth of soft tissues into the thickness of the implant and a better process of implant engraftment and its subsequent resorption.
The mixture melting is preferably set to 190° C., because this is optimal temperature of melting of PCL pellets. When the mixture melting temperature is <100° C., it is inefficient because the mixture will not completely melt to retain the desired properties of the final implant. When the mixture melting temperature is >300° C., it is inefficient because the chemical composition will be damaged.
The extrusion machine nozzle and printer head nozzle can be optimized to fit the printer and standards. Most commonly used diameters are 1.63 mm, 1.75 mm and 3 mm.
The printer head extruder T°C is preferably set to 160° C. for optimal extrusion to limit or prevent the damage to the polymer chemical composition.
The printer bed temperature is preferably set to 0° C. At >100° C., the conditions are inefficient, because the implant can be deformed by constant heating effect on the lower layers of the implant. The composition and process conditions which result in the chemical properties of the implant are optimized to prevent the implant deformation effect.
The printing speed is preferably set to 25 mm/s to provide accuracy in the printing process. At a printing speed of more than 50 mm/s, the process will cause poor-quality printing. It may result in smears of the composition and defects during printing due to fast movement of the printer head. When the printer head moves too fast, it does not allow to accurately apply the extrudable composition to the specified coordinates.
The thread soaking time and implant soaking time are preferably set to 24 hours. When the soaking times exceed 72 hours, the process is inefficient because the number of microorganisms and particles that form on the surface of the material.
One embodiment of the system of the present invention is comprised of the following devices:
One embodiment of the process of the present invention is comprised of the following steps:
1. A method for producing a modified polymer-based bioresorbable implant comprising: making a compound of a calcium-based powder up to 40% and a biodegradable polymer up to 90% to create a homogeneous mixture;
2. The method according to claim 1, wherein hydroxyapatite nanopowder is used as the calcium-based powder.
3. The method according to claim 1, wherein polycaprolactone pellets are used as the biodegradable polymer.
4. The method according to claim 1, wherein the composition of a homogeneous mixture is 10% of hydroxyapatite nanopowder and 90% of polycaprolactone pellets.
5. The method according to claim 1, wherein the composition of a homogeneous mixture is 20% of hydroxyapatite nanopowder and 80% of polycaprolactone pellets.
6. The method according to claim 1, wherein the composition of a homogeneous mixture is 30% of hydroxyapatite nanopowder and 70% of polycaprolactone pellets.
7. The method according to claim 1, wherein the ethanol solution is used as an antiseptic solution for soaking the thread.
8. The method according to claim 7, wherein the concentration of an ethanol solution is up to 80%.
9. The method according to claim 1, wherein the thread soaking time is set to 24 hours.
10. The method according to claim 1, wherein the 3D printer parameters are set to: extruder temperature is 160° C., bed temperature is 0° C., printing speed is 25 mm/s.
11. The method according to claim 1, wherein the ethanol solution is used as an antiseptic solution for soaking the implant.
12. The method according to claim 11, wherein the concentration of an ethanol solution is up to 80%.
13. The method according to claim 1, wherein the implant soaking time is set to 24 hours.
14. The method according to claim 1, wherein the calcium-based powder is selected from the group of chemical compounds consisting of calcium and/or phosphorus with the Ca/P ratio of 1.5-1.67, tricalcium phosphate, monocalcium phosphate, dicalcium phosphate, tetracalcium phosphate, hydroxyapatite, alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium oxide(II) and mixtures thereof.
15. The method according to claim 1, wherein the extrusion machine nozzle diameter is 1.75 mm.
16. The method according to claim 1, wherein the extrusion machine nozzle diameter is 3 mm.
17. The method according to claim 1, wherein the printing head nozzle diameter is 1.75 mm.
18. The method according to claim 1, wherein the printing head nozzle diameter is 3 mm.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/045384 | 8/10/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63063483 | Aug 2020 | US | |
| 63063485 | Aug 2020 | US |
