LV14492B - Porous hydroxyapatite ceramics with bimodal distribution of pores and method for manufacturing thereof - Google Patents

Abstract

The proposed porous hydroxyapatite ceramics with a bimodal pore distribution and preparation method thereof belongs to field of medicine, traumatic and orthopedics, usable in maxillofacial surgery as scaffolds for tissue engineering or drug delivery systems, as well as fillers in bone (spongy parts) defects. Hydroxyapatite powder is used as basic material, glycerol as plasticizer, de-ionized water as moistening agent, and ammonium bicarbonate as a pore-former substance. Ceramic manufacturing technology is based on the foaming process in situ.The new technical quality of invention is working out ceramics with a bimodal pore distribution and preparation method thereof that provides total porosity of 65 to 75 % containing 53 to 62 % open macro-porosity with pore’s diameter in the range from 50 to 500 micro-meters, and micro-porosity with pore’s diameter in range from 0.05 to 0.2 micro-meters. Closed porosity is 12 to 14 %. Compressive strength of ceramics is 8 to 11 MPa.Composition of ceramic mass and its fabrication method provides implant biocompatibility, porosity with interconnected pore system (macro- and micro-pores), that stimulates the body’s cell growth and increases the adsorption of proteins and mechanical properties that corresponds to quality of trabecular bone.

Description

The present invention relates to the medical field and is useful in traumatology and orthopedics, in facial-jaw bone surgery as a basis for bone tissue engineering or in drug delivery systems, and as a filler for bone defects.

There is a known process for the production of porous, moldable articles from metal, ceramic and composite powders [1] using ammonium salts as the pore forming agent, incl. ammonium bicarbonate (NH4HCO3), which decomposes above 60 ° C, forming pores in the material structure. Polyvinyl acetate or polyethylene is administered as a surfactant and absolute ethanol or petroleum ether as the wetting agent. The resulting products are mainly used in the building materials industry.

Also known is the technological process for the production of porous AI2O3 ceramics based on the decomposition of the pore maker NH4HCO3 during the heat treatment (60-80 ° C) process [2]. NH4HCO3 was added as a pore forming component to the mass as water. Potato starch was introduced into the ceramic as a plasticizing additive, which at 80 ° C facilitates the coagulation (gelling) of the suspension, and as a dispersant - substance A6114. The use of porous AI2O3 ceramics obtained from these studies is limited in the medical field because it is classified as an inert implant material around which a connective tissue capsule is formed, which limits the use of these implants in areas subject to dynamic loading. It has gained widespread application, as indicated in [2], in chemical technology and apparatus construction for the manufacture of catalytic reaction accelerators, separation filters and thermal insulators.

Also known are Dutch scientists' studies on the production of macroporous hydroxylapatite substrates for bone tissue engineering [3]. For the production of porous HAp ceramics, a two-phase foam HAp suspension and polymer blend technique is used. As the pore-forming agent, for 25% carbonate solution (NaHCO ₃ CaCCfi, NH4HCO3) and citric acid. A mixture of polymethyl methacrylate (PMMA) and methyl methacrylate monomer (MMA) is used as a polymerization initiator. The technological cycle consists of blast drying, pyrolysis and firing at 1250 ° C for ~ 60 hours. The obtained samples have a total porosity of 50-68% with an average pore size of 456 µm. The microporousness of the samples after calcination is 2%. A disadvantage of the process is that the polymerization initiators introduced into the ceramic mass must be additionally pyrolysed, which prolongs the technological process. The ceramics obtained in this way are characterized by very low microporousity, which significantly reduces protein adsorption. The higher the porosity, the greater the surface area of the implant and the better the sorption of proteins. . The method is considered to be time- and energy-intensive and environmentally unfriendly with relatively low total micropores.

Also known are studies by English scientists on the effect of dispersant concentration on the pore morphology of hydroxylapatite [4]. The aim of the research was to find out the potential of ceramic materials as substrates for bone regeneration. The HAp ceramic used as a pore builder is a polyvalent organic alcohol - tergitol (Cu ^ oCh), as a cellular structure stabilizing agent - methylcellulose. After heat treatment at 65 ° C, pores are formed by decomposition of tergitol, and after heat treatment at 250 ° C, when burned with methylcellulose, the pores are fixed in the ceramic structure. The total porosity of the calcined sample was found to be 85%, pore size 391 - 495 pm. It has been experimentally shown that the shape and size of the pores depend on the viscosity of the bulk suspension, the amount of raw material components and the foaming capacity of the pore forming agent. The drawback is the low compressive strength of the obtained ceramic substrates, which is characterized by 1.09 - 1.76 MPa. As a result, they are not recommended for bone replacement in stressed areas and the mechanical fixation of the implant is difficult. Their use could be selective, i.e. in places where the material is not subjected to mechanical stress during operation.

Also known is the German patent [5], which uses HAp powder with various particle size distribution (average particle size from 5 pm to 20 pm, fine particle size) as raw material for the production of porous calcium phosphate (Ca / P = 1.5 - 1.7). particles less than 1 pm), water, surfactants - malamide and / or methylcellulose, carboxylmethylcellulose, polyoxyethylene lauryl ether. By mass homogenizing and mechanically foaming, pore formation occurs, as the pore forming agent is the atmospheric air involved in the mass. After foaming, the resulting gel is dried at 83 ° C (2 h). The drying process is followed by firing at 1200 ° C, which results in ceramics with a porosity of 85% and a pore size of 50-500 µm. The structure exhibits micropores with an average diameter of 0.8 µm. Micropores form a mesh-like structure that promotes sorption of proteins onto the ceramic surface and then the growth of bone tissue. Such implants can be used as filler for bone defects. The disadvantages of the invention are: high molecular weight polymer compounds introduced into the material as surfactants and binders, which decompose during heat treatment to release CO ₂ , which increases its emissions to the environment, is technologically and time consuming. A drawback is that the porosity of the trabecular bone is between 55 and 70% [6], but the material obtained by this method is characterized by relatively higher porosity (85%) and consequently lower mechanical strength than natural trabecular bone. . The difference in thermal expansion coefficients between the organic and inorganic phases results in cracks in the material during the heat treatment process, which in turn also reduces the mechanical strength and longevity.

Hydroxylapatite (HAp) ceramics with bimodal pore partitioning and its manufacturing method have been chosen as the prototype [7]. The method is based on the production of HAp ceramics from a mass composition containing HAp and gelatin (plasticizer) in a ratio of 1: 0.1-0.3. The technological process first involves making HAp pellets. Hydroxylapatite granules are made by slurry mixing the HAp powder with 10% aqueous gelatin solution and dispersing the resulting slurry in a spatula. As a result of surface tension forces, spherical shaped granules are formed, which are washed from oil and dried. The fraction from 500 to 1000 pm is separated by means of a sieve. The pellets are dried in a press in an isostatic pressing process at a pressure of 10 to 100 MPa. The extruded blanks are air-dried for 24 hours and baked in the air at 900 - 1250 ° C for 0.5 to 5 hours. The decisive technological parameters on which the porosity and pore distribution of the material depend are the pressing and firing mode. The ceramics produced by the technological process of ceramics is characterized by bimodal pore size distribution, which includes closed micropores with diameter <10 pm and open macropores formed upon burning of gelatin with diameter> 100 pm. Samples have a total porosity of 41-70%, including 15-54% of micropores between 1 and 10 µm and macropores between 4 and 37% between 50 and 150 µm.

The process is technologically evaluable as it is time consuming, it requires additional energy resources for granulation and drying of powdered particles. In addition, one of the drawbacks of isostatic pressing is the fact that by simple isostatic pressing it is possible to obtain elements of simple construction (plates, discs, etc.) and it is not possible to ensure uniform density distribution in the molded part [8].

The main disadvantage is that the obtained ceramics is characterized by a relatively low amount of open, permeable macropores (4-37%) and relatively small size of open pores, which does not ensure efficient growth and fixation of new bone and blood vessels in the implant volume [9]. the formation process depends on the pressing pressure and the sintering temperature of the blanks.

The aim of the present invention is to develop porous HAp ceramics with an easy-to-implement technology that provides bimodal pore partitioning in the implant (macropores and micropores) by increasing the size of macropores and their size range in the ceramic structure to facilitate bone growth and vascular growth.

The object of the invention is achieved by the development of a new composition of ceramic mass and the extraction of ceramics from it with a simple energy and material saving technique.

Proposed composition of ceramic mass (% by weight):

hydroxylapatite 45-50 deion. H ₂ O 4-5 glycerol 44 - 47

NH4HCO3 2-3

The following raw materials were used for the production of the mass: hydroxyapatite [10], deionized water (purified by Crystal E machine (R> 0.055 pS / cm)), glycerol (Bio-Venta A / S, Lot 19041-2009, purity 99, 8%), ammonium bicarbonate (NH4HCO3) (Enola Ltd. EC213-911-5) The technological process of ceramic production to form a porous structure is based on the foaming process in situ, ie the pore structure is formed during the heat treatment, when ammonium bicarbonate decomposition results in gaseous substances (CO ₂ , NH 3, H ₂ O) and foaming of the suspension.

The process for obtaining porous HAp bioceramics can be carried out in the following order:

- HAp powder preparation (grinding, screening) and dosing;

- preparation of a mixture of glycerol and water;

- gradual addition of HAp powder to the prepared glycerol-water mixture with continuous stirring until a homogeneous viscous fluid mass is formed (viscosity decreases from 9-10 ³ Pa-s to 0.9-10 ³ Pa-s during the mixing process);

- addition of NH4HCO3 pore former with continuous stirring (initially viscosity increases from 0.17-10 ³ Pa-s to 0.2-10 ³ Pa-s, but decreases to 0.09-10 ^J Pa-s with continued stirring );

- filling the prepared mass into molds of a size and configuration selected according to the shape and dimensions of the implant required;

- realization of the heat treatment process in 2 stages, of which in the first stage at 80 ° C with a holding time of 1-2 hours, intense pore formation takes place in the ceramic mass by decomposition of NH4HCO3 and release of gaseous substances. The glycerol-water system is the mass component that contains the HAp particles together. The mixture of water and glycerol covers the powder particles and creates a lubricant effect, in which the HAp particles can easily move during mass foaming. In the second stage, realized at 120 ° C for a holding time of 20 hours, the added water is liberated and partially glycerol begins to evaporate. During the second drying stage, the formation and consolidation of the formed porous structure occurs, an important parameter in this stage is the ratio of HAp to glycerol mass in the formed mass: 1: 0.88-1.04

- removal of samples from the molds and roasting in an electric muffle furnace in air

1100-1200 ° C with a maximum temperature of 2 hours and a rise rate of 5 ° C / min. The annealing-cooling cycle lasts 11 hours.

The influencing factors that determine the amount of pores and their size in the ceramic structure are the weight ratio of the raw materials HAp and NH4HCO3, the granulometric composition (particle size) and the sintering temperature. The optimum size of the HAp particle fraction has been experimentally determined to be 45 µm <d <100 µm, which provides a higher total, incl. open porosity. During the sintering process, finer HAp particles (d <45 pm) provide a denser microstructure of the material (sintering process), which reduces open but increases closed porosity. If the porosity NH4HCO3 particles are larger than 300 µm, the resulting ceramic structure exhibits less total and open porosity after firing.

At firing temperatures below 1000 ° C, the ceramic is not sufficiently sintered and is characterized by a lower mechanical strength than that required for the regeneration of the porous bone. At sintering temperatures above 1200 ° C, the porosity of the ceramic structure is reduced, as well as a possible decomposition of the crystalline phase of HAp to form a second crystalline phase, β-tricalcium phosphate (β-TCP).

The optimum particle size of HAp agglomerates was 45-100 µm and NH4HCO3 (at the weight ratio HApiNHz / HCCb 1: 0.04-0.07) - 100-300 µm to establish bimodal pore size distribution in the ceramic implant structure.

At this particle size, micropores between 0.05-0.2 pm and macropores between 50-500 pm can be found in the ceramic structure after firing at 1150 ° C.

The total porosity in the volume of the material is 65-75%, incl. open porosity - 53-62%, which is analogous to the pore size and distribution of the porous portion of the natural bone (trabecular bone). It promotes bone formation and growth in the implant material, as well as the formation of blood vessels, ensuring the osteoconductivity of the implants.

Experimental examples of the composition of the ceramic mass and characterization of the structure and mechanical strength of the obtained ceramic (cured at 1150 ° C) are shown in Table 1 in comparison with the prototype.

Table 1

Composition designation Mass composition Stru <characteristics of the hold Endurance juicer MPa Raw material Quantity,% by weight Common porosity, % Open porosity, % Closed porosity, % Macropore diameter, pm Micropore diameter, pm 1. HAp H ₂ O Glycerol NH4HCO3 45 5 47 3 75 62 13th 50-500 0.05-0.2 9th 2. HAp H ₂ O Glycerol NH ₄ HCO ₃ 46 5 46 3 70 57 13th 50-500 0.05-0.2 10th 3. HAp H ₂ O Glycerol NH ₄ HCO ₃ 48 5 45 2 68 54 14th 50-500 0.05-0.2 8th

4. HAp h ₂ o Glycerol NH4HCO3 50 4 44 2 65 fifty three 12th 50-500 0.05-0.2 11th Prototype HAp: Gelatin 1: 0.1-0.3 41-70 4-37 15-54 50-150 1-10 -

Compared to the prototype [7], the developed porous HAp ceramic technology is simple, economical and provides a greater range of open pore sizes and pore volume, which improves tissue growth in the implant material, new bone formation, ensuring implant integration in the body.

The results of the in vitro ceramic biocompatibility and cytotoxicity test as well as initial in vivo studies demonstrated that the material is biocompatible and does not show cytotoxic effects, and that the microstructure of the material has open and permeable pores corresponding to the size of vertebrate bone cells [6]. can move successfully in the volume of material. Cell growth and proliferation as well as cell morphology observed during the experiment correspond to cells in the control plot.

Micropores, in turn, increase the total surface area of the implant and promote protein adsorption, as well as providing efficient drug delivery systems, since the release of administered drugs occurs gradually over a longer period of time.

LITERATURE USED

1. Patent DE, N ° 19726961C1. Verfahren zur Herstellrung poroser Formkorper aus Metals, Keramik oder kompositwerkstoffen. Int. cl. C22C 1/08, B 22 F3 / 11; B29C 67/20; C04B 38/06, 1998.

2. T. Banno, Y. Yamada, H. Nagae. Fabrication of Porous Aluminum Ceramies by Simultaneous Thermal Solidification: // J. ofthe Ceram. Soc. of Jap., 117 [5], 2009, p 713716.

3. Shi Hong Li et. al. Synthesis of macroporous hydroxyapatite scaffolds for bone tissue enguneering: // J. of Biomed. Mater. Res., V. 61,1.1., 2002, p. 109-120.

4. Cyster L.A., Grant D.M. et.al. The Influence of Dispersant Contentation on Pore Morphology of Hydroxyapatite Ceramies for Bone Tissue Engineering: // Biomaterials, 26, 2005, p. 697-702.

5. Patent DE, N ° 102004057212A1. Porose Calcium-phosphatkeramik und Verfahren to deren Herstellung. Int. cl. C04B 38/00; C04B 35/447; A61L27 / 12; Α 61K6 / 033, 2005.

6. Dorozhkin S.V. Calcium orthophosphates in nature, biology and medicine. Materials, 2, 2009, p. 399-498.

7. Π3Τ. RU 2303580C2, Int. cl. C04B 35/477, C04B 35/00; A61L27 / 12. CnocoS H3roTOBjieHHH ru ^ poKcnanaTOTOBOH KepaMHKu c 6HMonanBHbiM pacnpeņeneHneM nop, 2007.

8. ^ Harun X. ToHKaa TexHnnecKasi KepaMHKa. ElepeB. c an. M.: MeTajiJiyprna, 278 (1986).

9. Mandrinos M. et. al. Porogen-based solid freeform fabrication of polycaprolactonecalcium phosphate scaffolds for tissue engineering. Biomaterials, 2006,27, 4399-4408.

10. Salma K., Berzina-Cimdina L., Borodayenko N. Calcium phosphate bioceramics prepared from wet chemically precipitated powders. Proceeding and Application of Ceamics, 2010, 4 (1), p. 45-51.

Claims (9)

l. Porous hydroxylapatite (HAp) ceramic with bimodal pore distribution contains HAp, water, plasticizer and pore former and differs in that glycerol CsHslOHL is used as plasticizer and ammonium hydrogen carbonate is used as the pore former in the following percentages by weight: hydroxylapatitis 45-50 water (deionized) 4-5 glycerol 44-47 ammonium bicarbonate 2-3 2. Porous HAp ceramic with bimodal pore distribution according to l. The process of Claim 1 is characterized in that the ceramic mass composition is made up of HAp powder with a particle size of 45 pm to 100 pm and NH4HCO3 with a particle size of 100 pm to 300 pm. 3. The particle size distribution according to claim 2, characterized in that it provides bimodal pore partitioning in the ceramic microstructure, since the weight ratio of HAp powder to pore-forming substance HApTttLHCCh is 1: 0.04-0.07. 4. The process for producing porous HAp ceramics comprises pulverizing and sieving the weight components and characterized in that the weight ratio of HAp powder to plasticizer additive according to claim 1 is 1: 0.881.04 HAp: glycerol. 5. The ceramic manufacturing process involves preparing the slurry from the weight components according to the weight ratios given in paragraph 1, characterized in that the raw materials are mixed in a specific order to ensure homogeneity and fluidity of the ceramic slurry (viscosity 0.09-10 ³ Pa-s at shear time 60 s). 6. The ceramic manufacturing process of claim 4, wherein the foaming of the mass is accomplished in situ by the addition of a -NH4HCO3 pore former. 7. The method of making porous HAp ceramics according to claims 2 to 5, characterized in that the ceramic is formed by filling the fluid in necessary configurations, thus providing implant configurations of different configurations and profiles (depending on practical need). 8. The method of making ceramic articles according to claim 6, characterized in that the molded parts are heat-treated at 80 ° C (1-2 hours) and, after raising the temperature to 120 ° C, continue the heat treatment for 20 hours. 9. The method of claim 7, wherein the samples are fired at 1100-1200 ° C for 2 hours. The roasting and cooling cycle lasts 11 hours.