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WO2009069879A1 - Nano-composites de biopolymère/apatite immobilisés sur film mince de phosphate de calcium déposé par évaporation sous faisceau d'électrons, et leur méthode de préparation - Google Patents

Nano-composites de biopolymère/apatite immobilisés sur film mince de phosphate de calcium déposé par évaporation sous faisceau d'électrons, et leur méthode de préparation Download PDF

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Publication number
WO2009069879A1
WO2009069879A1 PCT/KR2008/004710 KR2008004710W WO2009069879A1 WO 2009069879 A1 WO2009069879 A1 WO 2009069879A1 KR 2008004710 W KR2008004710 W KR 2008004710W WO 2009069879 A1 WO2009069879 A1 WO 2009069879A1
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calcium phosphate
biopolymer
thin film
beam evaporation
cyt
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In-Seop Lee
Sung-Min Chung
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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Priority claimed from KR1020080079380A external-priority patent/KR101035375B1/ko
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/005—Reinforced macromolecular compounds with nanosized materials, e.g. nanoparticles, nanofibres, nanotubes, nanowires, nanorods or nanolayered materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2300/00—Characterised by the use of unspecified polymers
    • C08J2300/16—Biodegradable polymers

Definitions

  • the present invention relates to a biopolymer/apatite nano-composite with a biopolymer immobilized in a calcium phosphate thin film formed by electron beam evaporation. More particularly, the present invention relates to a biopolymer/apatite nano-composite prepared by immobilizing a biopolymer in a calcium phosphate thin film formed by electron beam evaporation, which can promote ossification and are useful as biomaterials for bone cementation such as used in dental and orthopedic implants thanks to the employment of a calcium phosphate thin film instead of bulky materials.
  • biomaterials are intended to be in contact with and interact with physiological environments, their surface properties are critical for the biocompatibility thereof given a specific use.
  • various methods for improving the surface properties of biomaterials have been studied, with the most intensive attention having been given to the osseointegration of bone grafts.
  • titanium and its alloys have offered the best clinical results. Titanium and its alloys are widely used as implant materials for artificial tooth roots and joint prostheses because they offer good biocompatibility as well as excellent mechanical properties such as corrosion resistance, durability and strength.
  • titanium cannot promote bone ingrowth due to the biological inactivity thereof, so that it takes a long period of time for bone healing with titanium grafts.
  • titanium implants show weak bonding strength with peri-implant bones.
  • most studies have focused on improving bonding strength of implants with peri-implant bones by increasing the surface areas of implants or modifying the surface composition and topography of implants.
  • none have exceeded the inherent material limitations of titanium. Since the 1990s, various surface modifications have been tried in an effort to increase the osseointegration of implants with the minimal absorption of peri-implant bones and to increase affinity and bonding strength of implants to surrounding tissues .
  • the anodic oxidation treatment of titanium has recently attracted a great deal of attention ([1] Das K et al., Acta Biomater. 2007; 3: 573-85; [2] Park KH et al., J.
  • Examples of the calcium phosphate coating methods currently used in the surface modification of metallic implants include plasma spraying, powder sintering, acid etching, particle blasting, micro-arc anodic oxidation, ion beam sputtering deposition, pulsed laser deposition and ion-beam- assisted deposition (IBAD) .
  • plasma spraying powder sintering, acid etching, particle blasting, micro-arc anodic oxidation, ion beam sputtering deposition, pulsed laser deposition and ion-beam- assisted deposition (IBAD) .
  • IBAD ion-beam- assisted deposition
  • bFGF Basic fibroblast growth factor
  • Fibroblast growth factors have critical properties for osteogenesis and wound-healing processes.
  • the present invention provides a biopolymer/apatite nano-composite in which a biopolymer is immobilized in a calcium phosphate thin film deposited by electron beam evaporation.
  • the present invention provides a method for preparing a biopolymer/apatite nano-composite, comprising:
  • step 3 dissolving a biopolymer in the DPBS solution of step 2) to give a biopolymer-containing DPBS solution
  • step 1) immersing the calcium phosphate thin film of step 1) in the biopolymer-containing DPBS solution to immobilize the biopolymer in the calcium phosphate thin film.
  • biopolymer/apatite nano-composites of the present invention in which a biopolymer is immobilized in the calcium phosphate thin film deposited by electron beam evaporation can promote ossification and can be applied to various uses thanks to the employment of a calcium phosphate thin film instead of bulky materials.
  • the biopolymer/apatite nano- composites are useful as biomaterials for bone cementation such as used in dental and orthopedic implants.
  • FIG. 1 is a histogram showing the amount of cyt C immobilized in the cyt c-calcium phosphate composite layer of different samples.
  • FIG. 2 is of SEM showing the morphology of the three groups of samples before and after incubation in a DPBSC solution for 2 days at 37°C [ (a) M700, before immersion, (b) and (c) M700, after immersion, (d) A450, before immersion, (e) and (f) A450, after immersion, (g) A350, before immersion, (h) and (i) A350, after immersion.
  • the scale bars are 30 ⁇ m long in (a), (b) , (d) , (e) , (g) and (h) , and 3 ⁇ m long in (c) , (f) and (i) in length] .
  • FIG. 3 is of an X-ray photoelectron spectra of sample M700 (a) and sample M700 after immersion into DPBSC solution (b) .
  • FIG. 4 is a graph showing the amounts of cyt C released from the cyt C-calcium phosphate composite layers.
  • FIG. 5 is of SEM micrographs of surfaces of cyt C- calcium phosphate composite samples after immersion in the physiological salt solution for 3 days at 37°C [M 700 (a) and
  • the scale bars are 30 ⁇ m long in (a) , (b) and (c) , and 3 ⁇ m long in (d) , (e) and
  • FIG. 6 shows the surfaces of anodized Ti samples (a) and (b) and coated Ti samples (b) and (d) in SEM photographs.
  • FIG. 7 shows X-ray diffraction (XRD) patterns of the crystal structures of Ti samples, recorded with the use of Cu K radiation [Ti-control (a) , anodized Ti (b) , coated Ti (c) ] .
  • FIG. 8 shows the TEM micrographs and SAD patterns of the anodized Ti samples coated with a calcium phosphate thin film by electron beam evaporation before a) (as-deposited) and after heat treatment at 350 0 C (b) (heat-treated) .
  • FIG. 9 is of SEM photographs of Ti samples after incubation in the DPBS solution [anodized Ti sample after incubation for 1 hr (a) , coated Ti sample after incubation for
  • FIG. 10 shows XRD patterns of a coated Ti sample (a) and a coated Ti sample after incubation at 37 °C for 24 hrs in the DPBS solution (b) .
  • FIG. 11 is a SEM photograph showing the coated Ti sample after incubation at room temperature for 24 hrs in the DPBSF solution.
  • FIG. 12 shows XPS spectra of the surface of a coated Ti before (a) and after immersion at room temperature for 24 hrs in DPBSF (b) .
  • FIG. 13 shows MTT assay results in which formazan absorbance was expressed as a measure of cell viability from
  • MC3T3 cells cultured on (a) coated Ti, (b) coated Ti incorporated with bFGF, and (c) polystyrene plate wells as a positive control .
  • Asterisks ( * ) indicate statistically significant difference (p ⁇ 0.05) between (b) and (a) .
  • FIG. 14 is of SEM photographs of MC3T3 cells cultured on the coated Ti sample (a) and on the coated Ti sample incorporated with bFGF for 5 days (b) .
  • FIG. 15 is a radiograph showing implants and peri- implant regions, taken in an animal implant test.
  • FIG. 16 is of light micrographs showing sections of the implant and peri-implant tissue 8 weeks after healing [anodized Ti (a), coated Ti (b) , (Original magnification x 10)] .
  • the present invention pertains to a biopolymer/apatite nano-composite in which a biopolymer is immobilized onto a calcium phosphate thin film deposited by electron beam evaporation.
  • the biopolymer useful in the present invention includes physiologically active protein such as cyt C, fibroblast growth factors (bFGF or FGF-2) with molecular weights and isoelectric points similar to those of Cyt C, peptides, laminin and the like.
  • physiologically active protein such as cyt C, fibroblast growth factors (bFGF or FGF-2) with molecular weights and isoelectric points similar to those of Cyt C, peptides, laminin and the like.
  • bFGF or FGF-2 fibroblast growth factors
  • the following peptides may be used in the present invention:
  • RGD a tripeptide consisting of Arg-Gly-Asp, having influence on cell attachment, OGP (osteogenic growth peptide) : to induce the differentiation of osteoblasts, and
  • step 1) a calcium phosphate thin film is formed by electron beam evaporation. Calcium phosphate is deposited on a substrate by electron beam evaporation and then thermally treated.
  • the thermal treatment of the calcium phosphate deposit may be conducted at 300 ⁇ 800°C.
  • the calcium phosphate deposit may be heated at a rate of 5°C/min up to the desired temperature .
  • the thermal treatment is performed for one hour. After the thermal treatment, it is cooled to afford a calcium phosphate thin film on the substrate.
  • a calcium phosphate thin film deposited on a machined surface of a substrate by electron beam evaporation is heated at an elevation rate of 5°C/min to 700 0 C in a furnace and then guenched (M700) .
  • a calcium phosphate thin film is deposited on an anodized surface of a substrate by electron beam evaporation, followed by thermally treating the calcium phosphate deposit at an elevation rate of 5°C/min to 450°C in a furnace followed by quenching (A450) .
  • a calcium phosphate thin film deposited on an anodized film of a substrate is thermally treated at an elevation rate of 5°C/min to 350 0 C in a vacuum and quenched (A350) .
  • Step 3 is obtaining a biopolymer-containing DPBS solution.
  • a physiologically active protein similar in molecular weight and isoelectric point to cyt C such as a fibroblast growth factor (bFGF or FGF-2), a peptide or laminin, may be used.
  • the DPBS solution is free of calcium and magnesium.
  • Step 4) is immobilizing the biopolymer to the calcium thin film.
  • the calcium phosphate thin film of step 1) is immersed at 35-38 0 C and preferably at 37 °C for 1-3 days and preferably for 2 days in the biopolymer-containing
  • the sample A350 contains the greatest amount of cyt C incorporated thereinto.
  • flakes like crystals cover the surfaces of the samples.
  • the morphologies of the crystals exhibited only negligible differences between sample A450 and sample A350, while the crystals formed on sample M700 grow larger.
  • Dissolution and precipitation occur simultaneously in the solution. At the mean time of the dissolution of the deposited calcium phosphate, it precipitated on the surface of the samples. The easier the dissolution occurs, the more calcium and phosphate ions are in the solution, and the more the cyt C- apatite composite is further formed on the surface of the samples. Thus, sample A350 was incorporated with the largest amount of cyt C.
  • the deposition of calcium phosphate by electron beam evaporation does not change the porous morphology of the anodized Ti surface.
  • the incubation in DPBS solution allows a new apatite layer to be easily formed on the calcium phosphate deposit formed by electron beam evaporation.
  • the incubation of the calcium phosphate thin film formed by electron beam evaporation in a DPBS solution in the presence of bFGF results in the immobilization of bFGF into a newly formed apatite layer.
  • the binding of calcium phosphate deposit onto the anodized surface by electron beam evaporation shows a synergistic effect on osseointegration in vivo.
  • the samples incubated in the presence of FGF-2 were found to have more homogeneous and fine surfaces .
  • the bFGF molecules provide nuclei for homogeneous crystals while maintaining spaces of newly formed crystals and inhibiting the growth of crystals, thereby inducing the formation of more fine surfaces.
  • biopolymer/apatite nano-composites of the present invention in which a biopolymer is immobilized in the calcium phosphate thin film deposited by electron beam evaporation function to promote ossification and can be applied to various uses thanks to the employment of a calcium phosphate thin film instead of bulky materials.
  • the biopolymer useful in the present invention may include cyt C and physiologically active proteins similar in molecular weight and isoelectric point to cyt C.
  • the biopolymer/apatite nano-composites according to the present invention are therefore useful as biomaterials for bone cementation such as used in dental and orthopedic implants.
  • Thin calcium phosphate films were deposited on respective Ti disks to a thickness of 500 nm by electron-beam evaporation (10 kW, an acceleration voltage: 7.5 kV, acceleration current: 140 mA, deposition time: about 1 hr) .
  • Dulbecco's Phosphate buffered saline (Calcium/Magnesium free, Gibco BRL Life Technologies, USA) and CaCl 2 (100 mg/L) were dissolved in ultra-pure water to prepare a DPBS solution.
  • cyt C Sigma Chemicals, USA, 40 ⁇ g/ml
  • EXPERIMENTAL EXAMPLE 1 Quantification of Cyt C Incorporated in Calcium Phosphate Thin Film
  • the cyt C concentration of the DPBSC solution after immersion of the samples (M700, A450, A350) of Example 1 was measured using the BCA method (Micro BCATM protein assay kit, Pierce Biotechnology Inc, USA) . Before the test, 0.1 mL of 0.1 M HCl solution was supplemented to dissolve any calcium phosphate precipitate dispersed in the solution. The amounts of the released cyt C in the physiological salt solution were also analyzed by the BCA method.
  • the cyt C concentration of the DPBSC solution was decreased in all of the three groups (M700, A450, A350) .
  • sample A350 loaded the maximum amount of cyt C (4.546 ⁇ g/disk) .
  • the surface areas of the anodized samples were found to be larger than that of the machined sample because of roughness.
  • heating in a vacuum resulted in a less uniform structure of calcium phosphate deposited on the Ti disk by electron beam evaporation than did heating in air because of the absence of oxygen.
  • sample A350 was incorporated with the largest amount of cyt C.
  • Example 1 The samples prepared in Example 1 (M700, A450, A350) were washed twice with ultrapure water and dried at room temperature. Observations were made on the surfaces of the samples under a scanning electron microscope (SEM, S-4200, Hitachi, Japan) .
  • FIG. 2 are shown the morphologies of the three groups of samples (M700, A450, A350) before and after incubation in DPBSC solution for 2 days at 37°C.
  • the surfaces were analyzed using X-ray photoelectron spectroscopy (XPS, PHI 5700) with Al Ka X-rays.
  • XPS X-ray photoelectron spectroscopy
  • the photoelectron take-off angle was set at 45° for XPS.
  • the X-ray photoelectron spectra of the cyt C-calcium phosphate composite (M700) are shown in FIG. 3 (before (a) and after immersion in the DPBSC solution) .
  • nitrogen which existed only in cyt C among the reagents used in the experiment, was observed on sample M700, thus indicating that a thin new calcium phosphate layer incorporated with cyt C was formed on sample M700.
  • Example 1 The samples of Example 1 (M700, A450, A350) were washed twice with a physiological salt solution and immersed in 1 ml of the physiological saline before incubation at 37 0 C for 10 days in a water bath.
  • the physiological salt solution was prepared by dissolving NaCl (142 ⁇ iM) in ultra-pure water and buffering to a PH of 7.4 at a temperature of 37 °C using TRIS (50 inM) and 1 M HCl. Before use, all the solutions were sterilized by filtration using a membrane with a pore size of 0.22 ⁇ m.
  • samples (M700, A450, A350) were observed for surface changes in the cyt C-calcium phosphate composite layers after immersion in the physiological salt solution for 3 days under SEM.
  • FIG. 4 The amounts of cyt C released from the cyt C-calcium phosphate composite layers are depicted in FIG. 4.
  • cyt C was slowly released from the newly formed calcium phosphate layers of the samples (M700, A450, A350) over 10 days in the physiological salt solution. According to the release curves of M700 and A450, there is a burst release within 1 day, and the amount of released cyt C almost reached to one-half of that released for 10 days. Since then, the release rate remained slow. In contrast, the release rate of cyt C for Sample A350 remained rather constant throughout the whole 10 day period. The constant release of cyt C implied the homogenous incorporation of cyt C in the cyt C-calcium phosphate composite layer.
  • physiologically active protein molecules having molecular weights and isoelectric points similar to those of cyt C, such as bFGF, FGF-2, peptides and laminin, might be immobilized in substrates using the method of the present invention.
  • the samples were anodized at 270 V with a pulse power (660 Hz, 10% duty) for 3 min.
  • the electrolyte solution contained 0.15 M calcium acetate and 0.02 M calcium glycerophosphate.
  • Evaporants of calcium phosphate were prepared by sintering the powder mixtures of CaO (Cerac, USA) and hydroxyapatite (Alfa, USA) at 1200°C for 2 hrs in air.
  • an electron beam evaporator (Telemark, USA) at 8.5 kV and about 0.1 A and an end-hall type ion gun (Commonwealth Scientific, USA) at 130 V and 1.0 A were employed.
  • Each sample was immersed into 2.0 ml of the DPBS solution at 37 0 C for 24 hrs at the most, and in 2.0 ml of the DPBSF solution at 25°C (to avoid the denaturation of bFGF) for 24 hrs. All the solutions were sterilized by filtration using a membrane with a pore size of 0.22 ⁇ m before use.
  • the XRD patterns show the crystal structure of the sample surfaces (FIG. 7) . Peaks of titanium (T) substrate are read on all the XRD patterns. Except for the Ti-control, the other two samples showed features of the oxide film' s crystal structure. Both Anodized Ti and Coated Ti showed a strong peak near 25.3 ° and weaker ones near 48 ° , 53.8 ° and 55.2 ° corresponding to the reflection of anatase (A) . It is noticed that the deposited film did not produce any new crystalline diffraction peaks even after heat treatment at 350 0 C.
  • TEM transmission electron microscopy
  • SAD selected area diffraction
  • FIG. 8 shows the TEM micrographs and SAD patterns of the coated film before and after heat treatment at 350 0 C. Particles of nanometer-size were seen. After heat treatment, the particles grew larger. The locations of the SAD patterns are marked by asterisks. Both patterns indicate the crystalline structure of the coated film, but the crystalline phase has changed after heat treatment.
  • the film consisted of HA, J ⁇ -TCP and calcium oxide before heat treatment and only HA was detected after heat treatment.
  • Example 2 Each of the samples of Example 2 was incubated at 37 0 C for a predetermined time period in the DPBS solution, washed twice with ultra-pure water and cooled naturally at room temperature. The surfaces of the samples were observed by SEM and XRD patterns (Rigaku, Tokyo) with the use of Cu K radiation to evaluate surface structure of the samples.
  • Example 2 The samples of Example 2 were immersed in the DPBSF, washed twice with ultra-pure water and naturally cooled at room temperature before SEM observation.
  • a newly formed homogeneous layer was observed on the coated surface after incubation in DPBS solution for 24 hrs, as shown in FIG. 11.
  • the concentrations of bFGF in the DPBSF solutions decreased after soaking the sample for 1 day at room temperature. It was considered that the decrease of bFGF in the solution was fully incorporated with samples.
  • the amount of bFGF incorporated with one sample was 2.76 ug on average.
  • the surfaces of the samples before and after immersion in the DPBSF solution were analyzed using X-ray photoelectron spectroscopy (XPS, PHI 5700) with Al Ka X-rays.
  • the photoelectron take-off angle was set at 45° for XPS.
  • the bFGF concentration of the DPBSF solution after soaking with samples was measured using the BCA method (Micro BCATM protein assay kit, Pierce Biotechnology Inc., USA) .
  • the decreased amount of bFGF was calculated according to the bFGF concentration of the DPBSF solution incubation without any sample.
  • DPBS and DPBSF Two solutions of DPBS and DPBSF were prepared, in the same manner as in Example 2, as simulated biological environments to account for the modifications that take place when implants are inserted in the human body.
  • MC3T3 cells were cultured on the Ti disks and the polystyrene plates for 1, 3 and 5 days, followed by MTT assay in which formazan absorbance was expressed as a measure of cell viability from the cultured MC3T3 cells.
  • EXPERIMENTAL EXAMPLE 8 In vivo Assay for Biocompatibility of bFGF-Calcium Phosphate Composite Layer
  • Block sections including segments with implants were preserved and fixed in 10% neutral buffered formalin.
  • the specimens were dehydrated in ethanol, embedded in methacrylate, and sectioned in the mesio- distal plane using a diamond saw (Exakt®) . From each implant site, the central section was reduced to a final thickness of about 20 ⁇ m by microgrinding and polishing with a cutting- grinding device (Exakt®) .
  • the sections were stained with hematoxylin-eosine. General histological findings were observed with a stereoscope and a microscope.
  • Radiographs of each mandible were taken immediately after sacrifice of the animals and were used to locate the implants.
  • FIG. 15 shows the representative resulting radiograph. Implants were found to be contacted closely to the host bone.
  • FIG. 16 The typical sections comprising the implant and surrounding tissues are shown in FIG. 16. Appositional bone formation occurs around the surfaces of both anodized implant and coated implant, which seemed more pronounced in the bottom. Compared to the anodized implants, coated implants have an improved characteristic of contact osteogenesis in soft bone, with coverage of the implant surface with a bone layer as a base for intensive bone formation and remodeling in 8 weeks, in both apical and mid portions. The newly formed bone was immature and exhibited a trabecular pattern. In the apical portion, the present tissue was composed mostly of woven bone with only a small quantity of preexisting lamellar bone. For coated implants, the calcium phosphate coating did not separate from the implant surfaces .
  • the present invention provides biopolymer/apatite nano-composites in which a biopolymer is immobilized in a calcium phosphate thin film deposited by electron beam evaporation, which can promote ossification and can be applied to various uses thanks to the employment of a calcium phosphate thin film instead of bulky materials.
  • Cyt C and physiologically active proteins similar in molecular weight and isoelectric point to cyt C can be used as the biopolymer.
  • the biopolymer/apatite nano-composites according to the present invention are useful as biomaterials for bone cementation such as used in dental and orthopedic implants.

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Abstract

L'invention porte sur des nano-composites de biopolymère/apatite immobilisés sur film mince de phosphate de calcium déposé par évaporation sous faisceau d'électrons, et sur leur méthode de préparation. Ces composite de biopolymère/apatite favorisent l'ossification et peuvent s'appliquer à nombre d'utilisations du fait de l'emploi d'un film mince de phosphate de calcium au lieu de matériaux massifs. On peut utiliser comme biopolymères des Cyt C et des protéines physiologiquement actives d'un poids moléculaire et d'un point isoélectrique similaires à ceux des Cyt C. Lesdits nano-composites s'avèrent utiles en tant que biomatériaux de cémentation de l'os, utilisables pour les implants dentaires et orthopédiques.
PCT/KR2008/004710 2007-11-28 2008-08-13 Nano-composites de biopolymère/apatite immobilisés sur film mince de phosphate de calcium déposé par évaporation sous faisceau d'électrons, et leur méthode de préparation Ceased WO2009069879A1 (fr)

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KR20070121836 2007-11-28
KR10-2007-0121836 2007-11-28
KR1020080079380A KR101035375B1 (ko) 2007-11-28 2008-08-13 전자빔 증착에 의해 형성된 칼슘 포스페이트 박막 상에 생체고분자를 고정화시킨 생체고분자/아파타이트 나노 복합체 및 이의 제조방법
KR10-2008-0079380 2008-08-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030070713A (ko) * 2002-02-26 2003-09-02 김현만 고형표면의 칼슘포스페이트 결정박막 형성방법
KR100713619B1 (ko) * 2005-11-14 2007-05-02 재단법인서울대학교산학협력재단 유도 골재생을 위한 콜라겐/아파타이트 복합체 멤브레인의제조방법
KR20070063114A (ko) * 2005-12-14 2007-06-19 주식회사 덴티움 금속 임플란트 및 그 제조방법

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Publication number Priority date Publication date Assignee Title
KR20030070713A (ko) * 2002-02-26 2003-09-02 김현만 고형표면의 칼슘포스페이트 결정박막 형성방법
KR100713619B1 (ko) * 2005-11-14 2007-05-02 재단법인서울대학교산학협력재단 유도 골재생을 위한 콜라겐/아파타이트 복합체 멤브레인의제조방법
KR20070063114A (ko) * 2005-12-14 2007-06-19 주식회사 덴티움 금속 임플란트 및 그 제조방법

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Title
SOGO, YU ET AL.: "Coprecipitation of cytochrome C with calcium phosphate on hydroxyapatite ceramic", CURRENT APPLIED PHYSICS, vol. 5, no. 5, July 2005 (2005-07-01), pages 526 - 530 *

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