TWI399227B - 骨植入物 - Google Patents
骨植入物 Download PDFInfo
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- TWI399227B TWI399227B TW095103954A TW95103954A TWI399227B TW I399227 B TWI399227 B TW I399227B TW 095103954 A TW095103954 A TW 095103954A TW 95103954 A TW95103954 A TW 95103954A TW I399227 B TWI399227 B TW I399227B
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- ceramic layer
- bone implant
- microns
- substrate
- bone
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- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 52
- 239000007943 implant Substances 0.000 title claims abstract description 41
- 239000000919 ceramic Substances 0.000 claims abstract description 55
- 239000000758 substrate Substances 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 24
- 229920001222 biopolymer Polymers 0.000 claims abstract description 14
- 238000007373 indentation Methods 0.000 claims abstract 5
- 230000003100 immobilizing effect Effects 0.000 claims abstract 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical group [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 26
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 24
- 102000008186 Collagen Human genes 0.000 claims description 22
- 108010035532 Collagen Proteins 0.000 claims description 22
- 229920001436 collagen Polymers 0.000 claims description 22
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 13
- 229910044991 metal oxide Inorganic materials 0.000 claims description 12
- 150000004706 metal oxides Chemical class 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 230000011164 ossification Effects 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 229910010413 TiO 2 Inorganic materials 0.000 description 14
- 210000000963 osteoblast Anatomy 0.000 description 13
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 239000010936 titanium Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
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- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
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- 201000008968 osteosarcoma Diseases 0.000 description 2
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- 102000004169 proteins and genes Human genes 0.000 description 2
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- 239000012266 salt solution Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 229910001868 water Inorganic materials 0.000 description 2
- CXCHEKCRJQRVNG-UHFFFAOYSA-N 2,2,2-trifluoroethanesulfonyl chloride Chemical compound FC(F)(F)CS(Cl)(=O)=O CXCHEKCRJQRVNG-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 102000008108 Osteoprotegerin Human genes 0.000 description 1
- 108010035042 Osteoprotegerin Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- -1 amino, hydroxyl Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
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- 230000008468 bone growth Effects 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
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- 238000003486 chemical etching Methods 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
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- 239000012531 culture fluid Substances 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 210000004268 dentin Anatomy 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001652 electrophoretic deposition Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010884 ion-beam technique Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
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- 238000011587 new zealand white rabbit Methods 0.000 description 1
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 1
- 230000000278 osteoconductive effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229910052573 porcelain Inorganic materials 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
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- 230000008929 regeneration Effects 0.000 description 1
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- 230000008439 repair process Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 230000009645 skeletal growth Effects 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/06—Titanium or titanium alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Description
本發明有關於一種骨植入物,其包含一生物惰性基材且該基材被一層含有多個凹陷處且為生物可分解性的陶瓷層所覆蓋。
骨植入物從骨頭上鬆脫的問題一直是重建手術與關節替換術中所關心的事情。脫落的原因曾經被歸咎於生長在植入物周圍處的纖維組織層會降低該植入物與骨骼間之界面的完整性與機械穩定性。在西元1950年代,曾有文獻指出鈦金屬(titanium)可永久性地結合至骨骼中,也就是現今所說的骨整合(osseointegration)。骨整合植入物的特色在於缺乏相對活動性以及在該植入物與骨骼之間不會出現軟組織(參閱Branemark,1983,J.Prosthet.Dent.
50:399-410)。植入物的表面可塗覆以骨引導性材料(osteoconductive materials),以更進一步提升該植入物的骨整合性。雖然目前市面上販售許多骨植入物,但仍需求著具有超群骨整合性的植入物。
本發明是根據在骨植入物上塗覆一層具有的羥基磷灰石塗層(hydroxyapatitic coating)以促進骨整合。
在一態樣中,本發明特徵在於一種包含一種生物惰性基材的骨植入物,且該基材被一層具有多個凹陷處的陶瓷層(例如,羥基磷灰石塗層)所覆蓋著。該等凹陷處的總表面積佔該陶瓷層總表面積的30-70%,例如約佔50-60%。該等凹陷處的總面積係所有凹陷處開口表面積的總合。該陶瓷層的總表面積則是該等凹陷處的總表面積加上未有凹陷處之表面面積。
該生物惰性基材可由各種材料所製成,舉例來說,諸如鈦或鈦合金等金屬,以及諸如瓷(porcelain)等陶瓷材料。較佳者,該生物惰性基材表面的一部份具有多個寬為10-30微米(如15-20微米)且高為10-30微米(如15-20微米)的小突脊,以及該表面的另一部分則具有寬約60-100微米(如70-90微米)且高約40-80微米(如50-70微米)的大突脊。當該生物惰性基材是由金屬或金屬合金所製成時,可將其表面氧化以形成一層由一種或多種金屬氧化物所構成的氧化層。
該陶瓷層以覆蓋著具有該等大突脊的該惰性材料表面處為佳,但不覆蓋具有該等小突脊的該表面。該陶瓷層可能由諸如羥基磷灰石等無機材料所構成。該陶瓷層的表面亦可藉著共價鍵結固定一種生物聚合物。適合的生物聚合物範例包括蛋白質(如膠原蛋白)或是含有諸如醣蛋白(proteoglycan)等的巨分子。此類蛋白質的功能可能是作為細胞黏著與遷移的支撐骨架,以幫助新的骨組織再生。如有需要時,亦可在該陶瓷層上共價鍵結一種骨形成促進因子(即,蝕骨細胞分化抑制因子(osteoprotegrin))。骨形成促進因子會促進骨骼組織的生長以及維護骨質。
在另一態樣中,本發明特徵在於一種製造骨植入物的方法,該方法包含三步驟:(1)附加一陶瓷層在一生物惰性基材的表面上,且該生物惰性基材的表面預先經過處理;(2)在該陶瓷層中形成多個凹陷處,其中該等凹陷處的總表面積佔該陶瓷層總表面積的30-70%;以及,(3)將一生物聚合物藉由共價鍵結固定至該陶瓷層上。在進行該附著步驟之前,該生物惰性基材可經過處理,以在一部分的該表面上形成多個寬約10-30微米且高約10-30微米(μ m)的小突脊,以及在另一部份的該表面上形成寬約60-100微米且高約40-80微米的大突脊。較佳者,該生物惰性基材係由鈦合金所製成,且在進行該附加步驟之前,先將其表面氧化以形成一層金屬氧化物。
本發明之一個或多個實施例的細節說明係描述於下。並可從後附說明內容及申請專利範圍來了解本發明的其他特徵、目的與優點。
本發明有關於一種骨植入物,其包含一生物惰性基材且該基材被一層含有多個凹陷處且為生物可分解性的陶瓷層所覆蓋。
該生物惰性基材可以是由多種材料所構成,例如金屬金屬或陶瓷材料。通常使用鈦或鈦合金。鈦金屬是一種能幫助骨整合的生物惰性材料。不論鈦金屬或是鈦合金均可從市面上購得或是由已知的方法所製備而成。
該生物惰性基材的表面可經過處理,以形成成具有特定粗糙度的圖案,例如在一部分的表面上具有小突脊且另一部分的表面上則具有大突脊。可使用機械、化學、電化學以及任何習知方法來執行該表面處理。通常,小突脊可利用化學蝕刻或電漿噴塗來形成(參閱如Ronoldet al
.,2003,Biomaterials
24:4559;Jonasovaet al
.,2004Biomaterials
25:1187;以及Parado da Silvaet al
.,2000,Mat.Res.
3(3):61)。大突脊則可利用諸如噴砂、研磨劑準分子雷射處理、水噴射珠擊法(water jet peen)以及電化學微加工法(參閱GonzaAlez-GarcoAaet al
.,1999,Thin Solid Films
352:49;Mellaliet al
.,1996,Surface and Coatings Technology
81:275;Bereznaiet al
.,2003,Biomaterials
24:4197;Arolaet al
.,2002,Wear
249:943;以及Madoreet al
.,1997,J.Micromech.Microeng
7:270)。
舉例而言,該整個表面係先在諸如800℃或更高的高溫及一大氣壓下於氣爐中回火(anneal)一段時間,之後將其冷卻至室溫。隨後在一酸溶液以稍微高於室溫的溫度來蝕刻該表面一段預定時間,以形成多個寬約10-30微米、高約10-30微米的小突脊。接著可使用諸如抗腐蝕膠布等物品覆蓋住該表面的上部份。該表面的剩餘部份則在濃度更濃且溫度更高的條件下更近一步一段較長的時間,以形成寬約60-100微米、高約40-80微米的大突脊。所得到的基材表面的一部份具有小突脊(例如,該表面的頂部),而剩餘的部份則具有大突脊。使用的時候,可採用將具有小突脊的部份面向外(例如,使其與上皮層接觸)並使具有大突脊的部份與面向內(例如,與骨骼接觸)的方式把該骨植入物置於任何植入位置。該等小突脊有助於纖維母細胞的增生並減少細菌感染。該等大突脊則能幫助骨母細胞的黏附。如有需要的話,可使該基材(如鈦合金)氧化以形成例如厚度約5-10微米的金屬氧化物層(如,二氧化鈦,TiO2
),以避免或延緩腐蝕基材的作用。
該生物可分解性陶瓷層可由諸如羥基磷灰石等無機材料所構成。羥基磷灰石是一種天然存在於骨骼、牙齒琺瑯質或象牙質的成分,多年來被作為骨骼取代物或塗層材料(參閱如Frame,1987,Int.J.Oral Maxillofacial Surgery 16:642
-655
與Parsons et al.,1988,Annals N.Y.Academy of Sciences
523:190-207)。羥基磷灰石可利用已知的方法來製備或向供應商購買。羥基磷灰石可以是純的Ca1 0
(PO4
)6
(OH)2
化合物,或是含有諸如碳酸鹽(carbonate)、氟、氯或鋇等離子。可利用諸如電漿噴塗、溶膠法(sol-gel process)、離子束或射頻濺鍍(ion beam or radio frequency sputtering)、脈衝雷射蒸鍍法(pulsed laser deposition)、熱均壓法(hot isostatic pressing)以及電泳沉積法(electrophoretic deposition)等方法將羥基磷灰石施加在基材表面上以形成羥基磷灰石系的陶瓷層(參閱Geesniket al
.,1990,Clin.Orthop.
261:39-58;Ratneret al
.,“Plasma Deposition and Treatment for Biomedical Applications”inPlasma Deposition,Treatment and Etching of Polymers
,edited by R.d’Agostino,Acadimic Press,Inc.,1990;以及Kawakamiet al
.,1998,Biotechnology and Bioengineering
32:369-373)。通常羥基磷灰石系陶瓷層的厚度約介於25-70微米之間。此種能促進骨骼的貼附生長作用(bone apposition)塗層以施用在具有大突脊的基材表面為佳。為了達到這個目的,在將羥基磷灰石系陶瓷層施用在基材上時,可先將具有小突脊的表面遮蓋起來,僅讓具有大突脊的表面塗覆有該陶瓷層。
可藉著機械性的方法(如噴砂或珠擊法)或其他適當方法來移除該陶瓷層的多處部份以形成該陶瓷層中的多個凹陷處。這些凹陷處通常具有圓柱型輪廓且直徑一般介於350-650微米之間,例如約介於400-600微米之間。在這些凹陷處中的陶瓷材料通常被完全移除而使基材暴露出來。該等凹陷處有助於骨母細胞的填入與停留。該等凹陷處可以平均地或隨機地分布在該陶瓷層中。
該陶瓷層可共價性地與諸如膠原基生物聚合物(collagen-based biopolymer)等生物聚合物鍵結,以幫助新骨骼的成長。舉例來說,該陶瓷層的表面可經過修飾使其具有諸如氨基等官能基(functional group)。可利用電漿沉積或化學塗覆(chemical priming)等方法將官能基導入該陶瓷層上。可用於電漿噴塗的材料包括氧化鋁電漿、丙烯胺(allylamine)電漿以及任何由含有氨基、羥基或其他反應基團之氣體所構成的電漿(參閱Sanoet al
.,1993,Biomaterials
14:817-822);以及Wang與Hsiue,1993,J.Polymer Science
,Part A:Polymer Chemistry
31:2601-2607)。通常該陶瓷層的表面以及該陶瓷層中凹陷處所暴露出來該生物惰性基材表面會以官能基進行修飾。
膠原蛋白便是能用在本發明植入物中的其中一種生物聚合物。膠原蛋白(如,第一型膠原蛋白)可從人類或動物的肌腱、皮膚、骨骼或韌帶等組織中分離出來(例如參閱Miller與Rhodes,1982,Methods in Enzymology
82:33-64)。可利用能保留末端胜肽(telopeptide)的方法(美國專利案3,114,593號)或是使用移除末端胜肽的方法(美國專利案4,233,360號)來純化膠原蛋白。並利用化學藥劑進行交聯作用(參閱美國專利案5,876,444與6,177,514案)或其他的方法(如照射紫外線)恢復膠原蛋白的結構。膠原蛋白可共價鍵結至該羥基磷灰石系陶瓷層上。膠原蛋白中諸如羧酸等官能基直接與修飾後之羥基磷灰石中的官能基(如氨基)形成共價鍵,或是透過諸如交聯劑(cross-linker)等第三分子而間接地形成該共價鍵。交聯劑是一種具有至少兩個官能基的藥劑,其中一個官能基會與生物聚合物鍵結,而另一個官能基則會與修飾過的羥基磷灰石鍵結。交聯劑的範例包括戊二醛(glutaraldehyde)、環氧氯丙烷(Epichlorohydrin)、氯化三氟乙碸(trifluoroethanesulfonyl chloride,簡稱tresyl choloride)與N-羥基-丁二酸亞醯胺(N-hydroxy-succinimide)。
該陶瓷層更可共價鍵結諸如蝕骨細胞分化抑制因子(Osteoprotegerin)等骨骼生成促進因子。蝕骨細胞分化抑制因子在美國專利申請公開案2003-0045942號中有詳細敘述,並將其全文納入此處以供參考。骨骼生長促進因子可與膠原蛋白一併黏接至該陶瓷層上,例如可使具有該陶瓷層的基材在含有膠原蛋白與蝕骨細胞分化抑制因子的溶液中浸泡一段適當的時間使得膠原蛋白與蝕骨細胞分化抑制因子一起黏附在陶瓷層上。隨後將該基材從溶液中取出,以空氣乾燥或冷凍乾燥方式來乾燥之。或者,可先將膠原蛋白固定在具有陶瓷層的基材上後,再將該基材浸泡在含有蝕骨細胞分化抑制因子的溶液中。
舉例而言,本發明之骨植入物可如下述方式來加以製備:先將鈦合金基材的整個表面於鹽酸(HCl)水溶液中進行蝕刻直到形成多個小突脊;之後將該基材除了頂面部分以外的其他表面進行回火以形成大突脊;接著以氧氣噴吹整個基材表面形成一金屬氧化物層;再利用電漿噴塗法在具有大突脊的表面上塗佈一層羥基磷灰石;利用噴砂法或珠擊法來移除部份的該羥基磷灰石層以形成多個凹陷處;之後,以氨基或羥基(hydroxyl)對該表面進行官能基修飾;隨後借著使膠原蛋白上的官能基與基材表面上的官能基反應而將膠原蛋白固定在該表面上;並可利用相同方法以蝕骨細胞分化抑制因子對該基材做更進一步的修飾。
可藉由標準手術程序使用本發明之骨植入物來修復骨骼的缺陷,例如齒槽骨的缺陷。
下方的特定實施例僅作為示範之用,且不會對其他揭露內容有任何的限制。該領域中的習知技藝者在不需要更進一步的說明的情況下便能根據本文中的敘述內容將本發明應用至最大範圍。文中所引用的所有公開文獻均全文納入此處以供參考。
製備多孔性羥基磷灰石系基質(porous hydroxyapatite
-based matrix)
利用下述反應之濕式化學方法來製備羥基磷灰石粉末:10Ca(NO3
)2
+6(NH4
)3
PO4
+2NH3
.H2
O=Ca1 0
(PO4
)6
(OH)2
+20NH4
NO3
。並利用下列步驟來製備一多孔性羥基磷灰石系基質,步驟如下:(i)製備一種含有羥基磷灰石粉末、碳化矽(silicon carbide)、氧化鎂(magnesia)與水的漿料;(ii)將諸如聚氨酯(polyurethane)、聚氯乙烯(polyvinyl chloride)或聚乙二醇(polyethyleneglycol)網狀結構材料模鑄成想要的形狀;(iii)將該漿料塗佈至該網狀結構材料上;以及(iv)利用離心移除過多的漿料。如果有必要,可重複執行步驟(i)-(iv)。將所得到的含羥基磷灰石基材置於1200℃的溫度下鍛燒(sintered)後冷卻備用。該鍛燒時的溫度係緩慢地升高使得該網狀結構材料慢慢的分解而不致於造成破裂情形。如以一來,可獲得一種平均孔隙大小約200-350微米的多孔性羥基磷灰石系基質。經過清洗後,使該基質於強度為20kGy的γ射線進行滅菌。
萃取與純化第一型膠原蛋白
從紐西蘭白兔或其他適當哺乳動物的肌腱萃取並純化出第I型的膠原蛋白。係將該些肌腱取出、切片並使用冷蒸餾水清洗數次以移除血漿蛋白質,隨後於4℃下以含有0.5M氯化鈉(NaCl)之50mM的Tris-HCl溶液(pH7.4)以固定的速度攪拌整個晚上後,丟棄上清液並以冷蒸餾水清洗剩餘物數次以去除鹽分,隨後將剩餘誤置於0.5M的醋酸溶液(HOAc,pH2.5)於4℃下置放一個晚上以獲得一水溶液萃取物。將一鹽類溶液(0.9M的氯化鈉溶液)加入該萃取物中,並產生沉澱。以13,000 rpm的轉速離心10分鐘以收集該些沉澱物,之後將收集到的沉澱物溶解於0.05M的醋酸溶液中(HOAc)以形成一含有膠原蛋白的溶液。將兩倍於含膠原蛋白溶液體積的另一種鹽類溶液(0.02M的磷酸氫二鈉,Na2
HPO4
)加入該含膠原蛋白溶液中反應24-48小時以形成沉澱。離心收集該些沉澱物並溶解於50mM的醋酸溶液中以得到另一個含膠原蛋白溶液。以5mM的醋酸溶液來透析該含膠原蛋白溶液後,冷凍乾燥之。
可從Cruvible Material Corporation公司(Pittaburgh,PA,USA)購得具有螺紋的基材。該等基材係由太合金(Ti6A14V)所製成,且直徑約3.25毫米(mm)至5毫米,長度則介於8毫米至18毫米之間。該基材的表面係先在氣爐(gas furnace)中以介於870-1050℃間的溫度於一大氣壓下回火1-3個小時,隨後冷卻至室溫。之後,使該基材表面於30-50℃的溫度下在1-3M濃度的鹽酸水溶液中蝕刻1-3小時以形成小突脊(寬約10-30微米且高約10-30微米)。將該基材頂部2-3微米部份的表面以抗腐蝕膠布覆蓋住。並使剩餘的表面於50-90℃的溫度下在1-6M的鹽酸水溶液中進一步蝕刻3-6小時,以形成大突脊(寬為60-100微米且高為40-80微米)。之後,以氧氣噴吹該表面以形成一層厚度為5-10微米的金屬氧化物層。利用電漿噴塗技術在所得到的基材上塗佈一層羥基磷灰石。該羥基磷灰石層的厚度約40-50微米。隨後利用噴砂技術移除部份的羥基磷灰石層以形成多個凹陷處。該等凹陷處的直徑約介於400-600微米之間。並將所得到的基材以氨基進行官能化(functionalized with amino)後,將該基材接上膠原蛋白。
對下列六個盤狀物進行鈣沉積實驗,分別為:(1)RT:未經過處理的鈦合金盤;(2)RT-HCl:經過鹽酸(HCl)蝕刻以形成多個小突脊的鈦合金盤;(3)RT-952-HCl:於950℃下回火並經過鹽酸(HCl)蝕刻以形成多個大突脊的鈦合金盤;(4)RT-950-HCl-TiO2
:於950℃下回火並經過鹽酸(HCl)蝕刻以形成多個大突脊,以及氧化後形成一金屬氧化物層的鈦合金盤;(5)RT-950-HCl-TiO2
-HAF:於950℃下回火、進行鹽酸(HCl)蝕刻以形成多個大突脊、氧化形成一金屬氧化物層以及表面上完全覆蓋一層羥基磷灰石的鈦合金盤;以及(6)RT-950-HCl-TiO2
-HAP:於950℃下回火、進行鹽酸(HCl)蝕刻以形成多個大突脊、氧化形成一金屬氧化物層以及一部分的表面上覆蓋一層羥基磷灰石的鈦合金盤。該等盤狀物的直徑範圍約2-3公分且厚度約3-5毫米(mm)。將每個盤狀物分別置於6-孔盤的孔中,並以含有10%FBS及5%抗生素的McCoy氏5A培養液於37℃下,將從人類骨肉瘤(osteosacroma)所獲得U2骨母細胞培養在每個孔中的盤狀物上。培養四天後更換新的細胞培養液。並再培養四天後測定每個盤狀物之細胞培養液中的鈣含量。此實驗中觀察到用於RT-950-HCl-TiO2
-HAP、RT-950-HCl-TiO2
-HAF與RT-950-HCl-TiO2
之培養液中的鈣沉積量多於用於RT-952-HCl、RT-HCl與RT之培養液中的鈣沉積量。此結果暗示著沉積在該RT-950-HCl-TiO2
-HAP、RT-950-HCl-TiO2
-HAF與RT-950-HCl-TiO2
表面上的鈣多於沉積在RT-952-HCl、RT-HCl與RT表面上的鈣。
實施例3中所提到的六個盤狀物亦進行骨母細胞堆積實驗測試。將每個盤狀物分別置於6-孔盤的孔中,並以含有10%FBS及5%抗生素的McCoy氏5A培養液於37℃下,將從人類骨肉瘤(osteosacroma)所獲得U2骨母細胞培養在每個孔中的盤狀物上。培養四天後移除培養液,並於電子顯微鏡下觀察每個盤狀物的表面。當移除培養液時,會將大部分的骨母細胞會從RT表面上移除,因此僅有少數骨母細胞出現在RT的表面。同樣地,移除培養液時也會將大部分的骨母細胞會從RT-HCl的表面上移除,因此在該RT-HCl表面上觀察到的少數的骨母細胞。但有顯著數量的骨母細胞沈積在RT-950-HCl表面的大突脊上。以及在RT-950-HCl-TiO2
表面的大突脊上也沉積明顯數量的骨母細胞。沉積在RT-950-HCl-TiO2
-HAF之金屬氧化物層之大突脊上的骨母細胞多於沉積在RT-950-HCl與RT-950-HCl-TiO2
的骨母細胞。而相較於RT-950-HCl-TiO2
-HAF,則有更多的骨母細胞沉積在RT-950-HCl-TiO2
-HAP之金屬氧化物層的大突脊上。
本說明書中所揭露的所有特徵可以任意的組合方式來合併使用。說明書中所揭露的每一個特徵可用另一個能達到相同、相等或類似目的之其他特徵來替換。因此,除非另有說明,否則文中所揭露的各個特徵均為一系列均等或相似特徵的代表範例。
根據上述說明內容,該領域中的習知技藝者可輕易地明白本發明的必要特徵為何,且在不偏離本發明精神與範圍下,能根據不同的用途與條件來做出各種變化與修飾。因此,其他的實施例亦為後附申請專利範圍所涵蓋。
Claims (23)
- 一種骨植入物,包含:一生物惰性基材,該生物惰性基材包括一表面,該表面具有一第一部分及一第二部分,該第一部分含有多個小突脊(ridges),每個小突脊具有10至30微米的寬度及10至30微米的高度,且該第二部分含有多個大突脊,每個大突脊具有60至100微米的寬度及40至80微米的高度,其中該骨植入物經配置使得當該骨植入物置於一受試者的一植入位置時,該第二部分與一骨骼接觸。
- 如申請專利範圍第1項所述之骨植入物,其中每個大突脊具有70至90微米的寬度及50至70微米的高度。
- 如申請專利範圍第1項所述之骨植入物,其中每個小突脊具有15至20微米的寬度及15至20微米的高度。
- 如申請專利範圍第1項所述之骨植入物,其中該生物惰性基材為一金屬系基材。
- 如申請專利範圍第4項所述之骨植入物,其中該基材為一鈦合金系基材。
- 如申請專利範圍第4項所述之骨植入物,更包含一金屬氧化物層設置於該生物惰性基材上。
- 如申請專利範圍第1項所述之骨植入物,其中該第二部分被一陶瓷層所覆蓋,該陶瓷層含有複數個凹陷處(indentation),該等凹陷處佔該陶瓷層之總表面積的30至70%。
- 如申請專利範圍第7項所述之骨植入物,其中該等凹陷處佔該陶瓷層之總表面積的50至60%。
- 如申請專利範圍第7項所述之骨植入物,其中該陶瓷層為一羥基磷灰石層。
- 如申請專利範圍第6項所述之骨植入物,其中該第二部分被一陶瓷層所覆蓋,該陶瓷層含有複數個凹陷處,該等凹陷處佔該陶瓷層之總表面積的30至70%。
- 如申請專利範圍第10項所述之骨植入物,其中該陶瓷層為一羥基磷灰石層。
- 如申請專利範圍第7項所述之骨植入物,更包含一生物聚合物共價鍵結至該陶瓷層。
- 如申請專利範圍第12項所述之骨植入物,其中該生物聚合物為一膠原基生物聚合物(collagen-based biopolymer)。
- 如申請專利範圍第7項所述之骨植入物,更包含一骨形成促進因子共價鍵結至該陶瓷層。
- 一種製造一骨植入物的方法,該方法包含:取得一生物惰性基材,該生物惰性基材具有一表面,該表面有一第一部分及一第二部分;以及於該第一部分上形成多個小突脊,每個小突脊具有10至30微米的寬度及10至30微米的高度,並在該第二部分上形成多個大突脊,每個大突脊具有60至100微米的寬度及40至80微米的高度,其中該骨植入物經配置使得當該骨植入物置於一受試者的一植入位置時,該第二部分與一骨骼接觸。
- 如申請專利範圍第15項所述之方法,其中該生物惰性基材為一金屬系基材。
- 如申請專利範圍第16項所述之方法,其中該金屬系基材為一鈦合金系基材。
- 如申請專利範圍第16項所述之方法,其中在該形成步驟之後,更包含:氧化該生物惰性基材之該表面以形成一金屬氧化物層。
- 如申請專利範圍第18項所述之方法,其中在該氧化步驟之後,更包含:將一陶瓷層附加在該第二部分上;以及在該陶瓷層中產生複數個凹陷處,其中該等凹陷處佔該陶瓷層之總表面積的30至70%。
- 如申請專利範圍第19項所述之方法,其中該陶瓷層為一羥基磷灰石層。
- 如申請專利範圍第19項所述之方法,其中在該產生步驟之後,更包含:藉由共價鍵結將一生物聚合物固定在該陶瓷層上。
- 如申請專利範圍第21項所述之方法,其中該生物聚合物為一膠原基生物聚合物。
- 如申請專利範圍第19項所述之方法,其中在該產生步驟之後,更包含:共價地將一骨形成促進因子連結至 該陶瓷層。
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US8323348B2 (en) | 2012-12-04 |
ATE464074T1 (de) | 2010-04-15 |
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