生体吸収性ポリマーの応用展開vascular tissue tissue induction 1. skin 2. nerve 3....
TRANSCRIPT
生体吸収性ポリマーの応用展開
木村 良晴
京都工芸繊維大学 繊維科学センター
1. 序
2. 繊維系材料
3. ポリ乳酸ーポリエーテル系ブロック共重合体
4. ポリ乳酸に基づく材料開発
内容
ヒトの周りで使うものの開発
Health care だけではない
インプラント型医療機器
人工内耳 （Cochlear implant）は、聴覚障害者の
内耳の蝸牛に電極を接触させ、聴覚を補助する器具である。 子供が成長にともな
い言葉を覚えるように、成人の時に手術を受け（人工）聴覚を初めて得る場合より、子供の時のほうが脳の人工内耳からの信号に対する対応がはやい。
元々聴覚者であり聴覚を失った場合は埋め込み手術をした後、音に慣れるために1～2ヶ月ぐらいのリハビリテーションが必要になる。
リハビリテーション後は電話での会話も出来るほどに回復する例も多い。
http://www.nidek.co.jp/visual_prosthesis/about/index.html
人工視覚システム
脳刺激型
http://www.nidek.co.jp/visual_prosthesis/about/type.html
バイオポリマーの適用範囲と動向
第一段階生体吸収性ポリマー
第二段階生分解性プラスチック
第三段階バイオベースポリマー
目的 生体内吸収性 生分解による環境適合植物由来によるカーボンニュートラル、再生可能資源の利用
目標 生体の一時修復材料 汎用プラスチックの代替 構造材料の代替
用途医用材料、DDS手術糸、骨折固定材等
比較的短命な用途ゴミ袋、日用品
長期に使用する用途電気製品・自動車部品等
代表例
ポリ--オキシ酸 脂肪族ポリエステル ポリエステル等
PGA, PLLA, Peptide, etc.
PLLA (Nature Works®)PHB, PBS (GS Pla®)PBSA (Ecoflex®) PEAT (Maxon®), etc.
sc-PLA, PTT, PMBL, etc.
社会認知
再生医療 法的インフラの支援 環境ブランド戦略
企業化 1980年から 2000-2004年 2005-2007年
PGA:バリアー樹脂 PLLA:フィルム、成形樹脂 Sc‐PLA: 繊維、構造材料
酵素分解型 多糖類 セルロース、デンプン、キチン、デキストラン、アルギン酸キチン・キトサン、プルラン、ヒアルロンサン
ペプチド コラーゲン、ゼラチン、フィブロイン、セリシン、カゼイン、フィブリン
核酸ポリヒドロキシアルカン酸
自然分解型 ポリアミノ酸 ポリリジンなどポリデプシペプチドポリアミド ナイロン4、ナイロン2/ナイロン6共重合体
脂肪族ポリエステル ポリグリコール酸(PGA)、ポリ乳酸(PLA)、ポリカプロラクトン(PCL)、ポリジオキサノン(PDX)、ポリヒドロキシ酪酸
(PHB)、ポリコハク酸ブチレン (PBS)共重合ポリエステル PBATa)、PEATb)
トリアジン重合体ポリジヒドロピランポリ酸無水物ポリオルトエステルポリカーボネートポリシアノアクリル酸エステル
ポリリン酸エステル
無機素材 ポリホスファゼン、ヒドロキシアパタイト、炭酸カルシウム
主たる生体内吸収性材料
a) ポリ（アジピン酸/テレフタル酸ブチレン）：poly(butylene adipate/terephthalate) b) ポリ（アジピン酸/テレフタル酸エチレン）：poly(ethylene adipate/terephthalate)
Degradation‐absorption mechanism
many inter‐related factors:
• chemical stability of the polymer backbone• presence of catalysts• additives• impurities or plasticizers• geometry of the device• location of the device
Generic curves showing the sequence of polymer‐molecular weight, strength, and mass‐reduction over time
化合物寿命
材料寿命
Accelerated polymer degradation
• More hydrophilic monomer• More hydrophilic, acidic end groups• More reactive hydrolytic group in the backbone• Less crystallinity• Smaller device size
用 途 形状 例
縫合材料 手術糸、クリップ、添え木 、接着剤
ポリ（α－ヒドロキシ酸）、ポリ（1、4-ジオキサン-2-オン）、グリコリド-トリメチレンカーボネート共重合体、カットガット、α-シアノアクリル酸エステル重合体
止血材料 綿、ガーゼ、粉末、スプレー フィブリノーゲン
骨折固定材 プレート、ねじ、ロッド、ピン、シートポリ乳酸、ポリグラクチン、ヒドロキシアパタイト
癒着防止材 ゼリー、スプレー、メッシュ ゼラチン、酸化セルロース、 ヒアルロン酸
組織再生用足場
スポンジ、メッシュ、不職布、管 コラーゲン、セリシン、ポリグラクチン
人工腱、人工靭帯
繊維 ポリ乳酸
人工血管 繊維、多孔体 ポリ乳酸、ポリグラクチン
創傷被覆材（人工皮膚）
繊維、ゲル コラーゲン、キチン、ポリグラクチン
DDS用材料 マイクロカプセル、マイクロスフェア すべての生体吸収性高分子
生体吸収性材料の応用例
Biomedical applications of biodegradable polymers (current study)
1. Medical devicesOrthopedic devicesDrug-eluting stents (DES)Disposable medical devices
2. Tissue engineering
3. Drug delivery and control release
4. Gene deliveryPoly(l-lysine), Poly(-amino ester)s, Polyphosphoester, Polyethylenimine modified with degradable polymersOthers
poly[d,l-(lactide-co-glycolide)] -based microparticle,poly[d,l-(lactide-co-glycolide)]-pDNA microparticles co-formulated with
poly(-amino ester)s
5. Bioseparation and diagnostics applications
各種の外科手術用縫合糸
〔1〕非吸収性縫合糸金属: 鋼線、タンタル、銀などのモノ・マルチフィラメント天然繊維: 絹、木綿、麻、馬毛合成繊維: ポリエステル（ダクロン、テトロン、それらのシリコーン、テフロン
コーティグ）、ポリアミド（ナイロンのモノ・マルチフィラメント、Supramid
Extra）、ポリオレフィン（モノフイラメント）、 テフロン、ポリウレタン
〔2〕吸収性(溶解性)縫合糸天然材料: 腸線（catgut）、コラーゲン、ゼラチン、フィブリン合成材料: Polyamino acids （polyglutamic acid、同methyl and benzyl esters、
proline‐glutamic acid共重合体、polydepsipeptide）、Polyvinyl alcoho1(polyvinyl alcohol、セルロース、でんぶん、ゼラチン、アルブミン、有機酸との結合、 poly(vinyl butyral)）、β‐Polyesters （poly‐β‐propiolactone、 poly‐β‐hydroxybutyrate）、α‐Polyesters （polyglycolic acid、 polylactic acid、polyglycolide lactide共重合体）、 Copolyaminotriazole
1) biodegradable2) biocompatible3) sustained over 1 month4) processable5) high‐strength and high‐modulus6) injectable microcapsules7) zero order release
Difficult to control mechanical properties,biodegradation ratesto make chemical modification
Poly(‐hydroxy acid)s
‐(‐OCHCO‐)‐R
強度 弾性率 伸び Tg 融点(MPa) (GPa) (%) (℃) (°C)
縫合糸ポリグリコール酸 890 8.4 30 36 230 Dexon, etc.ポリグラクチンa 850 8.6 24 40 220 Vicrylポリジオキサノン 490 2.1 35 ＜20 106 PDSポリグリコナートb 550 2.4 45 ＜20 213 Maxonポリグリカプロンc 400 1.2 -10 200 Monocrylカットガット 520創傷被覆材キチン 750 12 Beschitinコラーゲン 360 4 20 Biobren一般用途ポリ-L-乳酸 550 5 35 56 178 Lactronポリカプロラクトン 800 27 60
Copolymers of glycolide (90) with (a) lactide, (10) (b) trimethylene carbonate (10), and (c) e-caprolactone (10).
繊維 商標名
生体吸収性繊維の性質
左：冠動脈用IGAKI-TAMAI® STENT右：下肢用IGAKI-TAMAI® STENT
左：病変部右：下肢用IGAKI-TAMAI® STENTを埋め込んだ後の病変部
PLLA繊維
Different types and appearances of passive, interactive, and bioactive wound dressing materials: (a) gauze, (b) tulle, (c) polyurethane membrane, (d) polyurethane foam, (e) hydrogel, (f ) hydrocolloid, (g) alginate, (h) collagen, and (i) hydrofiber.
Polymers for Advanced Technologies, 21, 77-95, (2009 )
吸収性縫合補強材
グンゼ
吸収性人工硬膜
PGA不織布L-ラクチド・ε-カプロラクトン共重合体フィルムをPGA不織布で強化
Tissue Engineering (GTR法)による組織・器官の再生
Cell Transplantation1. Cartilage（軟骨）2. Bone3. Urothelium（尿管）4. Intestine5. Nerve
PrevascularizationVascular tissue
Tissue Induction1. Skin2. Nerve3. Esophagus（食道）4. Anterior Cruiciate Ligament（前十字靭帯）5. Bone
Fig. 19. In the process of tissue engineering, cells are cultured on a scaffold to form a natural tissue, and then the formed tissue is implanted in the defect part in the patients. In some cases, a scaffold or a scaffold with cells is implanted in vivo directly, and the host’s body works as a bioreactor to construct new tissues.
Some applications and potential applications of synthetic biopolymers.
Polymer Tissue engineeringPolyanhydrides Bone tissue engineering Polyurethane Vascular tissue engineering
Bone tissue engineeringPolyelectroactive materials Nerve tissue engineering Polyphosphoester Bone tissue engineering Poly(propylene fumarate) Bone tissue engineering Polyester-urathane Genitourinary tissue engineering
（泌尿器）
Biopolymers with responsive activities1. Stimuli-responsive biopolymers
Temperature responsive, pH-responsive biopolymersPhoto responsive biopolymers, Redox responsive biopolymers
2. Electroactive biomaterials3. Specific bonding biopolymers4. Biopolymers for tracing and bioimaging
Biopolymers for optical tracing and bioimagingBiopolymer-based organic probes.Biopolymer-based inorganic probes
Biopolymers for MRIBiopolymer-based paramagnetic probesBiopolymer-based superparamagnetic probes.
5. Other biopolymer-based tracing and bioimagingplanar gamma scintigraphy (PGS),single photon emission computed tomography (SPECT),positron emission tomography (PET), ultrasound imagingX-ray computerized axial tomography (CT)
Biodegradable electrically conducting polymer (BECP)
Huang LH, Zhuang XL, Hu J, Lang L, Zhang PB, Wang YS, Chen XS, Wei Y, Jing XB., Biomacromolecules 2008, 9, 850–858.
Fig. 13. Wei et al. demonstrated that the electroactive silsesquioxane precursor, ATQD, containing aniline trimer covalently modified by oligopeptide could be a kind of promising biomaterial for tissue engineering.Bioactive material ATQD-RGD could support PC-12 cell adhesion and proliferation and could stimulate spontaneous neuritogenesis in PC-12 cells in the absence of NGF as shown in this figure. (A) Phase contrast images of PC-12 cell morphology of (a) TCP, (b) TCP with NGF, (c) ATQD-RGD, and (d) ATQD-RGD with NGF on day 10; (B) Neurite length distribution chart for ATQD-RGD substrates with and without NGF.
Silsesquioxane precursor, N-(4-aminophenyl)-N-(4-(3-triethoxysilylpropylureido)-phenyl-1,4-quinonenediimine) (ATQD), containing aniline trimer covalently modified by oligopeptide
Fig. 14. Triblock and multiblock copolymers of PLA and aniline pentamer possessed good electroactivity, solubility and biodegradability similar to pure PLA. In vitro cell evaluation showed that the electroactive copolymers were innocuous and could indeed promote the attachment and growth of rat C6 glioma cells. Moreover, in the comparison experiments with and without applying electrical potentials, the doped electroactive copolymers had the ability of improving the differentiation of PC-12 cells. (A) Representative fluorescence micrographs of PC-12 cells for the substrates (a) TCPS (−) without electrical stimulation, (b) TCPS (+) exposed to electrical stimulation, (c) EM PLAAP (−) doped with CSA without electrical stimulation, (d) EM PLAAP (+) doped with CSA exposed to electrical stimulation on day 4; (B) the mean neurite length of PC-12 cells cultured on the substrates of EM PLAAP (−), TCPS (+), and EM PLAAP (+) on day 4.
aniline oligomers (aniline pentamer with dicarboxyl end groups) incorporated with PLA, PCL and natural biopolymer chitosan, to prepare new biodegradable electroactive biomaterials
tissue-culture-treated polystyrene (TCPS), camphorsulfonic acid (CSA)
Polymer Melting point(C)
Glass transition temperature (C)
Modulus (GPa)
Elongation (%)
Degradation time
(months)poly(glycolide) 225-230 35-40 7 15-20 6 to 12poly(L-lactide) 173-178 60-65 2.7 5-10 >24
poly(DL-lactide) Amorphous 55-60 1.9 3-10 12 to 16poly(e-caprolactone) 58-63 -65 - -60 0.4 300-500 >24
poly(dioxanone) N/A -10 - 0 1.5 N/A 6 to 12PGA-TMC N/A N/A 2.4 N/A 6 to 1285/15 DLPLG Amorphous 50-55 2 3-10 5 to 675/25 DLPLG Amorphous 50-55 2 3-10 4 to 565/35 DLPLG Amorphous 45-50 2 3-10 3 to 450/50 DLPLG Amorphous 45-50 2 3-10 1 to 2Bone 10-20
Steel 210
Physical, mechanical, and degradation properties of selected biodegradable polymers used for biodegradable orthopedic fixation devices （整形外科用）
Tensile or flexural modulus.Time to complete resorption.
PGA: poly(glycolide)LPLA: poly(L‐lactide)DLPLA: poly(DL‐lactide)LDLPLA: poly(DL‐lactide‐co‐L‐lactide)DLPLG: poly(DL‐lactide‐co‐glycolide)LPLG: poly(L‐lactide‐co‐glycolide)PGA‐TMC: poly(glycolide‐co‐trimethylene carbonate)PCL: poly(‐caprolactone)PDO: poly(dioxanone)SR: self‐reinforced
Application Trade name Composition Manufacturer
Fracture fixation SmartPins SR-LPLA Bionx Implants
Fracture fixation SmartPins SR-PGA Bionx Implants
Fracture fixation SmartScrew SR-LPLA Bionx Implants
Fracture fixation SmartTack SR-LPLA Bionx Implants
Fracture fixationPhantom SofThread Soft Tissue Fixation
ScrewLPLA DePuy
Fracture fixation Orthosorb Pin PDO J & J Orthopedics
Interference screws Full Thread Bio-Interference Screw LPLA Arthrex
Interference screws Sheathed Bio-Interference Screw LPLA Arthrex
Interference screws Phantom Interference Screw LPLA DuPuy
Interference screws Biologically Quiet Interference Screw 85/15 DLPLG Instrument Makar
Interference screws BioScrew LPLA Linvatec
Interference screws Sysorb LLPLA Sulzer Orthopedics
Interference screws Endo-Fix Screw PGA-TMC Smith and Nephew
Craniomaxillofacial fixation LactoSorb Screws and Plates 82/18 LPLG Biomet
Meniscus repair Menicus Arrow SR-LPLA Bionx Implants
Meniscus repair Clearfix Meniscal Dart LPLA Innovasive Devices
Meniscus repair Clearfix Meniscal Screw LPLA Innovasive Devices
ACL reconstruction Biologically Quiet Staple 85/15 DLPLG Instrument Makar
Meniscus repair Meniscal Stinger LPLA Linvatec
Meniscus repair SD sorb Meniscal Staple 82/18 LPLG Surgical Dynamics
Biodegradable orthopedic fixation devices (pins, rods, screws, tacks, ligaments)
Suture anchors Bankart Tack SR-LPLA Bionx Implants
Suture anchors SmartAnchor-D SR-LPLA Bionx Implants
Suture anchors SmartAnchor-L SR-LPLA Bionx Implants
Suture anchors Phantom Suture Anchor LPLA DuPuy
Suture anchors BioROC EZ 2.8 mm LPLA Innovasive Devices
Suture anchors BioROC EZ 3.5 mm LPLA Innovasive Devices
Suture anchors Biologically Quiet Biosphere 85/15 DLPLG Instrument Makar
Suture anchors Biologically Quiet Mini-Screw 85/15 DLPLG Instrument Makar
Suture anchors Bio-Anchor LPLA Linvatec
Suture anchors GLS LPLA Mitek Products
Suture anchors Panalok LPLA Mitek Products
Suture anchors Panalok RC LPLA Mitek Products
Suture anchors Suretak 6.0 PGA-TMC Smith and Nephew
Suture anchors Suretak 8.0 PGA-TMC Smith and Nephew
Suture anchors Suretak II w spikes PGA-TMC Smith and Nephew
Suture anchors TAG 3.7 mm Wedge PGA-TMC Smith and Nephew
Suture anchors TAG Rod II PGA-TMC Smith and Nephew
Suture anchors SD sorb 2 mm 82/18 LPLG Surgical Dynamics
Suture anchors SD sorb 3mm 82/18 LPLG Surgical Dynamics
Suture anchors SD sorb E-Z TAC 82/18 LPLG Surgical Dynamics
Suture anchors Bio-Statak LPLA Zimmer
Biomaterials, 21 (2000), 2335‐2346
DDSに用いられる高分子キャリヤー
非水溶性高分子シリコーン、エチレン・酢酸ビニル共重合体、ポリアクリル酸エステルエチルセルロース、セルロースアセテート
ゲル形成性高分子ポリアクリルアミド、ポリHEMA架橋体、ポリアクリル酸架橋体、ポリビニルアルコール、ポリエチレンオキシド水溶性セルロース誘導体、海草・豆類の多糖類、キチン・キトサン、こんにゃく、プルラン
徐溶解性高分子メチルビニルェーテル・無水マレイン酸共重合体の部分エステル腸溶性高分子（キトサンなど）
生体内分解性高分子熱凝固・架橋アルブミン、架橋ゼラチン・コラーゲン、フィブリンポリシアノアクリレートポリエステル（ポリグリコール酸、ポリ乳酸、ポリ‐β‐ヒドロキシ酪酸、
ポリカプロラクトン）ポリオルトエステルポリカーボネート
被覆肥料
Polyol/dicarboxylic acid based bioelastomers: poly(glycerol sebacate) (PGS), poly(polyolsebacate) (PPS), poly(glycerol-sebacate-lactate) (PGSL), poly(glycerol dodecanoate) (PGD), poly(triol-ketoglutarate) (PTK), poly(erythritol dicarboxylate) (PErD), and poly(1,12-dodecandiol malate) (PDDM),
Thermo-cured degradable bioelastomers
Thermoplastic degradable bioelastomers
Photo-cured degradable bioelastomers
Crosslinked Biodegradable Elastomers
acrylated poly(glycerol sebacate) (PGSA), poly(octamethylene-maleate-citrate) (POMC), polycarbonate (PC) related, and poly(-caprolactone) (PCL) related.PC related bioelastomers: fumaric acid monoethyl ester based poly(1,3-trimethylene carbonate), (fumaric-based PTMC), pentaerythritol triacrylate based poly(1,3-trimethylene carbonate) (PeTriAcr-based PTMC), and acryloyl chloride based poly(1,3-trimethylene carbonate) (acrCl-based PTMC). PCL related bioelastomers: poly(-caprolactone-adipate-4-hydroxycinnamate) (PCLApHc),poly(-caprolactone-co-d,l-lactide) (poly(-CL-co-d,l-LA)), poly(-caprolactone-co-l-lactide-co-glycolide) (poly(-CL-co-l-LA-co-GA)), and poly(2-oxepane-1,5-dione-co--caprolactone) (poly(OPD-co--CL))
segmented polyurethane, poly(ether ester), poly(ester amide), polylactide related block copolymer and polycarbonate–poly(butylene succinate)–polycarbonate
Q. Liu et al. / Progress in Polymer Science 37 (2012) 715– 765
Scheme 3. Molecular structures of the polyol monomers and corresponding PPS bioelastomers
Scheme 9. Synthesis of the BCP cured poly(-CL-co-d,l-LA) bioelastomers
Scheme 11. Synthesis of the double-bond-cured PEGH bioelastomers
Fig. 1. (a) In vivo degradation and (b) in vitro enzymatic (lipase) degradation of the PGS bioelastomerscured for 42, 66, 90 and 114 h.
Fig. 2. Heart patch strategy using the PGS bioelastomers in which the heart patch is sutured onto the heart and serves two functions: (1) the primaryfunction is to deliver cells; (2) the secondary function is left ventricular restraint.
Fig. 3. Heart cell alignment guided by the accordion-like honeycomb PGS scaffolds. (a): SEM image of a representative accordion-like honeycomb PGS scaffold (scale bars: 100 m); (b): low-magnification image of the scaffold (neonatal rat heart cells cultured for 1 week on the scaffold) by confocal microscopy, demonstrating pores completely filled by neonatal rat heart cells grossly aligned in parallel to the preferred direction(scale bars: 200 m). Axes show preferred (PD) and cross-preferred (XD) material directions.
Scheme 17. Synthesis of the photo-cured poly(OPD-co--CL) bioelastomers
Fig. 23. Weight loss of the photo-cured poly(-CL-co-L-LA-co-GA) bioelastomers during in vitro degradation in phosphate buffer solutions (pH = 7.4, 37 ◦C). The high (9300 g/mol), medium (4800 g/mol), and low (1800 g/mol) molecular weight oligomers are denoted by H-x, M-x, and L-x, respectively, where x represents the percent content of -CL.
1. 序
2. 繊維系材料
3. ポリ乳酸ーポリエーテル系ブロック共重合体
4. ポリ乳酸に基づく材料開発
5. 生合成系への試み（生分解を含む）
6. その他
内容
oligo (L-lactic acid) n ~ 4
CHO
CH3
H C
O
OH
n
+ CHCH2
CH3
OOCH2CH2 OCH2CH2x
yx
OHH (CH2)10COOHHOOC+
-H2OCatalyst CHCH2
CH3
OOCH2CH2 OCH2CH2 CO
CH
CH3
Ox
yx
n
C
O
C
O
O2(CH )10
PN Dodecanedioc acid : DDA
+O
O O
O CH3
H3CHO H
x
CH2CH2O CH2CHO
CH3
CH2CH2Oy y'
Sn(OCOC7H15)2
L-lactide
CCHO
O
CH3
OCHC
O
CH3 mn x
CH2CH2O CH2CHO
CH3
CH2CH2Oy y'
LN(t)-a
160°C
PN
Tri-block copolymer
Multi-block copolymer
LN(m)‐a
PLLAとPluronic®のブロック重合体
PolymerFeed ratio
LA/PN (wt/wt)
LA/EO/PO (composition)
Polymeric product
Tm (°C)Tg (°C) Tensile properties of filmStrength (MPa) Modulus (GPa)
LA/EO/PO (composition) Mw/MnYield(%) LA/PN
(wt/wt)
Table. Characteristics of triblock type PLLA-PN-PLLA copolymers having different composition.
a) Determined by 1H NMR b) Determined by GPC (THF eluent) c) N.D : Not detected
a)Mn 10-4
b)
PLLA
LN(t)-10
LN(t)-15
LN(t)-20
178 172 170 168
59 36 30 21
57 55 47 40
1.23 1.10 0.96 0.74
100/0 90/10 85/15 80/20
100/0/0 85/12.0/3.0 79/16.8/4.2 72/22.4/5.6
93 94 95 92
1.96 2.14 2.09 1.54
100/0 90/10 85/15 80/20
100/0/0 85/12.0/3.0 79/16.8/4.2 72/22.4/5.6
10.2 7.0 4.6 3.8
PolymerFeed ratio
LA/PN(wt/wt)
LA/EO/PO (unit ratio)
Polymeric product
Tm (°C) Tg (°C)
156 132 N.D N.D N.D N.D
25 3 N.D N.D N.D N.D
90/10 80/20 70/30 60/40 50/50 30/70
85/12.0/3.0 72/22.4/5.6 60/32.0/8.0 49/40.8/10.2 39/48.8/12.2 22/62.4/15.6
LA/EO/PO (unit ratio)
Mn Mw/MnYield (%) LA/PN(wt/wt)
78.7 68.1 79.5 79.8 79.4 70.9
47,400 69,200 53,400 58,000 62,700 68,100
1.79 1.93 2.17 2.28 2.05 2.14
84/12.8/3.2 69/24.8/6.2 54/36.8/9.2 41/47.2/11.8 32/54.4/13.6 9/72.8/18.2
89/11 77/23 64/36 52/48 42/58 13/87
d)
a) At 180 °C for 30 h with 0.1 wt% of stannous oxide relative to all amount. b) Determined by 1H-NMR spectra. c) Determined by GPC with tetrahydrofuran as the eluent. d) N.D : not detected.
Table 6. Typical results of the multiblock copolymerizationa) of oligo(L-lactic acid) and PN and DDA at the optimum conditions.
c)b)
LN(m)-11 LN(m)-23 LN(m)-36 LN(m)-48 LN(m)-58 LN(m)-87
46
Changes in molecular weight of LT(m)-x films in vitro (phosphate buffered saline (pH=7.4, 37C) and in vivo.
Weight decreases of the LT(m)‐x films in phosphate bufferedsaline (pH=7.4, 37C) as compared with InterseedTM
Interceed®
(control)
LN(m)‐87
copolymer
癒着防止膜への適用
被覆時 1週間後摘出時
Injectable Hydrogel with Biodegradability and biocompatibility : Sol-gel Transition of Polylactide/ Poly(oxyethylene) Block Copolymers
Injectable Hydrogel with Biodegradability and biocompatibility : Sol-gel Transition of Polylactide/ Poly(oxyethylene) Block Copolymers
(1) R. Langer : PLA-PEG micelle for use to DDS(2) J. A. Hubbell : PEG-PLA diacrylate for medical device(3) L. Illum and S. S. Davis : Analysis of PLA-PEG micelle(4) S. W. Kim : PEG-PLLA-PEG as thermo-responsible gel(5) K. Kataoka : PEG-PLLA methacrylate for use to DDS
and gel for electrophoresis
PLLA-PEGO
OO
OH3C
CH3
O CH
CH3
C OCH2CH2
OHOCH2CH2 OCH3H OCH3
n
10mol%Sn(Oct)2
mn＋
Micelles in Water
100 C, 6h
PEG-PLA-PEG
+ O=C=N (CH2)6 N=C=O(OCHC)m
CH3
O(OCH2CH2)nH OCH3
CN(CH2)6NCH H
O O(OCHC)m(CCHO)m
CH3
O(OCH2CH2)n OCH3
O
CH3
(CH2CH2O)nCH3O
PLLA-PEG-PLLAO
OO
OH3C
CH3
O CH
CH3
C OCH2CH2
OHOCH2CH2 OHH OCH
CH3
CO
HOnmn
＋m
10mol%Sn(Oct)2
Synthesis
Photographs of an aqueous dispersion of PLLA-PEG-PLLA (a,b,c) and a mixed dispersion of PLLA-PEG-PLLA and PDLA-PEG-PDLA (d, e, f) at different temperatures. (a, d): at room temperature, (b, e): after heating at 37 °C for 1 h, (c, f): after heating at 75 °C for 1 h.
Macromol. Biosci., .1, No.5, .204‐208 (2001)
Changes in G' and G" as a function of the temperature for a mixed dispersion of PLLA-PEG-PLLA and PDLA-PEG-PDLA.
+
PLLA-PEG-PLLA
PDLA-PEG-PDLA
Polymer synthetic chemistry Lab.
Photograph of subcutaneous tissue implanted with the gels and dissected to take out them after 3days
The gel prepared at 37 C was completely absorbed within 3days, while the gel prepared at 75 C remained.
75 C
37 C
Development of cell-seeding materials
-- Parkinson's disease Neural stem cell transplant-- Acute myocardial infarction Skeletal myoblast transplant-- Buerger's disease -- Arteriosclerosis obliterans Mesenchymal stem cell transplant
gel
cellscaffold
PLA-PEG-PLA stereomixtureas an Injectable scaffold:Thermo-responsive and bioresorbable hydrogel
Application to Tissue Regeneration
GFP mouse MEF
MEF
“L”soln. “D”soln.
Preparation of suspensions of MEF cells from GFP mouse
Donner : C57BL/6-TgN(act-EGFP)OsbC14-Y01-FM131Cell : MEF (mouse embryonic fibroblast)
In vivo
Recipient : Inbred mouse(-/-) (GFP negative)
After 3 days
500μm
PBS
fluorescent cells
Polymer suspension
The sectioned tissue fromthe femoral region of mouse (a) optical and (b) fluorescent microscopes.
(a) (b)
Mixed dispersions of PEG-PLLA and PEG-PDLA
gel (rt) → sol (high T) → gel (rt)reversible
Mixed dispersions of PLLA-PEG-PLLA and PDLA-PEG-PDLA
sol (rt) → gel (high T) → gel (rt)irreversible
The gel strength was too low to fix the cells grown in it.
Gel-to-sol transition, being opposite
Two types of hydrogels
Synthesizing two enantiomeric copolymer mixtures of F-PEG-PLLA / PLLA-PEG-PLLA and F-PEG-PDLA /PDLA-PEG-PDLA with PEG having differentfuranyl terminal ratio.
Terminal modification
5 ˚C
37 ˚C
65 ˚C
Mixing of the aqueous micelles of enantiomeric copolymermixtures to induce the sol-gel transition.
The gelation behavior and the gel strength are controlledby changing the composition of diblock and triblockcopolymers.
F-PEG-PLLAPLLA-PEG-PLLA
Mixed micelle
F-PEG-PDLAPDLA-PEG-PDLA
Mixed micelle
Mixing
Synthesis of F-PEG-PLLA and F-PEG-PDLA
Ratio(theo.)
F-PEG-PLA(4k-4k)
2 1
PLA-PEG-PLA(4k-4k-4k)
2
F-PEG-F 1 2
FurfurylIsocyanate 20 % 40 % 60 % 80 %
F-PEG-PLLA 32 % 48 % 48 % 32 %
PLLA-PEG-PLLA 64 % 36 % 16 % 4 %
F-PEG-F 4 % 16 % 36 % 64 %
F-PEG-PDLA/ PDLA-PEG-PDLA polymer mixturesF-PEG-PDLA/ PDLA-PEG-PDLA polymer mixtures
20%, 40%,60%, 80%20%, 40%,60%, 80%
Removedby
reprecipitation
(Mn = 4000)
Mixture
Synthesis of PEG-PLA copolymersTable 1. Synthesis of polymers
ProductF-PEG-PLA
FurfurylIsocyanate
(mol)
Feed ratioPEG / PLA
(w/w)
Conversion(%)
CompositionPEG / PLA
(w/w)
Mn*2
(Da)Mw/Mn*2
FIContent*1
(%)
Ratio(theo.)Di- / Tri-(% / %)
Ratio*1
Di- / Tri-(% / %)
Yield(%)
20% 4k-4k L 5×10-4 50/50 95.2 52/48 9100 1.12 19 33/67 20/77 96.1
20% 4k-4k D 5×10-4 50/50 95.1 51/49 9000 1.14 19.8 33/67 17/70 87.5
40% 4k-4k L 1×10-3 50/50 94.1 53/47 8900 1.11 33.3 57/43 31/61 92.9
40% 4k-4k D 1×10-3 50/50 94.2 53/47 8700 1.09 41.1 57/43 35/59 92.1
60% 4k-4k L 1.5×10-3 50/50 96.4 50/50 8700 1.14 43.6 75/25 43/52 90
60% 4k-4k D 1.5×10-3 50/50 95.1 52/48 8700 1.14 43.6 75/23 45/49 91
80% 4k-4k L 2×10-3 50/50 93.9 52/48 9000 1.25 84.1 89/11 80/15 69.1
80% 4k-4k D 2×10-3 50/50 94.4 52/48 9000 1.23 84.9 89/11 85/9 66.4
Reaction temperature: 140℃Reaction time: 4 h
*1 Determined by 1H-NMR*2 Determined by GPC
The content of furanyl terminal (relative to the oxymethylene units and the lactate sequencedetermined by NMR) and the di-block copolymer ratio were increased with increasing thefeed ratio of furfuryl isocyanate.
polymer(dissolved in THF)
polymermicelle
ultra pure water
Evaporation of THF
Preparation of micelles of PEG-PLA
Polymer(9 wt%)
Temperature20% 4k-4k 40% 4k-4k 60% 4k-4k 80% 4k-4k
5 ˚C
37 ˚C
65 ˚C
Sol-Gel transition
FTIR
90014001900
Inte
nsity
Wavenumer (cm-1)170017501800
Inte
nsity
Wavenumer (cm-1)
20% L
20% LD40% L
40% LD
60% L
60% LD80% L80% LD
17551752
Looking at the extended region from 1700 to 1800 cm-1, the homopolymer dispersion showeda single band at 1755 cm-1 that was assigned to C=O stretching. On the other hand, aftermixing the enantiomer dispersion, it showed a single band at 1752 cm-1. This shift from 1755cm-1 to 1752 cm-1 was attributed to the stereocomplexation of PLLA and PDLA.
Time-dependent rheological changesfor the mixed micelles containingvarious copolymers in 9 wt/wt-% at37°C
Temperature-dependent rheologicalchanges for the mixed micellescontaining various copolymers in 9wt/wt-%
The G’ value of the mixed micelle solutions 80% 4k-4k showed final G’ value of 3.5 kPa after60 min. On the other hand, the micelle solution 20% 4k-4k showed lower G’ value of c.a. 500Pa, because of the higher ratio of triblock copolymer.
phase separation
0102030405060708090
100
5 10 15 20
G' (
Pa)
Temperature (℃)
80% 4k-4k G'80% 4k-4k G"
0102030405060708090
100
5 10 15 20 25 30
G' (
Pa)
Temperature (℃)
40% 4k-4k G'40% 4k-4k G"
0
5
10
15
20
25
30
5 10 15 20 25 30 35
G' (
Pa)
Temperature (℃)
20% 4k-4k G'20% 4k-4k G"
Gelation point (˚C) of the mixed dispersions containing various copolymers in 9wt/wt-%
0102030405060708090
100
5 10 15 20 25 30
G' (
Pa)
Temperature (℃)
60% 4k-4k G'60% 4k-4k G"
32.5 ˚C25.5 ˚C
20.5 ˚C
0
5
10
15
20
25
30
35
15 20 25 30 35 40 45
Gel
atio
n Po
int (
˚C)
Ratio of Dibolck Coplymer (%)
The gelation pointbecame lower withincreasing the content ofdiblock copolymer or byincreasing the feed ratioof furfuryl isocyanate inthe PEG modification.
PLLA micelle
PDLA micelle
Mixed
BMG
24 hr, 4 ˚C
Mixed micelle Mixed micelle(Diels-Alder reaction)
Diels-Alder reaction of the mixed micelle solution
Hydrophilic segmentDiels-Alder coupling
Hydrophobic segmentStereocomplex
L D
GPC curves after Diels-Alder reaction
Rheological behavior (11 wt%)
WAXD profiles of (a) the single micelle solution Di-80%-2k-L and the
mixed micelle solutions Di-80%-2k-DL in the (b) absence and (c) presence
of BMG (20 wt/wt-% in polymer concentration).
Crosslinked by Diels-Alder reaction with 1,8-bis(maleimido)diethylene glycol(BMG) as well as by stereocomplexation to attain increased mechanicalproperties of the gel.
F-PEG-PLLA/PLLA-PEG-PLLA
F-PEG-PDLA/PDLA-PEG-PDLAMixed
BMG
Conclusion
The F-PEG-PLA / PLA-PEG-PLA copolymers having a furanyl group onthe PEG terminal were synthesized by ROP of L- and D-lactides in thepresence of furanylated PEG.
The gelation point was decreased with increasing the content of diblockcopolymer or by increasing the feed ratio of furfuryl isocyanate in thePEG modification.
The copolymers were successfully chain-extended by the terminalDiels-Alder reaction with BMG to enhance the G’ of the gel.
The Diels-Alder reaction was found to be effective for enhancing theability of sc formation.
Hydrogels with higher strength and toughness can be made from the mixedmicelle solutions. They are expected to be utilized as injectable scaffoldsfor cell transplant.
New Dutch joint venture to supply resorbable polymers for controlled drug releaseThe Netherlands-based lactic acid producer Corbion and MedinCell, headquartered in France, have announced plans to
establish a 50/50 joint venture for the supply of PEG and PLA based co-polymers in the field of controlled release drug delivery. The joint venture will be called CM Biomaterials. It will sell the PEG / PLA co-polymers to MedinCell partners who license the MedinCell technology known as BEPO. Actual manufacture of the polymers will take place at Corbion’s medical biomaterials plants in the US and the Netherlands, while development and licensing of the technology remain the exclusive responsibility of MedinCell. CM Biomaterials will be established in the Netherlands.
MedinCell’s proprietary BEPO technology platform provides high flexibility and low manufacturing cost. Its physicochemical properties make it an ideal vehicle for a broad variety of Active Pharmaceutical Ingredients (APIs) such as peptides, proteins, antibodies and small molecules.
“Corbion and MedinCell have been in a joint development program since 2010, to optimize the manufacturing of PEG/PLA polymers for drug delivery,” said Marco Bootz, SVP Biochemicals, Corbion. “This cooperation has now successfully developed into a joint venture for the supply of PEG/PLA polymers. In this joint venture, Corbion will be responsible for manufacturing the polymers and with our complementary expertise in the field of polymers we will together develop the optimal polymers for MedinCell’s applications. “
He added: “Corbion is the global leader in the field of resorbable polymers for drug delivery and medical devices. This new technology will further enhance our position in medical biomaterials”.Christophe Douat, CEO of MedinCell said: “The creation of CM Biomaterials validates our balanced network company model that aims to gather leaders in many fields to create best-in-class medicines for Global Health. Based on a complementary partnership, CM Biomaterials will best serve BEPO partners and secure the quality of the polymers used for all BEPO applications.”
BEPO can be fine-tuned for delivery of hydrophobic and hydrophilic API. It is composed of mono-dispersed copolymers containing hydrophilic blocks (PEG) linked with hydrophobic blocks (PLA), which form a semi-solid depot when exposed to an aqueous environment. The hydrophilic blocks can interact with hydrophilic APIs and triggering their controlled release, whereas the hydrophobic blocks are able to solubilize and retain hydrophobic APIs.As a game-changing technology, BEPO combines many advantages compared to alternative drug delivery technologies, including improved patient compliance, efficacy and tolerability, as well as versatility, development speed and lower
10.08.2015
The technology BEPO copolymersBEPO components
BEPO is composed of diblock (DB) and triblock (TB) copolymers containing hydrophilic and water-soluble blocks (PEG – polyethylene glycol) linked with hydrophobic and amorphous blocks (PLA – Poly(D,L-lactic acid)), which form a semi-solid depot when exposed to an aqueous environment. The hydrophilic blocks can interact with hydrophilic APIs and permit for their controlled release, whereas the hydrophobic blocks are able to solubilise and retain hydrophobic APIs. BEPO copolymers Molecular Weight (MW) range from 3 to 35 kDa.BEPO also contain solvent and selected Active Pharmaceutical Ingredients (API). Its physicochemical properties make it an ideal vehicle for a wide range of APIs such as sensitive peptides, proteins, antibodies and small molecules.
1. 序
2. 繊維系材料
3. ポリ乳酸ーポリエーテル系ブロック共重合体
4. ポリ乳酸に基づく材料開発
5. 生合成系への試み（生分解を含む）
6. その他
内容
O
O
O
O
OBz
O
BMD
OO
O
O
O
O
Bz
OO
O
O
OH
O
H2 / Pd-C
n
ncat.
(Bz = benzyl)
A functional monomer consisting of glycolate and ‐benzyl ‐malate
Ring‐opening polymerization of BMD and subsequent hydrogenolysis
3‐(S)‐[(benzyloxycarbonyl)methyl]‐1,4‐dioxane2,5‐dione
Kimura, Y., Shirotani, K., Yamane, H., Kitao, T.: Macromolecules, 21 (11),3338-3340 (1988)Pounder, R. J., Dove, A. P.: Synthesis and Organocatalytic Ring-Opening Polymerization of Cyclic Esters Derived from L-Malic acid: Biomacromolecules, 11,1930-1939 (2010)
83
O
CH3
O
BMD
O
O
O
O
OBz
O
O
O CH3
O
O CH3
OO
O
O
OH
O
OO
O
O
O
O
Bz
H2 / Pd-C
P(3HB-co-BMD)
poly(3HB-co-GA-co-MA)
+
1
1m n
m n
cat.
(Bz = benzyl)
[RS]-BL
Ring‐opening copolymerization of [RS]‐BL and BMD and subsequent hydrogenolysis
84
OO CH3 O
O
n
Bacterial fermentationpoly(3‐hydroxybutyrate‐co‐3‐hydroxypropionate)
poly(3‐hydroxybutyrate‐co‐4‐hydroxybutyrate)
poly(3‐hydroxybutyrate‐co‐3‐hydroxyvalerate)
poly(3‐hydroxybutyrate‐co‐3‐hydroxyalkanoate)
O
CH3
O+
O
O
O
O
Chemically synthesis
Bacterial and chemical syntheses of biodegradable PHB derivatives
poly(3‐hydroxybutyrate‐co‐2‐hydroxyacetate)
85
Synthetic route to poly(3‐hydroxybutyrate‐co‐glycolate)
A new cyclic diester monomer consisting of3‐hydroxybutyrate and glycolate
O
O
CH3
O
O[R]‐3HB
GA
4‐[R]‐methyl‐1,5‐dioxepane‐2,6‐dione([R]‐MDP)
O
CH3
O
O
O
CH3
O
O[Sn]
[R]-MDP
OO
BL
CH3 O
O+
poly(3-hydroxybutyrate-co-glycolate) (P(3HB-GA))
n
OO
O
O
**
OO
Me
Me
O
O
**O
O
*
n
Ph
Me
MeH
H
H
OO
O
O
** O
O
O
OPh
Me n
* *+Ph
Me
homopolymerizationcopolymerization
PML2 PML1L-lactide MPDD
●マンデル酸ポリマー
マンデル酸は乳酸との直接重縮合による重合が困難であり、マンデル酸の環状二量体であるマンデライドの開環重合も進行しない。
そこで、L-マンデル酸と乳酸を構成単位とする環状ジエステルを合成し、開環重合およびL-ラクチドとの開環共重合を行い、目的とするpoly(mandelic acid-co-lactic acid) (PML)の合成を行った。
3‐methyl‐6‐phenyl‐1,4‐dioxane‐2,5‐dione (MPDD)
