*Department of Environmental Systems Science,Doshisha University,Kyoto
Telephone:+81-774-65-6878,*E-mail:dmi0302@mail4.doshisha.ac.jp, *** E-mail:htsujimobb@yahoo.co.jp
****E-mail:ahariwar@mail.doshisha.ac.jp
** Department of Surgical Endoscopy Institute for Juntendo Urayasu Hospital, University of Juntendo Telephone:+81-3-3813-3111, E-mail:yoshinorihirasaki84@gmail.com
Development of Novel Infectious Agent Free-Locally Administered Hemostatic Material Made from Chitosan
Ayumi HASHIMOTO* and Yoshinori HIRASAKI** and Hiroyuki TSUJIMOTO*** and Akeo HAGIWARA****
(Received May 9, 2009)
Hemostatic materials made from collagen of animal origin or from blood components of human being have been commonly administered locally in the bleeding sites during surgery at the present day. These collagen and blood components are principal proteins consisting the body-tissues and they are biocompatible. It is clinically, however, a serious problem that the above-mentioned materials may contain the infectious agents, such as virus and prion which can infect to human. To reduce the risks of the infectious agents, we have developed “chitosan sponge”, a novel hemostatic material from chitosan, which has much lower risks of the infectious agents because chitosan is originated not from animals and human but from crabs. Chitosan sponge was made with a freeze-drying method, and was evaluated in two kinds of basic properties as a hemostatic material in comparison with fibrin glue, one of the clinically most common hemostatic materials. The first property of tissue-adhesive effect was evaluated with shear stress, and the second property of hemostatic performance was compared using a model of bleeding from the kidney in rats. These two properties were almost equal between the two materials. These results suggest that chitosan sponge can be developed as a novel and “infectious agents-free” hemostatic material with a comparable hemostatic effect to fibirin glue.
-G[YQTFU: Infectious agent-free, hemostatic material, chitosan
ࠠࡢ࠼㧦㕖ᗵᨴᕈᱛⴊ᧚ᢱࠠ࠻ࠨࡦ
ࠠ࠻ࠨࡦࠍਥᚑಽߣߔࠆ㕖ᗵᨴᕈߩᣂⷙዪᚲᱛⴊ᧚ᢱߩ㐿⊒
ᯅᧄ ᱠ, ᐔፒ ᙗ▸, ㄞᧄ ᵗⴕ, ⪤ේ ㇢
ߪߓߦ
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ࠦࠥࡦࠍ↪ߚᱛⴊ᧚ߪޔࠦࠥࡦ⥄ߦ ᱛⴊലᨐ߇ࠆߣ߁ὐ߇ࠆޕ৻ᣇԙߪࡅ࠻
ⴊᶧಝ࿕࿃ሶࠍਥᚑಽߣߔࠆߚޔᱛⴊലᨐ߇㜞
ߎߣޔ߹ߚ↪ᓟߦ⥄Ꮖ⚵❱ߣห᭽ߦ↢ߦ ๆߐࠇޔᶖᄬߔࠆߥߤߩఝࠇߚᕈ⢻ࠍᜬߟޕߒ ߆ߒޔਔ⠪ߣ߽േ‛↱᧪ߢࠆߎߣߦ࿃ߔࠆ࠙
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Table. 1. Shear strength, Beriplast vs Chitosan sponge
Beriplast group
Chitosan sponge group
1 6.19 5.67 2 4.34 5.18 3 3.79 5.15 4 5.92 6.24 5 8.68 5.15 6 5.90 7 6.13 mean 5.85 5.48 SD 1.57 0.48
Unit:N
0 1 2 3 4 5 6 7 8
shear stress(N±SD)
Beriplast group Chitosan sponge group
Fig. 3. Shear strength of Beriplast group or chitosan spongegroup
Data were expressed as mean and standard deviation(SD), Chitosan sponge: n=7, Beriplast P(conventional product): n=5
ᱛⴊലᨐߩᬌ⸛
ࠠ࠻ࠨࡦࠬࡐࡦࠫ⟲ߩⴊ㊂ߪ rI 㧔OGCPr5&㧕ߢޔࠦࡦ࠻ࡠ࡞⟲ߩߘࠇߣᲧセߒ ߡ rIOGCPr5&㧕ߣᗧ㧔2㧕 Experimental
number
Experimental groups
ߦዋߥ߆ߞߚ㧔6CDNG㧕(KIޕ Table. 2. Hemorrhage volume
Experimental groups
Ccontrol Beriplast Chitosan sponge group group group 1 0.12 0.23 0.01 2 0.04 <0.01 <0.01 3 0.68 0.02 0.08 4 0.30 0.06 0.01 5 0.48 <0.01 <0.01 6 0.26 0.36 0.14 7 0.21 <0.01 0.09 8 0.01 mean 0.30 0.10 0.05 SD 0.22 0.14 0.05 Unit: g These data were evaluated by the use of rat bleeding from kidney model.
0 0.1 0.2 0.3 0.4 0.5 0.6
hemorrhage volume(g㫧SD)
control*
Beriplast group***
Chitosan sponge group**
p<0.01 p=0.066
p=0.316
Fig. 5. Hemorrhage volume
Control group*: Control group composed of rat treated with no hemostatic materials., Beriplast group**: Beriplast group composed of rat treated with hemostatic materials as BeriplastR, Chitosan sponge group***: Chitosan sponge group composed of rat treated with hemostatic materials as Chitosan sponge, Data were expressed as mean and standard
deviation(SD), control: n=7, Beriplast: n=7, Chitosan sponge: n=8
⠨ኤߣ⚿⺰
ዪᚲᱛⴊ᧚ᢱߦ᳞ࠄࠇࠆ㊀ⷐߥᕈ⾰ߣߒߡޔ
⚵❱ធ⌕ᕈ߇ߍࠄࠇࠆ 㧕ޕᧄ⎇ⓥߢߪޔᓥ᧪⥃
ᐥߢᦨ߽ᐢߊ↪ࠄࠇߡࠆዪᚲᱛⴊ᧚ᢱߩ ߟ ߢޔࡅ࠻ⴊᶧ↱᧪ߢࠆࡈࠖࡉࡦࠣ࡞㧔ࡌ
ࡊࠬ࠻4㧕ߣߩኻᲧߦ߅ߡޔࠠ࠻ࠨࡦࠍਥᚑ ಽߣߔࠆᣂⷙᱛⴊ᧚ᢱߩߖࠎᢿᔕജࠍ᷹ቯߔࠆߎ ߣߦࠃࠅ⚵❱ធ⌕ᕈࠍᲧセߒߚޕߘߩ⚿ᨐޔࠠ࠻
ࠨࡦࠬࡐࡦࠫ⟲ߩߖࠎᢿᔕജߪᓥ᧪ຠߢࠆࡌ
ࡊࠬ࠻⟲ߩߘࠇߣ߶߷ห╬ߢࠅޔ߶߷ห╬ߩ
⚵❱ធ⌕ᕈ⢻ࠍ␜ߒߚ(KIޕ
ᱛⴊലᨐߦߟߡߪޔ࠶࠻ߩ⣢⤳ߦᵈ㊎ߢ
⓫ሹߐߖߡⴊߐߖࠆࡕ࠺࡞㧔(KI㧕ࠍ↪ߡޔ ᱛⴊലᨐࠍᬌ⸛ߒߚ6CDNG(KIޕᱛⴊ࿎㔍 ߥⴊߪᄢߒߡᄥⴊ▤ოࠍ⋥ធ៊்ߒߚߚ
ߦⴊߔࠆⴊ▤ო߆ࠄߩⴊߣޔ⣢⤳⢄⤳⣛
⤳ߥߤߩታ⾰⤳ེࠍ៊்ߒߡⴊߔࠆታ⾰⤳ེ
ⴊ߇ࠆޕ೨⠪ߪ⚿⚤߿❔วߦࠃࠆᱛⴊಣℂ߇ᣉ ߐࠇࠆ႐ว߇ᄙߊޔዪᚲᱛⴊ᧚ᢱ߇↪ߐࠇࠆߩ ߪޔᓟ⠪ߢࠆޕ⪺⠪ࠄߪታ⾰⤳ེⴊߦኻߔࠆ ᱛⴊᠲߦ߅ߡ↪ߐࠇࠆዪᚲᱛⴊ᧚ᢱߩ㐿⊒
ࠍᔨ㗡ߦ⟎߈ޔ⣢⤳ࠍ⓫ೝߔࠆߎߣߦࠃࠆⴊࡕ
࠺࡞ࠍߒޔߎࠇߦኻߔࠆᱛⴊലᨐࠍᲧセᬌ
⸛ߒߚޕߘߩ⚿ᨐޔࠠ࠻ࠨࡦࠍਥᚑಽߣߔࠆᣂⷙ ᱛⴊ᧚ᢱ↪⟲ߩⴊ㊂ߪޔᱛⴊᠲࠍᣉߐߥ
ήಣ⟎⟲ߣᲧセߒߡᗧ㧔R㧕ߦዋߥ߆ߞߚ (KIޕ߹ߚޔᧄታ㛎ߢߪޔᗧᏅߪࠄࠇߥ ߆ߞߚ߇ޔᓥ᧪ຠߢࠆࡌࡊࠬ࠻⟲ߩᐔဋ
ⴊ㊂ߣᲧセߒߡࠠ࠻ࠨࡦࠬࡐࡦࠫ⟲ߩᐔဋ㊂ߪඨ ಽߢߞߚޕߎߩߪޔࠠ࠻ࠨࡦࠬࡐࡦࠫߩᱛⴊ ലᨐߪዋߥߊߣ߽ᓥ᧪ຠߩࡌࡊࠬ࠻ߣห╬߹
ߚߪߘࠇએߢࠆࠍ␜ߒߡࠆߣ⠨߃ࠄࠇࠆޕ ᧄⴊࡕ࠺࡞ߪޔήಣ⟎⟲ߦ߅ߡ߽ 5& ߇ OGCP ߩ એߣᄢ߈߆ߞߚޕߎߩታߪᧄⴊࡕ࠺
࡞ߢߪⴊ㊂ߩ߫ࠄߟ߈߇ᄢ߈ߊޔᱛⴊലᨐߩ⛔
⸘⊛ᗧᏅߩᬌቯ߇࿎㔍ߢࠆߎߣࠍᗧߒߡ
ࠆޕᓟ߫ࠄߟ߈ߩዋߥⴊࡕ࠺࡞ࠍߒޔ ࡌࡊࠬ࠻ߣࠠ࠻ࠨࡦࠬࡐࡦࠫߩᱛⴊലᨐߦ
ᗧᏅ߇ࠆ߆ุ߆ࠍౣᬌ⸛ߔࠆᔅⷐ߇ࠆߣ⠨߃ ࠄࠇࠆޕ
ᣂⷙߩዪᚲᱛⴊ᧚ᢱߣߒߡߪޔวᚑ᧚ᢱࠍේ᧚ ᢱߣߒߚᄖ⑼↪ធ⌕᧚ᱛⴊ᧚ߣߒߡࠪࠕࡁࠕࠢ
Number of rat
࠻㧔ࠕࡠࡦࠕ࡞ࡈࠔ #4ߥߤ㧕߇ታ↪ൻߦ⥋
ߞߡࠆ߇ޔಽ⸃ㆊ⒟ߢኂ‛⾰ࠍ↥↢ߒ ዪ ᚲ⊛↪߇ᒝߣ߁⍴ᚲߦട߃ߡޔ᧚ᢱߩ⎬
ߐ߆ࠄ↢ㆡวᕈߦഠࠆߥߤߩ㗴ὐ߇ᜰ៰ߐࠇ ߡࠆޕ࠴ࡦ᧚㧔ࠬࡐࡦ࡞ 4ߥߤ㧕߽ታ
↪ൻߦ⥋ߞߡࠆ߇ޔ࠴ࡦ⥄ߦߪ࿕ߩᱛ ⴊലᨐߪߥߊޔ߹ߚ⚵❱߳ߩធ⌕ജ߇ᒙߚኈ ᤃߦߪ߇ࠇ߿ߔߥߤߩ㗴ὐ߇ࠅޔᱛⴊലᨐ ߇ૐߩߢ⥃ᐥ⊛ߦ↪ߔࠆ㗫ᐲ߇ዊߣߥߞߡ߈ ߡࠆޕߎߩ᭽ߥ⍴ᚲߦኻߒߡޔ࠴ࡦߩធ⌕
ജࠍߍࠆߚߦޔ࠴ࡦߦൻቇ⊛ߥಣℂࠍട ߃ߡᔕߐߖࠆຠ߽ታ↪ൻߐࠇߡࠆ߇㧔)4(
ࠣ࡞4ߥߤ㧕ޔߎࠇߦߟߡ߽᨞ᯅߦࠃࠆ
↪߇㗴ߣߥߞߡࠆޕએߩ᭽ߦޔᗵᨴᕈ
࿃ሶߩ㗴ὐࠍసߔࠆߴߊ㐿⊒ߐࠇߡ߈ߚᣂⷙ ߩዪᚲᱛⴊ᧚ᢱߪޔዪᚲ߳ߩ↪╬ߩ㗴ὐ߇ ᄙߊޔ⥃ᐥ⊛ߦᐢߊ↪ߐࠇࠆߦߪ⥋ߞߡߥޕ
ᧄ⎇ⓥߢ⌕⋡ߒߚࠠ࠻ࠨࡦߪޔಽሶౝߦࠕࡒࡁ ၮࠍߒߡ߅ࠅޔᱜߦᏪ㔚ߒߡࠆߚ⽶ߦᏪ㔚 ߒߚⴊዊ᧼ߩ⚦⢩⤑ࠍᒁ߈ነߖޔⴊዊ᧼ಝ㓸↪
ࠍଦㅴߔࠆߎߣߢᱛⴊലᨐࠍ⊒ើߔࠆߣ߁㐳ᚲ ߇ࠆ৻ᣇޔᱜߦᏪ㔚ߒߡࠆߎߣߢἻ∝ᔕࠍ
ߎߒ߿ߔߣ߁㗴ὐ߽ᜰ៰ߐࠇࠆޕߒ߆ߒޔ
ࠠ࠻ࠨࡦߪᣢߦઁߩ⋡⊛ߢ⥃ᐥ↪߇⸵นߐࠇߡ ߅ࠅޔߦዪᚲ⊛↪߇⊒ߒߚߣߒߡ߽⥃ᐥ
⊛ߦ⸵ኈ▸࿐ౝߣ⠨߃ࠄࠇࠆߩߢޔ⸥ߩᣂⷙ
᧚ߦ߅ߌࠆዪᚲ⊛↪ߩࠃ߁ߦቯ⊛⍴ᚲߦߥ ࠆน⢻ᕈߪૐߣ⠨߃ࠄࠇࠆޕ
࿁ߩᬌ⸛ߢޔࠠ࠻ࠨࡦࠬࡐࡦࠫߩ⚵❱ធ⌕ᕈ ߣᱛⴊലᨐߪᓥ᧪߆ࠄᦨ߽⥃ᐥ⊛ߦ㗫↪ߐࠇߡ
ࠆࡈࠖࡉࡦࠣ࡞ߣዋߥߊߣ߽ห╬ࠆߪߘ ࠇએߢࠆߣ⠨߃ࠄࠇࠆߩߢޔᓟߪ⥃ᐥᔕ↪
ߦะߌߡޔᧄᱛⴊ᧚ᢱߩᦝߥࠆᡷༀࠍ⹜ߺߡ߈ ߚߣ⠨߃ࠆޕ
੩ㇺᄢቇౣ↢ක⑼ቇ⎇ⓥᚲߩਛ㆐㓶ಎᢎ߅ ࠃ߮ᚲዻߐࠇࠆవ↢ᣇߦߪޔ⹜ᢱណข⹜ᢱ᷹ቯ
╬ߦ߅ߡߏදജޔߏᜰዉࠍߚߛߚޕ߹ߚޔ ߖࠎᢿᔕജ᷹ቯߪ੩ㇺᄢቇౣ↢ක⑼ቇ⎇ⓥᚲߦߡ ⴕߞߚޕߎߎߦ⸥ߒߡ⻢ᗧࠍߔࠆޕ
ෳ⠨ᢥ₂
ደ㇌༑̌⣄ᬁᚻⴚߦ߅ߌࠆዪᚲᱛⴊ᧚㧔ᓸ❫⛽
ᕈࠦࠥࡦ㧦ࠕࡆ࠹ࡦ㧔4㧕㧕ߩᣂߒ↪ᴺ̌
2JCTOC/GFKEC
⮮⋥᮸ౝ㊁⚐৻᧻ਅㅢ̌ᣂߒක≮᧚ ᢱ↪ౕ ᱛⴊ᧚ᢱធ⌕̍ᄖ⑼⸻≮ ․㓸
ᚻⴚቶ᧚ᢱ↪ౕࡑ࠾ࡘࠕ࡞ ภ
ᳰ↰ᵏᴦ᧖↸ผጟผ㇢ንᎹ⋓㓷Ⴆᧄୃ
৻ᎹፒൎᏆጊผᤚ᳗ᄢテ┻ਛ⾫ᴦ
̌⢄ಾ㔌㕙ߩⴊ㒐ᱛߦኻߔࠆᶧ⁁ࡈࠖࡉࡦ♟
ߣࡐࠣࠦ࡞㉄ࡈࠚ࡞࠻૬↪ߩ↪ᕈߦ 㑐ߔࠆၮ␆⊛⎇ⓥ̍⥃ᐥߣ⎇ⓥ
ᧄᵏ̌ࡈࠖࡉࡦធ⌕ߩዉߣㅴᱠ̍
5WTIGT[(TQPVKGT
㋈ᧁᱜᓼᶏ㊁୶ ነ┻ౝඦዊ㊁Ꮉ ᔀᄢႦ⧷㇢Ꮉ᧻㊁ᱜ♿̌⚵❱ធ⌕
㐽㎮ߩ⒳㘃ߣ․ᓽ̍5WTIGT[(TQPVKGT
ጟ↰⟵ᤘᅏጊၷม᳓ᴛᏀⴡሶፉሶ⒳
Ꮢ㤗ሶᢪ⾐⩵ᳯዊቶൎ̌ࡈࠖࡉࡦធ
⌕ߩᓎഀߣోᕈ̍5WTIGT[(TQPVKGT
Masato Araki, Hiroyuki Tao, Naoki Nakajima, Hajime Sugai, Toshihiko Sato, Suong-Hyu Hyon, Takeshi Nagayasu and Tatsuo Nakamura, “Development of new biodegradable hydrogel glue for preventing alveolar air leakage”, evolving Technology, The Journal of Thoracic and Cardiovascular Surgery Volume 134, Number 5, 1241-1248 (2007)
⟵ᒾ̌᨞ᯅᕈߩ↢㜞ಽሶ߿⥄Ꮖ⚵❱ൻ
߇ᒻᚑߔࠆᣂⷙࡃࠗࠝࡑ࠹ࠕ࡞ߩක≮ᔕ↪̍
㜞 ಽ ሶ ⺰ ᢥ 㓸 㧔 -QDWPUJK 4QPDWPUJW 㧕
Ronit Bitton, Havazelet Bianco-Peled, “Novel Biomimetic Adhesive Based on Algae Glue”, Macromolecular Bioscience, 393-400 (2008)
Natalie Artzi, Tarek Shazly, Cristina Crespo, Adriana Bon Ramos, H. Keith Chenault, Elazer R. Edelman,
“Characterization of Star Adhesive Sealants Based On PEG/Dextran Hydrogels”, Macromolecular Bioscience, 1-12 (2009)
ㇹ৻⍮ਭ⦟ᒾ╣᎑໑ඳ̌ᄖ⑼ᴦ≮ធ⌕
ߩ ㅴ ᱠ ⁁ &GXGNQROGPV CPF RTCEVKEG QH UWTIKECNINWG̍⛱ว⥃ᐥ ⸻ᢿߩᜰ㊎ᴦ≮ߩᜰ
㊎
Singh RP, Maheshwari V, Verma AK , “Evaluation of gelatin/resorcinol/aldehyde as a hemostatic agent and tissue adhesive: an experimental study in rat.”, Int Surg, 93(1):25-31 (2008)