Biomaterials

2018-09-26

Natural
Biopolymers

https://www.stockfeel.com.tw/%E7%94%9F%E7%89%A9%E9%86%AB%E7%94%A8
%E6%9D%90%E6%96%99/

http://www.tse.com.tw/ch/products/publication/download/0001001043.pdf

Chapter 3:Polymeric Biomaterials

結締組織組成
Collagen

Elastin

Proteoglycan

Mucopolysaccharides
 Collagen
the main structural protein in the extracellular space in the various connective
tissues in animal bodies
making up from 25% to 35% of the whole-body protein content
mostly found in fibrous tissues such as tendons (肌腱; 肌肉連接到骨骼),
ligaments (韌帶) and skin
Depending upon the degree of mineralization, collagen tissues may be rigid (bone),
compliant (tendon), or have a gradient from rigid to compliant (cartilage)
abundant in corneas, cartilage, bones, blood vessels, the gut, intervertebral discs,
and the dentin (齒質) in teeth
The five most common types of collagen are:
Type I: dermis, tendon, ligaments and bone
Type II: cartilage, vitreous body, nucleus pulposus
Type III: skin, vessel wall, reticular fibres of most tissues (lungs, liver, spleen …)
Type IV: forms the basal lamina, the epithelium-secreted layer of the basement
embranes
Type V: lung, cornea, hair and fetal membranes
• ~ 30% of residues are Glycine
• ~ 30 of residues are Proline or Hydroxyproline (HyPro)
• 5-hydroxylysine (HyLys) also occurs; a site for glycosylation
• Hydroxylation of Pro, Lys is a post-translational modification,
requires vitamin C as a reactant
• The sequence of collagen bears long stretches of
Gly--Pro/HyPro-X repeats（要考）

OH
HO NH2
OH
R
R 4 3
4 3
N
5
5 N 2 2
1 1 O O
O R R NH
R R
4-HyPro 3-HyPro 5-HyLys
https://www.youtube.com/watch?v=Q6Csv2QWdCE
The presence of hyp residues
greatly increases the potential for
H-bonding between chains.

Hyp and pro make up 25% of

the residues of collagen
Amino acid sequence of collagen
Structure:

Primary sequence :Gly-X-Pro(HyPro)

Monomer( alpha chain)=> left handed helix,3 a.a. per turn

Trimer:coiled-coil =>stabilized by H-bond

crosslink between triple helixes(disulfide bond)
Trimer:coiled-coil =>
stabilized by H-bond
crosslink between triple helixes(disulfide bond)
An electron micrograph of collagen from
skin
Some Hydroxy lysine residues are covalently bonded to
carbohydrates making collagen a glycoprotein
 Covalent Cross-Links
共價連接

這些反應再經過進一步的化學重排後，會形成穩定的
共價性鍵結，對collagen的穩定度有重要影響
Genetic disorders of
collagen are numerous :
One such group of 10
different collagen deficiency
diseases is the Ehlers-Danlos
(E-D) syndrome.

The “India-rubber man” of

circus fame had an E-D
syndrome.

Osteogenesis imperfecta :
abnormal (fragile) bone Paganini may also have suffered
formation in human babies from an E-D condition known as
Marfan’s syndrome.
 Defective Hydroxylation Is One Of The
Biochemical Lesions in Scurvy (壞血病)
The importance of the hydroxylation of collagen becomes evident
in scurvy. A vivid description of this disease was given by Jacques
Cartier in 1536, when it afflicted his men as they were exploring
the Saint Lawrence River:

Some did lose all their strength, and could not stand on their feet… Others also had
all their skins spotted with spots of blood of a purple colour: then did it ascend up to
their ankles, knees, thighs, shoulders, arms, and necks. Their mouths became
stinking, their gums so rotten, that all the flesh did fall off, even to the roots of the
teeth, which did also almost all fall out.
 Menke’s disesaes

X染色體上的基因變異使得銅的代謝異常
結果:這個疾病常發生在男性嬰兒身上

因lysyl oxidase需要銅作為輔助因子，當缺乏銅時，會影響到lysyl oxidase的活性，令

collagen的連結受到影響。
症狀：毛髮捲曲 生長停滯

Osteogenesis imperfecta

俗名：玻璃娃娃、成骨不全症
症狀：骨骼不夠堅硬、發育不全
病因：遺傳疾病造成collagen不足或不全
 膠原蛋白三股螺旋結構內鍵結方式

Direct chemical bonds

Hydrogen bonds

Water-bridged crosslinks
Direct Chemical Bonds

Direct Chemical Bonds

Hydrogen Bonds
Water-Bridged Crosslinks
 異種組織材料必須經過

物理修飾

化學修飾

其內的膠原蛋白之後才可用於人體內
 Irradiation
將collagen分子內的peptide bonds 打斷形成free radicals

Free radicals 再重新形成鍵結

 物理修飾法的優點

Do not introduce toxic chemicals

May get sterilized simultaneously

 物理修飾法的缺點

May get denatured

Cannot resist degradation

Limited penetration depth

 化學修飾法
利用膠原蛋白分子上的自由官能基產生化學鍵結交聯
(cross-link)

-NH2: lysine, hydroxylysine, arginine,

histidine

-COOH: aspartic acid, glutamic acid

-OH: tyrosine, serine, threonine

Lysine、Hydroxylysine、Arginine及
Histidine的分子結構式示意圖
Aspartic Acid、Glutamic Acid的
分子結構式示意圖
Tyrosine 、Serine、Threonine的 分子結構式示意圖
 交聯劑cross-linker
Formaldehyde

Glutaraldehyde

Epoxy compounds

Hexamethylene diisocyanate (HMDI)

Acyl azide

Carbodiimides

Genipin

Reuterin
 影響交聯鍵結的因素
交聯劑濃度

反應時間

反應溫度

反應溶劑

pH值

https://www.youtube.com/watch?v=M8LbP593pKo
 Formaldehyde 化學修飾法
1960s年代開始使用
缺點：unstable, reversible, 毒性高
Formaldehyde Crosslinking Mechanism

Biomaterials 18 (1997) 95-105

甲醛與生物組織上自由胺基的反應
 Glutaraldehyde化學修飾法
1960s年代開始使用
目前臨床使用最多的化學交聯劑
反應通常在pH 7.4下
缺點：reversible、毒性高、組
織硬化、纖維化

Glutaraldehyde Crosslinking Mechanism

 Epoxy Compounds化學修飾法
1980s年代開始使用
反應通常在pH 9下
毒性較glutaraldehyde稍低
缺點：交聯程度不夠、毒性仍高
Monofunctional Epoxy Compounds
Bifunctional Epoxy Compounds
環氧化物在酸性環境下和自由胺基的反應機制
環氧化物在鹼性環境下和自由胺基的反應機制
Epoxy與-OH group的反應機制
Epoxy與-OH group的反應機制
 Chemical Structures of
Geniposide and Genipin
 梔子的花及果實

http://www.acelity.com/products/fibracol-plus

https://www.youtube.com/watch?v=W0NA1qgc8EI
 050024510001.jpg

050024510002.jpg

gelatin

翰強-可吸收膠原蛋白膜.pdf

https://www.shopwoundcare.com/p-Smith-Nephew-Biostep-Ag-Collagen-
Matrix-Dressing-with-Silver.html
What is chitin?
Chitin is a natural polysaccharide

Shellfish Sources Estimates of Potential Chitin Sources

A cicada emerges from its chitinous larval exoskeleton

Unique characteristics of chitin and chitosan:
 Biocompatible
 Biodegradable
 Non-toxic
 Remarkable affinity to proteins
 Ability to be functionalized
 Renewable
 Abundant
Structure similar to cellulose with hydroxyl group replaced by acetamido group
N-acetyl-glucosamine units in β-(1→4) linkage
N-glucosamine units in β-(1→4) linkage
N-deacetylation of chitin into chitosan is achieved by treating with 50% NaOH

Chitosan is the N-deacetylated derivative

of chitin
Chitin and Chitosan
 Isolation of Chitin from Shellfish and Fungi

Dimethylacetamide

Kohr E. Chitin: fulfilling a biomaterials promise. Elsevier Science, 2001

 Biomedical Applications

Wound Dressing
 Wound dressings are used to protect wound skin
form insult, contamination and infection
 Chitin-based wound dressings
- Increase dermal regeneration
- Accelerate wound healing
- Prevent bacteria infiltration
- Avoid water loss
 Chitin surgical threads - strong, flexible,
decompose after the heals
Chitosan wound dressings
Anticoagulation

Anticoagulation is essential for open-heart

surgery and kidney dialysis
Preventing blood from clotting during the
surgery
Sulfated chitin derivatives have good
anticoagulant activity
What is Alginate? 藻酸、褐藻酸、海藻素

Alginate is a natural polysaccharide that comprises from 30 to

60% of brown algae(on dry weight basis).

Alginic acid usually accumulates in seaweeds as "jelly bodies" after

combining with minerals from seawater

https://zh.wikipedia.org/wiki/%E6%B5%B7%E8%97%BB%E9%8
5%B8#.E5.8C.BB.E8.8D.AF
 Chemical Structure

Alginic acid, a polysaccharide is composed of two types of Uronic acid:

Mannuronic acid unit (M) and Guluronic acid unit (G), which from three kinds of
polymer segments of blocks:

https://www.youtube.com/watch?v=FjjYHwwT73k
M blocks : comprised only of M-M bonding

G blocks : comprised only of G-G bonding,

 M&G random blocks : comprised of M-G random bonding,

Differences in M/G ratio and block configuration account for the

differences in alginate properties and functionality, especially in gelling
capability and gel strength

The M/G ratio is dependent upon such factors as the species of seaweed, the
part of the seaweed used, the harvest location, and the harvest season.
 Manufacturing Process

https://wenku.baidu.com/view/d0592b37ee06eff9aef8079a.html
 Applications with Alginates
Food
ice cream, jelly, lactic drinks, dressings, instant noodle, beer, et
cetera .Safety of alginate for food applications is certified by FAO/WHO, as
one of the safest food additives

Pharmaceutical
Alginate acid is used in pharmaceutical area with several applications. Alginic
acid is compounded into tablets to accelerate disintegration of tablet for faster
release of medicinal component. Alginate forms gel in the high-acidic stomach
and protect stomach mucosa.
http://www.anhsp.com.tw/LiAn/medinine/BuyChange/drugbuychangefile
/change_990804_Alginos.pdf
Cosmetics
Alginate is used in cosmetics area with several applications with its functionality
of thickener and moisture retainer. Alginate helps retaining the color of lipstick
on lip surface by forming gel-network.
https://www.google.com/patents/CN106580828A?cl=en&hl=zh-TW
 Manufacturing Alginic Acid

https://wenku.baidu.com/view/d0592b37ee06eff9aef8079a.html

https://www.artmolds.com/alginate-medical-clinical
 HYALURONIC ACID 透明質酸，又稱醣醛酸、玻尿酸

http://l5047.pixnet.net/blog/post/101513287-
nasha%E7%B4%9A%E7%8E%BB%E5%B0%BF%E9%85%B8
http://highscope.ch.ntu.edu.tw/wordpress/?p=8643
 STRUCTURE
-it consists of repeating disacharides units
D-N-acetylglucosamine
b-D-glucuronic acid
-the units are joined with repeating beta-1,4 and
beta-1,3 glycosidic bonds
Haworth projection of hyaluronan
 OCCURENCE AND PHYSIOLOGICAL
IMPORTANCE

-in the skin (about 50 % of the total hyaluronan in the

body)
-the vitreous humour of the eye
-in the synovial fluid (3-4 mg/ml)
-in the matrix around the oocyt during ovulation
(~0,5 mg/ml)
-in some situations rapid increase
(shock incidents, wound healing, septicaemia)
 USE
- in the late fifties hyaluronan was applied
for the first time to humans - as vitreous
humour replacement during eye surgery
- for healthy and fresh skin
- to improve the effectiveness of

local anaesthesia
- to prevent tissue destruction
- hyaluronates are widely used in
many branches of medicine like
orthopaedia, surgery,
ophthalmology, oncology,
dermatology, gynaecology
- in plastic surgery – for bigger an better lips

before after
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967437/

https://www.youtube.com/watch?v=l0sKstpunO4

https://smallcollation.blogspot.tw/2013/05/synovial-joint.html#gsc.tab=0