Lecture 4:�
Biomaterials Surfaces: Chemistry�
Hydrolysis�Supporting notes�
3.051J/20.340J Materials for Biomedical Applications, Spring 2006
1
Hydrolysis�
• Hydrolysis is a kind of “Solvolysis”, solvent + lysis: cleavage by the solvent.
Br
H2O
3
OH
OCH3
OCOH
l
CH OH
HCOOH
2-Bromo-2-methy propane
+ HBr Hydoloysis
+ HBr Methanolysis
+ HBr Formic acidolysis
2
Polymer Hydrolysis�
•�Polymers prepared by polycondensation can be susceptible to hydrolysis.
n 1,4-Butanediol
+ HO
OH
O
O
n O
O
H
H
Succinic acid
O
O*
*
O
O
n 2O l Δ
H+ -,
+ nHAs, Zn cata ysts,
, OH or enzyme
Poly(butylene succinate), PBS 3
Hydrolysable is “degradable”.�Synthetic polymers�· Polyesters · Polyamides · Polyanhydrides · Polyethers · Polyurethanes · Polycarbonates · Polyureas
Material properties can be tuned readily. Cheaper!
Naturally-occurring polymers · Proteins and polyamides
Collagen Fibrinogen and fibrin Gelatin Casein
· Polysaccharides Cellulose Starch and amylose Chitin and chitosan Dextran
· Polynucleotides DNA and RNA
4
Biodegradation:�An event which takes place through the action of enzymes and/or chemical decomposition associated with living organisms (bacteria, fungi, etc.) or their secretion products.
Albertsson and Karlsson, in Chemistry and Technology of Biodegradable Polymers 1994
O R C
O
N R C
OH
O R O C
O
Polyester Polyamide Polycarbonate
C R O C
OO
N P
R
R'O
O
O
O
R"
R'R
O
Polyanhydride Polyphosphazene Poly(ortho ester)
Typical examples of synthetic biodegradable polymers 5
Key factors in hydrolysis�
1. Bond stability
Example: Hydrolysis of polyester C Oδ+ δ-
Base-catalyzed polyester hydrolysis
δ-
δ+
O
CR O R'
- O
C-R O R'
OH
O-
CR O R'
OH
H+ O
CR OH + R’
OH
OH
6
Acid-catalyzed polyester hydrolysis
δ-
H+
δ +
O
CR O R'
O+
CR O R'
H O
C+R O R'
H O
CR O+ R'
H
H
O
H
O
CR O R'
H
O+H
H
-H+H2O + R’OH
O
CR OH
Polyamide hydrolysis
H2O O
CR N R'
H
O
CR OH + H2N-R’
7
Key factors in hydrolysis�
2. Hydrophobicity
3. Molecular weight & architecture
4. Morphology Crystallinity, porosity
5. Tg Mobility of polymer chain
Chance to contact with H2O
8
0 80
90
� a (
degr
ees)
100
120
12 24 36 48 0 12 24 36 48
Amorphous PLLA Crystalline PLLA
108 110
Alkaline Treatment Time (h) Alkaline Treatment Time (h)
113
Orthorhombic crystal structure of α-PLLA�
Figures removed for copyright reasons.
6.1
28.8
ddcrystal: 1.290 g/cm3
amorphous: 1.248 g/cm3
10.5 Å 10
Hydrolysable polymers�Polyanhydride O
CR O C R'
O
O
CR O R'
O
CR N R'
H
H2O O
CR OH
O
CR OH
O
CR OH
+
Polyester H2O +
Polyamide H2O +
Polyether OR R' OHR
H2O +
Polyether urethane O
CO N R'
H
R
R N
H
C
O
N R'
H
R O C
O
O R'
H2O OHR +
O
CHO R'
HO R'
H2N R'
HO R'
O
CHO N R'
H
Polyurea H2O R N
H
C
O
OH
R O C
O
OH
+ H2N R'
Polycarbonate H2O + HO R' 11
Poly(sebacic anhydride)�Properties: rapid degradation, Tg: 50 °C, Tm : 80 °C Uses: drug delivery matrices
O
O O
Table. Half-lives of hydrolyzable polymers
Incorporation ofPolymer class Half-life hydrophobic segment
Polyanhydrides 0.1 h
PLLA 3.3 years
83,000 years Poly(bis-(p-carboxyphenoxy)propane-co-sebacic anhydride)
C
O
O C3H6 O O
O O
C8H16
O
O
Polyamides
Tabata et al., Pharm. Res., 10, 391, 1993 Göpferich, Biomater., 17, 103, 1996 12
Poly(glycolide-co-lactide) (polyglactide)
Properties: rapid degradation, amorphous*, Tg: 45-55 °C Uses: bioresorbable sutures, controlled release matrices,
tissue engineering scaffolds *Depending on composition
O
O
O
O
Glycolate Lactate (GA) (DL-LA)
Dexon®: the first synthetic bioresorbable suture in 1960s. (PGA)�Histological response can be predictable in comparison to non-
synthetic materials. High-crystalline nature limits processability.
13
Poly(L-lactide), poly(L-lactic acid) (PLLA) Properties: rapid degradation, semicrystalline, Tg: 60 °C, Tm: 180 °C Uses: fracture fixation, ligament augmentation
O
O
*
PLLA
O
H
HO
H
HO
H
OH
OHHH
OH
HO
O
O
H* O
O
*
Fermentation -H2O
microorganisms e.g. Lactobacilli L-lactic acid
O
O O
O
*
*
PLLAD-glucose from agricultural product; -H2Ocorn, potato, rice
L-lactide 14
Physical properties of various plastics�
PLLA PET PS PP�
Density/g/cm3 1.27 1.34 1.04 0.90
Tensile strength/MPa 66.7 55.9 43.1 37.3
Yong’s modulus/MPa 3300 2600 3300 2100
Elongation@break/% 4 300 2 700
Cost/$/lb 1-5 0.75 0.55 -
*Polymeric materials were non-oriented (as prepared).
Tsuji, Polylactic acid, JPS press, Kyoto, 1997, Ikada, Macromol. Rapid Commun., 21, 117, 2000 15
O
Polyethylene oxide (PEO) Properties: water soluble, semicrystalline, Tg: -60 °C, Tm: 60 °C Uses: hydrogel, protein-resistant coatings
Two photos removed for copyright reasons.
PEO Figure 6 in Irvine, D., et al. "Nanoscale Clustering of RGD Peptides at
Surfaces Using Comb Polymers. 1. Synthesis and Characterization of
Comb Thin Films." Biomacromolecules 2, no. 1 (2001): 85 -94.
Rate of hydrolysis:
anhydride > ester >> amide >>>> ether etc.
Matrices for drug delivery 16
Hydrolysis of polymeric materials�
Acid- or base-catalyzed hydrolysis
Time
MW
Enzymatic hydrolysis -surface erosion-
Time
MW
17
Hydrolysis of Bionole® (PBS)�O
O*
*
O
O
Photos removed for copyright reasons.
Alkaline treated Lipase PS treatedTaniguchi I., unp ub lished results
18
Application of biodegradable polymers and minimal requirements of biomaterials
PAA: PBS: PCA: PCL: PEA: PGA:
PGALA:
PDLLA:
PDLLA
PGALA PGA
PCA
POE PAA Starch
PLLA PHA (PHB)
PCL PEC
PBS PES
PEA
Chitin PPZ
Fibrin
Application of Biodegradable Polymers
Poly(acid anhydride) Poly(butylene succinate) Poly(�-cyanoacrylate) Poly(�-caprolactone) Poly(ester amide) Poly(glycolide), Poly(glycolic acid) Poly(glycolide-co-lactide), Poly(glycolic acid-co-lactic acid) Poly(DL-lactide), Poly(DL-lactic acid)
PHA: PHB:
PLLA:
POE: PEC: PES:
Poly(hydroxyalkanoate Poly(3-hydroxybutyrate) Poly(L-lactide), Poly(L-lactic acid) Poly(orthoester) Poly(ester carbonate) Poly(ethylene succinate)
Oxidized cellulose
CelluloseHyaluronate
Collagen
Medical Application Ecological Application
Minimal Requirements of Biomaterials
B) Effective Functionality, Performance, Durability, etc.
C) Sterilizable Ethylene oxide, Θ-Irradiation, Electron beams, Autoclave, Dry heating, etc.
D) Biocompatible Interfacially, Mechanically, and Biologically
A) Non-toxic (biosafe) Non-pyrogenic, Non-hemolytic, Chronically non-inflammative, Non-allergenic, Non-carcinogenic, Non-teratogenic, etc.
Figure by MIT OCW.
19 Figure by MIT OCW.
Control
With S. waywayandensis JCM 9114
With A. orientalis subsp. Orientalis IFO 12362
Microbial degradation of PLLA (rare case)�
Photos removed for copyright reasons.
O
O
*Hydrolysable polymer Esterases do not degrade except proteinase K.
PLLA�
Figure. SEM images of PLLA film treated with microbe Jarerat et al., Macromol. Biosci., 2, 420, 2002
20�
21
Enzymatic degradation -Lipase-
Brzozowski, et al., Nature 1991, 351, 491
Lipase: an esterase (EC3.1.1.3)
O
CR O R'
O
CR OH HO R'+H2O+lipase
In toluene at 90 °C
stable in organic solvents @ high temp.
MW of the polyester is usually low (< 10 k).Poor mechanical properties.
Two figures removed for copyright reasons.