Energy and Power Engineering, 2010, 31-38
doi:10.4236/epe.2010.21006 Published Online February 2010 (http://www.scirp.org/journal/epe)
Amphiphilic Poly (3-Hydroxy Alkanoate)s:
Potential Candidates for Medical Applications
Baki HAZER
Department of C hemis t ry , Zonguldak Karaelmas University, Zonguldak, Turkey
Abstract: Poly (3-hydroxy alkanoate)s, PHAs, have been very attractive as biomaterials due to their
biodegradability and biocompatibility. These hydrophobic natural polyesters, PHAs, need to have hydrophilic
character particularly for drug delivery systems. In this manner, poly (ethylene glycol) (PEG) and hydrophilic
functional groups such as amine, hydroxyl, carboxyl and sulfonic acid have been introduced into the PHAs in
order to obtain amphiphilic polymers. This review involves in the synthesis and characterization of the
amphiphilic PHAs.
Keywords: poly (3-hydroxy alkanoate), PHA, amphiphilic polymer, biomaterial, chemical modification
1. Introduction
Biomaterials have been widely used in medical appli-
cations, such as drug delivery, tissue engineering, device-
based therapies and medical imaging [1,2]. Synthetic and
naturally occurring polymers have played important role
in the treatment of disease and the improvement of health
care. Among them, PHAs are promising materials for
biomedical applications in tissue engineering and drug
delivery system because they are natural, renewable,
biodegradable and biocompatible thermoplastics. PHAs
have been used to develop devices, including sutures,
nerve repair devices, repair patches, slings, cardiovas-
cular patches, orthopedic pins, adhesion barriers stents,
guided tissue repair/regeneration devices, articular carti-
lage repair devices, nerve guides, tendon repair devices,
bone-marrow scaffolds, tissue engineered cardiovascular
devices and wound dressing. However the direct use
these polyesters has been hampered by their hydrophobic
character and some physical shortcomings [3]. The key
to biocompatibility of biomedical implanttable materials
is to render their surface in a way that minimizes hydro-
phobic interaction with the surrounding tissue. Therefore,
hydrophilic groups have been introduced into the PHAs
in order to obtain amphiphilic polymer. This review has
been focused on the chemically modified PHAs en-
hanced hydrophilic character as biomaterials for medical
applications.
2. PHAs
PHAs are accumulated as intracellular granules as a
result of a metabolic stress upon imbalanced growth due
to a limited supply of an essential nutrient and the
presence of an excess of a carbon source. These novel
biopolymers have material properties ranging from rigid
and highly crystalline to flexible, rather amorphous and
elastomeric. There have been many studies reported on
the modification reactions to enhance mechanical and
thermal properties to prepare new biomaterials for the
medical applications [4–13]. PHAs can be classified into
three groups based on the number of carbon atoms in the
monomer units: short-chain-length (sclPHA) containing
3–5 carbon atoms that are produced by Ralstonia eutro-
pha (also referred Watersia eutropha, A. Eutrophus),
medium-chain-length (mclPHA) containing 6-14 carbon
atoms, and long-chain-length (lclPHAs), with more than
14 carbon atoms [14,15]. Pseudomonas oleovorans is a
very versatile for PHA production because it can produce
medium chain length polyesters (mclPHA) and long
chain length polyesters (lclPHA) from a wide variety of
carbon substrates. These types of the bacterial polyesters
have been summarized in Table 1.
3. Amphiphilic PHAs
Amphiphilic polymers can be synthesized by introducing
hydrophilic groups such as hydroxyl, carboxyl, amine,
glycol and hydrophilic polymers such as PEG, poly
(vinyl alcohol), polyacryl amide, poly acrylic acids,
hydroxy ethyl methacrylate, poly vinyl pyridine and poly
vinyl pyrrolidone to a hydrophobic moiety. Because of
their ability to form micelles, amphiphilic block
copolymers are strong candidates for potential applica-
tions as emulsifiers, dispersants, foamers, thickeners,
rinse aids, and compatibilizers [16,17]. Similarly, amp-
hiphilic PHAs can also be synthesized by introducing
hydrophilic groups such as hydroxyl, carboxyl, amine,

B. HAZER
32
Table 1. Classification of the bacterial polyesters
Poly (3-hydroxy alkanoate) (PHA) Thermal and Mechanical Properties
Carbon Source
Type Side chain (R) Name* Tg (°C) Tm (°C) Elongation (%)
Sugar, glucose, acetic
acid
Short chain
length Methyl, ethyl PHB PHV 15 170 5
Alkanoic acids, alkanes
and alkanols
Medium chain
length
Propyl, butyl, pentyl,
hexyl, heptyl
PHHx
PHHp
PHO
PHN
PHD
-40 60 800
Plant oily acids Long chain
length
More than 14 Carbon per
repeating unit -50 40 Soft, sticky
*B: butyrate, V: valerate, Hx: hexanoate, Hp: heptenoate, O: octanoate, N: nonanoate, D: decanoate. Tg and Tm are glass and melting temperatures,
respectively.
sulfonic acid, ethylene glycol and PEG. PEG is a poly-
ether that is known for its exceptional blood and tissue
compatibility. It is used extensively as biomaterial in a
variety of drug delivery vehicles and is also under invest-
tigation as surface coating for biomedical implants. PEG,
when dissolved in water, has a low interfacial free energy
and exhibits rapid chain motion, and its large excluded
volume leads to steric repulsion of approaching mole-
cules [18]. These properties make PEG excellent bio-
compatible material. Hydroxylation of the PHAs can be
carried out by using both biosynthetically and chemical
modification. The biosynthetic hydroxylation of the
PHAs has successfully been reviewed by Foster, re-
cently [19].
Chemical modifications of the PHAs have been
extensively studied [6,9,15,20,21]. In this review,
selective chemical modification reactions in order to
obtain amphiphilic PHAs and some potential applica-
tions in biotechnology will be discussed.
4. Synthesis of Amphiphilic PHAs
Selective chemical modification of the PHAs involves
functionalization and grafting reactions of the PHAs.
Hydrophilic groups such as hydroxyl, carboxyl, amine,
glycol and sulfonic acid can be introduced into the PHAs
by means of functionalization. In grafting reactions,
some hydrophilic groups have been attached in the PHA
chain to obtain amphiphilic polymer.
4.1 Trans Esterification
Some ester group(s) of the PHA is exchanged with an
alcohol in transesterification process. Transesterification
is carried out in melt or in solution. Hydroxylation of
the PHBs via chemical modification is usually achieved
by the transesterification reactions to obtain diol ended
PHB. Transesterification reactions in the melt between
poly (ethylene glycol), mPEG, and PHB yield diblock
amphiphilic copolymer with a dramatic decrease in
molecular weight [22]. Catalyzed transesterification in
the melt is used to produce diblock copolymers of poly
([R]-3-hydroxybutyric acid), PHB, and monomethoxy
poly (ethylene glycol), mPEG, in the presence of a
catalyst, in a one-step process. The formation of di-
blocks is accomplished by the nucleophilic attack from
the hydroxyl end-group of the mPEG catalyzed by bis
(2-ethylhexanoate) tin.
When the transesterification reaction between PHB
and ethylene glycol in diglyme as a solvent is carried out,
the telechelic PHB with MW at around 2000 Dalton is
obtained [23]. Stannous octanoate as a transesterification
catalyst causes the reaction of carboxylic end group and
diol, quantitatively. Basically, short chain diol or polyol
moiety can rarely renders a hydrophilic character to the
longer hydrophobic PHA. Therefore amphiphilic charac-
ter of the telechelic PHAs and PEGylated PHAs have
been stood poor.
Telecehelic PHB obtained by this way can be used in
the preparation of the polyester urethanes via diisocy-
anate chain extension reaction with synthetic aliphatic
polyester as soft segment [24]. PHB-g-PCL graft copoly-
ester urethane samples exhibited the elongation at break
up to 900 %.
Two segmented biodegradable poly (ester-urethane)
series, based on bacterial PHB as the hard segments, and
either PCL or PBA as the soft segments, were easily

B. HAZER 33
Figure 1. (a) Formation of the diol ended PHB via transe-
sterification in the presence of ethylene glycol. (b) Transe-
sterification reactions of PHB with (i) butane diol, (ii)
transamidation with bisaminopropyl ended PEG, and (iii)
transesterification reactions of PHB with methacryloyl oxy
ethylene glycol in solution
synthesized by one-step solution polymerizations. Tran-
sesterification reaction of PHB with methacryloyl oxy
poly (ethylene glycol) (MW: 526), poly (ethylene glycol)
bis (2-aminopropyl ether) with MW 1000 and 2000 was
achieved to obtain PHB-b-PEG telechelic diblock
copolymers [25]. Similarly, telechelic PHB can also be
obtained by transesterification with 1,4-butane diol in
1,2-dichloro benzene under reflux conditions. The tran-
sesterification reactions can be designed in Figure 1.
4.2 Oxidation of the Pendant Double Bonds
Most used unsaturated PHAs are mclPHAs obtained
from unsaturated edible oils and synthetic olefinic subs-
trates. When Pseudomonas oleovorans is grown on un-
saturated carbon source such as soybean oily acids,
7-octenoic acid and 10-undecenoic acid, unsaturated
PHAs are obtained [26]. Figure 2 shows the synthesis of
the unsaturated PHAs.
Microbial polyesters containing unsaturated side
chains are open the way for chemical modification
reactions to prepare PHA derivatives. Pendent double
bonds of the poly (3-hydroxy octanoate-co-10-undece-
noate), PH(O)U, can be oxidized to the diol (PHOU-diol)
and carboxylic acid (PHOU-COOH). KMnO4 is used as
an oxidizing agent. In mild conditions PHOU-diol is
obtained [27]. While PHOU was insoluble in a polar
solvent, PHOU-diol was soluble in methanol, acetone/
water (80/20, v/v) and DMSO, even with 40–60% of
double bonds unconverted, but it was insoluble in
non-polar solvents such as chloroform, THF, acetone.
Figure 3 shows the PHOU-diol.
10-undece noi c (U) acid
O
OH
+
octanoic (O) acid
O
OH
HOCH CH
2
C
O
OCH CH
2
C
O
OH
nl
PHOU
Poly(3-hy droxy- oc ta noat e- co -10-un dec enoate) (PHOU)
Pseudomonas
oleovorans
CH
2
CH
O
CH
2
O
C
O
O C
O
C
O
oleic acid
linoleic acid
linolenic acid
Soybean oil (Sy)
Pseudomonas
oleovorans
CH
CH
2
CH
2
C
O
O
CH
3
( )
x
CH
CH
2
CH
2
C
O
CH
CH
CH
2
CH
CH
CH
3
(
(
)
p
)
z
( )
y
PHA-Sy
Poly(3-hydroxy alkenoate) from soybean oil (PHA-Sy)
(PHU) (PHO)
Figure 2. Synthesis of two types of unsaturated PHAs from Pseudomonas oleovorans (i) grown on soybean (PHA-Sy) and (ii)
10-undecenoic acid and octanoic acid (PHOU)

34 B. HAZER
Figure 3. PHOU with pendant hydroxyl groups
Figure 4. PHOU with pendant car boxylic acids (PHOU-COOH)
The use of NaHCO3 even in hot solution (55℃)
resulted mainly in diol groups, not carboxylic groups,
while the same reaction at room temperature using
KHCO3, led to the conversion of the pendant unsaturated
groups to the carboxyl groups [28]. Figure 4 shows the
PHOU with pendant carboxyl groups.
Carboxylation of PHOU using OsO4 as oxidant can be
performed with the small decrease in MW after the
reaction [29]. The quantitative hydroxylation of pendant
vinyl groups of PHU with the use of either the
borobicyclononane or the borane−tetrahydrofuran com-
plex is also achieved in high yield [30]. After hydro-
xylation, the thermal stability and the molecular weight
of the hydroxylated PHU showed small decreases;
however, full solubility in methanol and almost full
solubility in water are achieved [30].
Water wettability of saturated PHAs, poly(3-hydroxy
butyrate) (PHB) and poly(3-hydroxy butyrate-co-3-
hydroxy hexanoate) (PHBHHx) can also be improved by
carboxyl ion implantation. Ion implantation is performed
at an energy of 150 keV with fluences ranging from
5x1012 to 1x1015 ions/cm2. Contact angle measurements
are confirmed that the ion implantation improves the
water wettability [31].
Epoxidation of the unsaturated polyester with m-ch-
loroperbenzoic acid, as a chemical reagent, yields to
quantitative conversions of the unsaturated groups into
epoxy groups [32]. Primary and secondary amines can be
reacted with epoxide groups to yield hydrophilic compounds.
Reaction between hexamethylene diamine with epoxi-
dized PHOU provides crosslinked polyester [33].
Enhenced hydrophilicity of the PHOU has recently
been achieved by the reaction between epoxidized
PHOU and diethanol amine to give highly hydrophilic
polyester, PHON [34]. The first reaction involved the
transformation of the vinyl-terminated side chains of
PHOU to epoxide groups (PHOE). Figure 5 shows to the
conversion reaction of epoxidized PHOU (PHOE) to
hydroxylated PHOU in the presence of diethanol amine
(PHON).
Figure 5. The conversion reaction of epoxidized-PHOU
(PHOE) to hydroxylated PHOU in the presence of diethanol
amine (PHON)
The successful side chain conversion was further
substantiated by the change in solubility when converting
PHOU to PHOE to PHON. As the functionalized side
chains became more polar, the polymer became soluble
in more polar solvents. In this respect, PHON was
soluble in water.
4.3 Quarternization and Sulfonation of the PHAs
Halogenation of the polymers is a versatile method to
open the way for further functionalization [25,35,36].
Addition of the chlorine and bromine into the double
bond is quantitative and halogenated PHAs can be easily
obtained by this way [25]. Chlorination is performed by
either the addition to double bonds of the unsaturated
PHA obtained from soybean oil (PHA-Sy) or substitution
reactions with saturated hydrocarbon groups [35,36].
Chlorination of the sticky, soft PHA-Sy with double
bond provides polyester with hard, brittle, and crystalline
physical properties depending on the chlorine content.
By this way, it is possible to introduce 35 wt% chlorine
to the PHA. In case of the chlorinated PHO, glass
transition temperature has been shifted to +2℃ from –40
℃ [36]. For further functionalization, quaternization
reactions of the chlorinated PHA with triethylamine (or
triethanol amine) can be performed. Additionally,
aqueous solution of Na2S2O3
.5H2O can be reacted with
solution of PHA-Cl in acetone to give sulfonate deri-
vative of the PHO [36].
4.4 Grafting Reactions of the PHAs
4.4.1 Chitosan Graftin g
Chemical modifications of chitosan by grafting method
are important to prepare multifunctional materials in
different fields of application and to improve its chemical,
physical, and mechanical properties [37]. Chitosan-g-
PHBV graft copolymer was synthesized and grafting
of linoleic acid on chitosan were performed by con-
densation reaction under vacuum at 90–95℃. Graft

B. HAZER 35
Figure 6. Chitosan-g-PHBV graft copolymer
copolymers exhibit different solubility behavior as a
function of degree of substitution of NH2 in other words
as a function of grafting percent such as solubility,
insolubility, or swelling in 2 wt % acetic acid and in
water while chitosan does not swell in water. Chitosan-g-
PHBV graft copolymer is shown in Figure 6.
4.4.2 Sugar Grafting
Glycopolymers are emerging as a novel class of neogly-
coconjugates useful for biological studies and they are
prepared either by copolymerization or grafting methods
[38]. Since it has been shown that thiosugars are potent
tools in glycobiology, 1-thiomaltose derivatives has been
grafted onto PHAs in two ways [39]; the thiol sugar
is added to the double bond and the reaction between thiol
sugar and bromo end groups of polyester biosynthesized
from 11-bromoundecanoic acid [40]. These new grafted
polymers are insoluble in dichloromethane and chloro-
form, but very soluble in N,N-dimethylformamide and
dimethyl sulfoxide, as opposed to their parent PHAs. As
expected, modified PHAs are more hydrophilic than their
parent compounds.
4.4.3 PEG Grafting
Diazo linkaged PEG, a polyazoester synthesized by the
reaction of PEG and 4,4’-azobis(4-cyanopentanoyl
chloride) creates PEG macro radicals which is easily
attack to the double bonds of the unsaturated PHA to
obtain the poly(3-hydroxyalkanoate)-g-poly(ethylene
glycol) crosslinked graft copolymers [41]. Poly(3-
hydroxyalkanoate)s containing double bonds in the side
chain (PHA-DB) were obtained by co-feeding Pseudo-
monas oleovorans with a mixture of nonanoic acid and
anchovy (hamci) oily acid (in weight ratios of 50/50 and
70/30). PHA-DB was thermally grafted with a [41].
Graft copolymers of the saturated mclPHAs can be
synthesized by using macro radicals via H-abstraction
from the tertiary carbon of the polyester [42]. Similarily,
macroradicals onto the PHAs are induced by the UV
irradiation via H-abstraction in the presence of a
PEG-macromonomer to prepare PEG-g-PHO graft
copolymers [43]. Homogeneous solutions of poly (3-
hydroxyoctanoate) (PHO) and the monoacrylate-poly
(ethylene glycol) (PEGMA) monomer in chloroform
were irradiated with UV light to obtain PEGMA-grafted
PHO (PEGMA-g-PHO) copolymers. The results of the
protein adsorption and platelet adhesion tests show that
the blood compatibility was also enhanced by grafting
the PEGMA chains. The adsorption of proteins and
Table 2. Methods for the synthesis of the amphiphilic PHAs
Poly (3-hydroxy alkanoate) (PHA) Thermal and Mechanical Properties
Carbon Source
Type Side chain (R) Name* Tg (°C) Tm (°C) Elongation (%)
Sugar, glucose,
acetic acid
Short chain
length Methyl, ethyl PHB PHV 15 170 5
Alkanoic acids,
alkanes and alkanols
Medium chain
length
Propyl, butyl,
pentyl, hexyl, heptyl
PHHx
PHHp
PHO
PHN
PHD
-40 60 800
Plant oily acids Long chain
length
More than 14
Carbon per
repeating unit
-50 40 Soft, sticky
*B: butyrate, V: valerate, Hx: hexanoate, Hp: heptenoate, O: octanoate, N: nonanoate, D: decanoate. Tg and Tm are glass and melting
temperatures, respectively.

36 B. HAZER
platelets was increasingly suppressed, as the DG of
PEGMA onto PHO increased. Glycerol 1, 3-diglycerol
diacrylate-grafted poly(3-hydroxyoctanoate) copolymers
are also prepared by heating homogeneous solutions of
PHO, diacrylate monomer and benzoyl peroxide initiator
[44]. The resulting copolymers have enhanced thermal
properties and mechanical strengths. The surfaces and
the bulk of the graft copolymers became more hydro-
philic as the diglycerol-diacrylate grafting density in the
copolymer increased. Many studies have reported that
hydrophilic surfaces, such as those of hydro gels and
PEG-grafted polymers, suppress protein adsorption and
platelet adhesion. The surfaces of these graft copolymers
become more hydrophilic with grafted diglycerol groups.
These surface characteristics make this graft copolymer
to prevent protein adsorption and platelet adhesion very
effectively. As a summary, Table 2 indicates the sum of
the chemical modification reactions to obtain amphi-
philic PHAs. In this manner, Renard et al. achieved the
amphiphilic copolymer based on PHOU and PEG [45].
Carboxilic acid terminal groups in the side chains are
reacted with PEG in the presence of dicyclohexyl car-
bamate at room temperature. Amphiphilic graft copoly-
mer obtained is soluble in the mixture of H2O/ acetone
(80/20) whereas precursor PHOU is not soluble.
5. Conclusions
Microbial polyesters are biocompatible and biodegra-
dable hydrophobic natural thermoplastics. Amphiphilic
PHAs from swollen in water to soluble in water are
much more desirable in the drug delivery system and
tissue engineering. In most attempts to synthesize amphi-
philic PHAs, degradation of the polyester chain has been
unavoidable. To obtain new amphiphilic PHAs with high
molecular weight and their medical applications have
been attractive for scientists.
6. Acknowledgment
This work was financially supported by TUBITAK
(grant no. 108T423) and ZKU Research Fund.
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