SYNTHESIS OF BIODEGRADABLE POLYMERS

A Project Report
Submitted in partial fulfilment for the award of degree
of

BACHELOR OF TECHNOLOGY
In

CHEMICAL ENGINEERING
By
VEMPARALA YAMINI POORNA CHANDRIKA 22011A0826
CILAVENI KOMAL KARTHEEK 22011A0833
BOORA ASHRITHA 22011A0836
SHIRISHA TEJAVATH 22011A0839
SIDDAGONI VYSHNAVI 22011A0840

JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY, HYDERABAD

UNIVERSITY COLLEGE OF ENGINEERING SCIENCE & TECHNOLOGY
HYDERABAD, Kukatpally-500085
 DECLARATION

We here by declare that the project report entitled “Synthesis of

Biodegradable Polymers "is submitted in the Department of Chemical
Engineering, JNTUH-UCESTH in partial fulfilment of the award of Bachelor of
Technology in Chemical.

Also, we declare that matter embedded in this project report has not been
submitted for the award of any degree of any other Institution or University.

Date:
Place: HYDERABAD

VEMPARALA YAMINI POORNA CHANDRIKA (Roll No: 22011A0826)

CILAVENI KOMAL KARTHEEK (Roll No: 22011A0833)

BOORA ASHRITHA (Roll No: 22011A0836)

SHIRISHA TEJAVATH (Roll No: 22011A0839)

SIDDAGONI VYSHNAVI (Roll No: 22011A0840)

 JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY, HYDERABAD
UNIVERSITY COLLEGE OF ENGINEERING SCIENCE & TECHNOLOGY
HYDERABAD, Kukatpally-500085

A project report on “Synthesis of Biodegradable Polymers”, done by

VEMPARALA YAMINI POORNA CHANDRIKA (22011A0826), CILAVENI
KOMAL KARTHEEK (22011A0833), BOORA ASHRITHA(22011A0836),
SHIRISHA TEJAVATH(22011A0839), SIDDAGONI VYSHNAVI
(22011A0840),submitted to the faculty of CHEMICAL ENGINEERING, in
partial fulfilment of the requirements for the Degree of BACHELOR OF
TECHNOLOGY with specialization in CHEMICAL ENGINEERING from
Jawaharlal Nehru Technological University Hyderabad University College of
Engineering Science and Technology Hyderabad.

Faculty In-Charge:
Dr. Ramesh Chandragiri
Assistant Professor
Department of Chemical Engineering
JNTUHUCEHSTH
 JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY, HYDERABAD
UNIVERSITY COLLEGE OF ENGINEERING SCIENCE & TECHNOLOGY
HYDERABAD, Kukatpally-500085

A project report on “Synthesis of Biodegradable Polymers”, done by

VEMPARALA YAMINI POORNA CHANDRIKA (22011A0826), CILAVENI
KOMAL KARTHEEK (22011A0833), BOORA ASHRITHA(22011A0836),
SHIRISHA TEJAVATH(22011A0839), SIDDAGONI VYSHNAVI
(22011A0840),submitted to the faculty of CHEMICAL ENGINEERING, in
partial fulfilment of the requirements for the Degree of BACHELOR OF
TECHNOLOGY with specialization in CHEMICAL ENGINEERING from
Jawaharlal Nehru Technological University Hyderabad University College of
Engineering Science and Technology Hyderabad.

Head of the Department:

Dr.K.Vidya
Professor and Head of Department
Department of Chemical Engineering
JNTUH-UCESTH
 ACKNOWLEDGEMENTS

First and foremost, we are deeply indebted to our guide Dr. Ramesh
Chandragiri for considering and allowing us to carry out research under his
esteemed guidance and support, we were able to engage in a broad range of
such research activities. He understands the individual needs of his
students and generates thoughtful insight about every aspect of science. His
expert advice and wisdom helped our team to finish this work and made my
study under his supervision enjoyable.
Then we would like to express our deep sense of gratitude to
Dr.K.VIDYA(Professor and Head of Chemical Engineering Department) who
gave us an excellent opportunity to do this project.
We would like to express our deep sense of gratitude to Dr.G.VENKATA
NARSIMHA REDDY (Principal) and all Assistant Professors of Department
of Chemical Engineering, Hyderabad, who gave us opportunity to do this
project.
Finally, we are really thankful to our parents, for being our inspiration and
constant encouragement, moral support throughout the life. The
completion of this project is not only fulfilment of my dreams but also the
dreams of our parents.

VEMPARALA YAMINI POORNA CHANDRIKA (Roll No: 22011A0826)

CILAVENI KOMAL KARTHEEK (Roll No: 22011A0833)
BOORA ASHRITHA (Roll No: 22011A0836)
SHIRISHA TEJAVATH (Roll No: 22011A0839)
SIDDAGONI VYSHNAVI (Roll No: 22011A0840)
 TABLE OF CONTENTS

S.no: Contents Page no:

Chapter-1 INTRODUCTION
1.1 Bio-degradable Polymer 1
1.2 Properties 1
1.3 Application 1
1.4 Structure 1
1.5 Mechanism of Biodegradation 2
Chapter-2 POLYLACTIC ACID
2.1 Introduction 6
2.2 Synthesis of Polylactic Acids 6
2.3 Properties of Polylactic Acids 11
2.4 Applications 12
Chapter-3 POLYGLYCIDOL
3.1 Introduction 16
3.2 Synthesis of Polyglycidol 16
3.3 Applications 20
Chapter-4 METHODS OF ANALYSIS OF BIODEGRADABLE POLYMERS
4.1 Chromatographical methods 23
Chapter-5 CONCLUSION
5.1 Conclusion for Polylactic Acid 24
5.2 Conclusion for Polyglycidol 25
Chapter-6 REFERENCES
6.1 References 26
 ABSTRACT
Polymeric materials obtained from petroleum resources are
nonbiodegradable. Defying degradation, they damage the environment as a result
of their ending up in the landfills. Synthesized biodegradable polymeric materials
(BPMs) have received increasing interest owing to the di iculty in procuring
reproducibility when using natural polymeric materials. Through the modification
of natural polymeric materials or materials via chemical, microbiological,
enzyme-mediated, and chemo-enzymatic synthesis, a comprehensive range of
variegated BPMs can be reaped. Amended natural polymeric materials such as
starch, cellulose, and chitin have enhanced properties, while synthetic BPMs such
as PLA, PGA, PCL, PDS, and PLGA are explicitly designed to pursue coveted
applications in multifarious domains such as whole diagnostics and therapeutics.
Synthesized BPMs can be embedded with tailored characteristics to justify the
neoteric entails of mankind.

Biodegradable polymeric represents a growing field. Owing to their wide-

ranging properties, both synthetic and natural polymeric materials perform a vital
and ubiquitous role in everyday life. Amended natural polymeric materials such as
starch, cellulose, lignin, chitosan, cottonseed shell (CTS), and cotton gin trash
(CGT) have enhanced properties, while synthetic Biodegradable polymeric
materials such as poly (vinyl alcohol) (PVA), biodegradable plastics,
biodegradable foams. Bioplastics are a kind of polymers able to be degraded by
di erent microorganisms to small molecules (e.g., H2O, CO2, and CH4).
Bioplastics are observed to solve waste materials and biodegradability is just a
new material to be exploited at the end of its life in specific terms. They should be
used for applications that require cheap methods to dispose of items after it has
fulfilled their job (e.g., for food packaging, agriculture, or medical products).

i
 CHAPTER-1
INTRODUCTION

1.1 BIODEGRADABLE POLYMER:

Synthetic plastics are resistant to degradation, and subsequently their disposal is
stimulating a global drive for the establishment of biodegradable polymers. Unlike
conventional plastics derived from fossil fuels, biodegradable polymers reduce
environmental pollution and waste accumulation. They can be sourced from
renewable materials such as plant starches or synthesized from bio-based
compounds like polylactic acid (PLA) and Polyglycolide or polyglycolic acid
(PGA).[1]

1.2 PROPERTIES:
 Biodegradability
 Environmentally friendly
 Renewable sources
 Biocompatibility
 Moisture sensitivity

1.3 APPLICATIONS:
 3-D Printing Filaments
 Biomedical Devices
 Capsules for Pharmaceuticals
 Compostable Bags
 Drug Delivery Systems

1.4 STRUCTURE:

Biodegradable polymers comprise ester, amide, or ether

bonds. In general, biodegradable polymers can be grouped into two large groups
on basis of their structure and synthesis.[2]

1
1.5 MECHANISM OF BIODEGRADATION:
Polymer degradation refers to any chemical, physical, or
biochemical reaction that involves breaking covalent bonds in the backbone of
the polymer, resulting in an irreversible change in its properties due to alterations
in the chemical structure and the reduction of molecular weight.[3]

2
1.5.1 HYDROLYSIS:
Hydrolysis is a chemical decomposition process that involves
breaking a bond by reacting with water molecules. The hydrolysis process is the
most important for initiating the biodegradation of synthetic polymers, especially
polyesters. Hydrolytic degradation is divided into three levels. The first level
involves degradation at the molecular level, in which hydrolysis is controlled only
by chemical reactivity. The second level is also molecular but is associated with
molecular mobility and water–polymer interactions. The third level is the
macroscopic one, where erosion and water di usion reaction are the governing
parameters for degradation.[4]
Hydrolysis occurs mainly in hygroscopic polymers and those
with water-sensitive groups in the polymeric backbone. During hydrolysis, the
polymer is always split into two components; otherwise, it will not be considered
hydrolysis (hydro = water; lysis = breakdown). If the products are not ionized, one
part gains a hydrogen atom the other gains a hydroxyl group (OH-) from the broken
water molecule.

Ranking of hydrolysis rate of main polymers that su er degradation when exposed

to humidity.

3
1.5.2 THERMOLYSIS:
Thermal decomposition, also known as thermolysis, is a
chemical reaction in which a reacting substance decomposes into at least two
new substances upon heating. In the case of polymers, thermal decomposition
generates molecules and atoms that are di erent from the precursor without the
simultaneous involvement of other reagents such as oxygen. Since the heat
received breaks the bonds of the molecules of the reactants, thermal
decomposition is generally an endothermic process. If the chemical energy of the
reactants is greater than that of the products, the decomposition reaction will be
exothermic (∆H), indicating that the reactants are highly reactive and the products
are stable. An exothermic decomposition reaction releases heat and may be
accompanied by an explosion or another chemical reaction.

1.5.3 OXIDATION AND THERMO OXIDATIVE FISSION:

We would like to emphasize that degradation in the presence
of oxygen not only leads to chain scission or the breaking of the σ bond (R-C-C-R),
but also breaks the π bonds (R-C=C-R), resulting in the insertion of an oxygen atom
(oxidation). Therefore, in oxidation reactions, a reduction in the average molar
mass of the polymer is not necessarily observed, but a marked change in its
physical and chemical properties, e.g., a colour change of the material, may
occur. Regardless of the atmosphere’s composition, polymers will start to
decompose if heated enough. However, thermal oxidation di ers from thermal
decomposition in that it generally catalyses oxidation reactions culminating in
material decomposition at milder temperatures.
Thermo-oxidative fission of polymers is a self-catalytic
process that occurs in three stages: initiation, propagation, and termination. The
oxygen molecule is considered a highly reactive chemical species, as it reacts
quickly with any environmental free radicals. In the first step, heat-catalysed
degradation is initiated when polymer chains form radicals (R*) either by hydrogen
abstraction or by homolytic scission of the C-C bond. Next, the propagation of
degradation involves a series of intermediate reactions.
The first intermediate step is the reaction of a free radical (R·)
with an oxygen molecule (O2), forming a per-oxy radical (ROO·) that abstracts a
hydrogen atom from another polymeric chain, producing a hydroperoxide (ROOH).
Hydroperoxides are highly unstable; therefore, they decompose into two new free
radicals, (RO·) + (·OH), which attack the polymer chain, abstracting labile
hydrogens and introducing new radicals [5]. The thermo-oxidative reaction ends

4
by recombining two radicals, forming stable products, or abstracting hydrogen or
π bonds.

5
 CHAPTER-2
POLYLACTIC ACID

2.1 INTRODUCTION:
It is recorded that Theophile-Jules Pelouze first synthesized
poly (lactic acid) (PLA) by polycondensation of lactic acid in 1845[1]. In 1932,
Wallace Hume Carothers et al. developed a method to polymerize lactide into
PLA. This method was later patented by Du Pont in 1954[2]. Until the late 1970s,
PLA and its copolymers were developed as biomedical materials based on their
bioabsorbable and biocompatible nature and have been utilized in many
therapeutic and pharmaceutical applications such as drug delivery systems
(DDS)[3,4] protein encapsulation and delivery[5,6] development of
microspheres[7,8,9,10] and hydrogels[11] .

2.2 SYNTHESIS OF POLYLACTIC ACIDS(PLA):

2.2.1 LACTIC ACID:
Lactic Acid is a monomer that consists of polylactic acid ,and
its existence is very common. It plays a vital role in the glycolytic energy cycle in
organisms, as well as being an important substance for maintaining the growth
and development of living organisms [20]. LA was first extracted from fermented
milk by Swedish scientists in 1881. As the simplest hydroxy acid, there is an
asymmetric carbon atom in the molecule that is optically active, so there are two
optical isomers, L-lactic acid and D-lactic acid, as shown in Figure 1 [21,22].
Lactic acid obtained from animal muscle is dextrorotatory lactic acid, while the
other, lactic acid obtained by fermentation, is laevorotatory lactic acid. In the
beginning, commercial lactic acid was mainly derived from the fermentation of
sugars by bacteria [23]. Sugars used for lactic acid fermentation include starch,
glucose, lactose, and maltose, produced by corn and potatoes. Fermentation is
typically carried out for 3–5 days under low pH (about 5.0) and low oxygen at a
temperature of about 40 °C [24]. However, this method produces a certain degree
of toxicity as the concentration of fermented lactic acid increases, and the
reaction continues. To obtain high-purity LA and improve the output efficiency of
lactic acid, purification also constitutes a major problem [25]. In the beginning,
the typical purification method was to add calcium hydroxide or calcium
carbonate to the fermentation broth to neutralize the acid. The resulting calcium

6
lactate could be evaporated, crystallized, and acidified to obtain further crude
lactic acid and insoluble calcium sulfate (gypsum). Lactic acid used in food or
medicine often needs to be further purified to obtain a higher degree of lactic acid.
Subsequent studies showed that it can then be neutralized with recycled
ammonia or sodium hydroxide. Subsequently, ultrafiltration, dyeing, and
electrodialysis were developed as new processes for the low-cost production of
lactic acid [26].

Figure 1. Enantiomers of lactic acid.

Chemical synthesis methods have also been applied for the
industrial production of lactic acid. These fall into roughly three types: (a) The
lactonitrile method. Lactonitrile is hydrolysed by sulfuric acid to obtain crude LA.
The crude LA is added to ethanol for esterification, and refined lactic acid is
obtained by distillation, concentration, and decomposition. (b) The acrylonitrile
method. Like the above method, but with acrylonitrile replacing lactonitrile,
hydrolysed with sulfuric acid. Then, the hydrolysed product is reacted with
methanol; the crude ester is sent to the distillation tower, and the refined ester is
heated and vacuumed to obtain the product. (c) The propionic acid method. Using
propionic acid as raw material, crude lactic acid is obtained through chlorination
and hydrolysis; then, the product is obtained through esterification, rectification,
and hydrolysis. Only a few manufacturers use this method due to the expensive
raw materials [27].
Although chemical methods are able to achieve large-scale
continuous production of LA, and the U.S. Food and Drug Administration (FDA)
has approved the resulting product, the raw materials are generally toxic. They do
not accord with the standards of green chemistry. Some recent studies showed
that, by adding bacteria and substrate-degrading enzymes for simultaneous
saccharification and fermentation, starch or cellulosic biomass can be
saccharified and simultaneously converted into lactic acid; this process can be
used as a replacement for the above-mentioned traditional fermentation steps
[28,29]. This process reduces costs and improves efficiency.

7
2.2.2 PLA POLYMER:
Since LA is a chiral molecule with D-type and L-type isomers,
three forms of polylactic acid are formed: poly-L-lactic acid (PLLA), poly-D-lactic
acid (PDLA), and poly-D,L-lactic acid (PDLLA). With respect to optical activity,
there are two compositions-L and D enantiomers-such that polylactic acid can be
crystallized into three forms (α, β, and γ) [30,31,32]. In 1932, Carothers (DuPont)
synthesized low-molecular-weight polylactic acid products. However, due to the
high cost of synthesis and poor product stability, this synthesis was not
considered a success [33]. In 1954, DuPont produced a higher-molecular-weight
polylactic acid, and applied for a patent intending to enter the commercial
market. Research on polymers attracted significant attention from society. With
advances in medicine and public health, polylactic acid began to be used in
surgical sutures and bone implants in the 1960s. Today, PLA resin has been
approved by the FDA and European regulatory authorities for use in food- and
drug-delivery systems [12,34]. This has also led people to realize that, while PLLA
has some advantages, it also has some disadvantages. For example, due to its
high crystallinity and slow degradation rate, it can trigger an inflammatory
response in the body. Fortunately, D-lactic acid degrades more quickly. If L-lactic
acid and D,L-lactic acid monomers are used to synthesize PLLA, the above
problems are avoided [35,36].
Three methods for the synthesis of polymer PLA (Mw > 10,000)
were reported: (a) direct condensation polymerization; (b) azeotropic dehydration
condensation; and (c) lactide ring-opening polymerization, as shown in Figure2.

Figure 2. Synthesis of polylactic acid (PLA) from L- and D-lactic acids [28].
Adapted from Auras et al. by permission of Wiley–VCH Verlag GmbH & Co. KGaA.

8
 Although the cost of the condensation-polymerization method
is low, it cannot directly synthesize polymer PLA. Rather, part of the cost
corresponds to the coupling agent and esterification accelerator used in the
synthesis process. The synthesis step is divided into two steps [37,38,39]. The first
step is the dehydration condensation of hydroxyl and carboxyl groups at
equimolar concentrations to produce low-molecular-weight polylactic acid. Next,
coupling agents and esterification adjuvants need to be added. Their addition can
modify the PLA and help amplify the chain. However, impurities in the reaction
process cannot be degraded in the body, which can cause serious complications
in medical applications [40]. To obtain a high-purity, low-molecular-weight
oligomer final product with no residual metal or catalyst, it is necessary to
introduce triphosgene to remove the adjuvant and byproducts in the reaction.
However, in addition to higher economic costs, this method uses flammable
solvents, thus increasing safety risks. Although later studies found that new chain
extenders could replace the esterification of the above-mentioned adjuvants,
there is still the problem that chain extenders and polymer impurities are toxic and
nonbiodegradable [41]. Although the azeotropic dehydration condensation
method avoids the use of adjuvants during the synthesis of PLA, the disadvantage
of this method is that dibasic acids and glycols are used as solvents in the reaction
while the catalyst remains. First, lactic acid is distilled under reduced pressure at
130 °C for 2–3 h to remove most condensed water. The catalyst and diphenyl ether
are added to the reaction. This is passed through a molecular sieve and returned
to the container for another 30–40 h at a temperature of 130 °C. The polymer can
then be separated or dissolved and precipitated for further purification. In the
subsequent production process, due to the effective removal of water, the
increase in the boiling point of the solvent results in an increased polymerization
rate. After testing a variety of catalysts, it was found that tin compounds have
higher catalytic efficiency. In addition, the content of impurities hinders the
synthesis to a certain extent. In follow-up industrialization research, it was
demonstrated that it is possible to remove the catalyst to a great extent without
degrading the polymer. However, the toxicity and nonbiodegradability of the
remaining catalyst can cause irreversible damage to the human body, so it cannot
be applied in the medical field.
The ring-opening polymerization of lactide is one of the
methods for industrial production of high-molecular-weight PLA. Lactide has
three stereo configurations—L-lactide, mesolactide, and D-lactide—as shown
in Figure 3 [42]. As a cyclic dimer, it can be formed by solvent-free dehydration
under mild conditions. Commercially feasible methods for obtaining and purifying
lactide involve steps such as condensing lactic acid at 115–179 °C, removing the
condensed water, and removing the mesolactic acid and low-molecular polymer
through recrystallization to obtain pure L- or D, L-lactide with high molecular
weight [9,43,44]. The industrial production method of lactide is the same as the
scheme mentioned above, but in different reactors, producing low-molecular-

9
weight prepolymers, and the final purification method is different. For example,
Cargill Inc. uses a reduced pressure–reflux method to remove residual water,
lactic acid, oligomers, and partial lactide [45]. Nemphos changed the purification
step, using a multistage melt recrystallized to remove LA and low-molecular
polymer. Bhatia and colleagues used inert gas to remove, recrystallize, and purify
lactide. Other methods include the use of lactide to gas-phase recrystallization to
increase yield and weakly alkaline water/solvent systems to extract lactide. In the
method described above, after removing impurities, high-purity lactide is
generally obtained.

Figure 3. Stereoforms of lactides.

After obtaining high-purity lactide, depending on the catalyst,
the ring-opening polymerization of lactide can adopt one of three mechanisms:
cation, anion, and coordination/insertion. Cationic initiators can generally be
divided into protic acid, Lewis acid, and alkylating or acylating reagents.
Kricheldorf and his colleagues found that triflic acid and methyl triflate, among
many cationic initiators, could effectively induce the polymerization of lactide.
The choice of different anion inducers causes deprotonation, resulting in
inconsistent polymerization and racemization, leading to polymers with different
molecular weights [46]. Considering that metal ions can cause toxicity problems,
it is not recommended to use butyl lithium or crown ether initiators. The use of
primary alkoxides, 6-valerolactone, or polyethylene glycol can produce clearly
defined polymers. The two above methods have high reactivity, and are usually
prone to racemization and transesterification during the solvent reaction process,
resulting in impurities. The use of metal carboxylates, oxides, and alkoxides with
lower activity to produce polylactide with low toxicity and few impurities has been
extensively studied in commercial production applications. Studies found that
the use of tin (II) and zinc produces fewer impurities during the synthesis of high-
molecular-weight polylactic acid, resulting in the purest polylactic acid. For
example, tin (II) di-2-ethyl hexanoic acid has high catalytic activity and low toxicity.
It was approved by the FDA, and it is a highly suitable inducer. In addition to tin
compounds, aluminum alkoxides and rare-earth compounds are other catalyst
systems that proceed through coordination/insertion mechanisms. Research
found that the polymerization rate of rare-earth compounds is still much higher
than that of aluminum alkoxides.

10
 Additionally, according to research, enzymatic polymerization
is more environmentally friendly than chemical synthesis methods are. Enzymatic
reactions require a mild environment, and enzymes are efficient, inexpensive, and
have high specificity. Chemical reactions require a single reactant to avoid side
reactions. However, not many references are available for this method [47].

2.3 PROPERTIES OF POLYLACTIC ACID(PLA):

Polylactic acid has very good market prospects and excellent
commercial value, with a range of applications from industrial to civilian use.
Interest in its mass production stems from its good performance; for example,
polylactic acid has good physical properties and can be used to yield various
plastic products, such as fast-food lunch boxes, and fabrics for industrial and
civilian use [44,48,49,50]. Good tensile strength and ductility make it suitable for
different processing means, such as melt-extrusion molding, injection molding,
blown film molding, foam moulding, and vacuum molding. Its good
biocompatibility has led it to be widely used in the field of biochemical medicine.
High-molecular-weight PLA has been used to produce non-dismantling surgical
sutures and low-molecular-weight PLA as a slow-release drug-packaging agent
[51].
Polymer polylactic acid possesses good characteristics with
regard to gloss, transparency, hand feel, and heat resistance. The dissolution of
PLA depends on its degree of crystallinity. Amorphous polymers are soluble in
various organic solvents, including acetone, acetonitrile, and methylene chloride.
Furthermore, crystalline PLA can only be dissolved in dichloromethane or
benzene at high temperatures. Mechanical properties and crystallization behavior
are closely related to the molecular weight and stereochemical composition of
the main chain. The hydroxy compound determines the molecular weight. The
degree of crystallinity affects the degradation of PLA [52,53]. Highly crystalline
polymers last for several months, with metabolism only taking place after a few
years, while polymers with low crystallinity can be decomposed in a few weeks.
Glass transition (Tg) directly affects the performance of the material with respect
to both use and processing [54]. The good news is that the crystalline state does
not affect the glass transition temperature. Jamshidi’s research found that the
glass transition temperature of PLA with a molecular weight of 22,000 g mol−1 was
55 °C, which is only 5 °C away from polymers of infinite molecular weight. Impact
resistance increases with increasing crystallinity and molecular weight. Pure
PDLA and PLLA have a melting point (Tm) of 207 °C. When they are mixed in equal
proportions, racemic crystals with better mechanical properties are formed. The
Tm of this crystal is 230 °C, and ultimate tensile strength is 50 MPa. Tg and Tm are

11
vital physical parameters with respect to the properties of polylactic acid. The
heat of fusion (△Hm) of 100% pure crystals is 93.7 J g −l. Subsequent research
results showed that, with low polylactic acid content, the Tm and Tg of polylactic
acid are decreased.
Polylactic acid has sufficient thermal stability to retard
degradation and maintain molecular weight and performance. At temperatures
greater than 200 °C, polylactic acid undergoes hydrolysis, lactide recombination,
oxidative main-chain scission, and intermolecular or intramolecular
transesterification.
The degradation of polylactic acid is contingent on many
factors, including time, temperature, low-molecular-weight impurities, and
catalyst concentration [27,55,56]. Studies found that simply modifying the
purified pure polymer affects degradation. For example, acetylation of the
hydroxyl end increases the decomposition temperature by 26 °C and ameliorates
the decrease in molecular weight. At present, there is a general theory that the
phenomenon resulting in PLA degradation is the process of simple proton-
catalysed hydrolysis chain scission [57]. Since the reaction is reversible, the purity
of the polymer affects the degradation process during the synthesis reaction
process, that is, the purity of the polymer can be used to explain the degradation
kinetics of PLA. Furthermore, the crystallinity of the compound, as described
above, determines the degradation rate and autocatalysis. When PLA is
hydrolysed and degraded in a biological environment, enzymes also participate.
However, the specific role of enzymes in the reaction is currently unclear.
Whether the reaction is catalysed directly or by removing byproducts, so that the
reaction is beneficial to forward progress, is not known. Supposing polylactic acid
is mainly degraded by hydrolysis, the degradation of polylactide is divided into two
stages: the nonenzymatic melting of ester groups and the random scission of low-
molecular-weight polymers by microorganisms to produce carbon dioxide and
water [58,59].

2.4 APPLICATIONS:
Good biocompatibility is an important reason for the wide use
of PLA in the field of biomedicine. The intermediate lactic acid product can be
metabolized by the human body and is nontoxic and harmless. Its degradation can
be used for drug release. By controlling the metabolism rate of the carrier in the
body, it is possible to ensure the e ective concentration of the drug while reducing
side e ects, which gives it obvious advantages for use both in drug delivery and as
a material for implants. Good biocompatibility also ensures that there is no
inflammatory reaction in the surrounding tissue due to rejection after it enters the
human body [75,76,77].

12
2.4.1 TISSUE ENGINEERING:
Blood transfusions carry with them the danger of viral
infection; for this reason, research into artificial blood has attracted a great deal
of attention. The main component of blood is red blood cells, which transport
oxygen [78,79,80,81]. Microcapsules can encapsulate animal haemoglobin
[82,83]. Oxygen enters the microcapsule through the membrane wall and is
combined with haemoglobin so that that the haemoglobin is able to transport
oxygen. This method of embedding can also prevent animal haemoglobin from
being produced in the blood. The antigen–antibody reaction extends the half-life.
Some studies used liposomes to encapsulate haemoglobin. However, liposomes
have a low entrapment rate and are unstable when entering the blood
circulation. They easily release haemoglobin and have a short half-life [84,85,86].
Su et al. found that, when polylactic acid was used as the membrane material,
the embedding rate of haemoglobin was very low, only 7.9%. When using a
polylactic acid–polyethylene glycol copolymer, the embedding rate reached 90%.
Additionally, when preparing the microcapsules, since the inner and outer water
phases are both aqueous solutions, the hydrophilic polyethylene glycol block
stretched toward both the inner and outer water phases. The PEG stretched
toward the inner water phase was biocompatible. It had good properties and a
certain protective e ect on haemoglobin, and helped maintain protein activity
during storage [87,88,89].

2.4.2 DRUG DELIVERY:

PLA can be degraded into LA in and metabolized by the human
body. It is a material approved by the FDA for biomedical use. In the 1970s, Yolles
et al. used PLA for drug-delivery research, and prepared a PLA complex containing
naltrexone. The in vitro release rate was 67% at 35 days. In vivo experiments
proved that the complex had a blocking effect on morphine. Ruan et al. used PLA
copolymers to prepare PLA–PEG–PLA microspheres containing paclitaxel [90,91].
The prepared microspheres were uniform in size and had a porous structure inside
that promoted drug release. In vitro release reached 49% in one-month,
prolonging drug action time in the body and improving its efficacy. This sustained-
release drug-delivery system avoids inconsistent local concentration due to drug
release, thereby enhancing the therapeutic effect. Compared with traditional
dosage forms, this slow-release “smart” drug-delivery system has many
advantages: reducing the side effects of drugs on the gastrointestinal tract and
avoiding high local drug concentrations within a given period, which may lead to
allergies or even poisoning. Additionally, degradable materials can be degraded in
specific environments, meaning that external polymer materials could be
modified to achieve the controlled release of drugs [92,93,94].

13
 For some specific diseases such as tumors and tuberculosis, therapeutic
drugs can possess high toxicity and extensive side effects. In addition to the killing
effect at the lesion site, they also cause great damage to normal tissue. At the
same time, the process of treatment requires multiple and frequent
administrations [95]. Therefore, targeted drug systems are worthy of study [96].
This kind of coating material, combined with target selection achieved through the
affinity of the functional group, can quickly target the lesion site with the drug,
improve its bioavailability, and reduce its toxic side effects and toxicity to other
tissue types [97,98]. However, the polymer must be chemically modified to be
more useful for targeting or eliciting a stimulatory response. As shown in Figure 4,
a kind of pH sensitive linkage was designed to modify doxorubicin loaded PLA
nanoparticles which make it easy to disintegrate in tumor microenvironment.
Therefore, modified polylactic acids such as PLGA (Polylactoglycolic acid) are
usually used in drug-delivery systems. Ferric oxide plays an important role in drug-
delivery systems for magnetic nanoparticles. Fang et al. used PLGA to embed
ferroferric oxide, and then encapsulated doxorubicin (DOX) inside to form a
nanocomposite carrier. This carrier maintains high sensitivity to the external
magnetic field, thus achieving magnetic targeting by the carrier. This medicine
also has good antitumor activity [99].

Figure 4. High drug loading and pH-responsivity PLA-g-doxorubicin (DOX)

nanoparticles [99]. Reprinted from Cheng with permission from Express Polymer
Letters.
Thermosensitive gels also play an important role in delivery. Most
thermosensitive gels have hydrophilic ends composed of PEG and hydrophobic
ends composed of degradable polyesters, such as PLA and PLGA, polyglycolic
acid (PGA), and polycaprolactone (PCL). Temperature-sensitive gels based on a
polylactic acid composition can be divided into block components of diblock,
triblock, multiblock, star, and other gel systems. The phase-change phenomenon
during the heating process takes place as described in Table 1 [100,101].
Table 1. Various types of thermo-induced physical hydrogel.

14
 The earliest report on PEG–PLLA diblock temperature-sensitive gels in nature
led temperature-sensitive physical gels to become a research hotspot. Triblock
copolymer PEG–PLLA–PEG takes PLLA as its center and exhibits a gel–sol phase
transition during the heating process. Multiblock copolymers can improve the
mechanical properties of gels. Compared with amorphous (PEG–
PDLLA)n multipolymers, stereoregular (PEG–PDLLA) n multiblock copolymers have
a lower phase-transition temperature, and higher gel storage modulus and
mechanical strength. Star-shaped micelles formed by PEG-g-PLGA have smaller
hydrodynamic radius and lower viscosity than those of linear copolymers with the
same molecular weight. The star-shaped structure is conducive to gelation [122].
The eight-arm PEG-(PLLA)n star copolymer prepared by Nagahama had a sol state
at room temperature, and formed a gel as the temperature was increased.
Degradation time in the phosphate buffer system exceeded one month. All these
factors make it an ideal sustained-release delivery model [123,124]. There is an
example of a gel drug delivery system as shown in Figure 5.

Figure 5. Schematic illustration of the concept of stereocomplex hydrogel formed

by mixing aqueous solutions of bio-polymers containing enantiomeric oligo(lactic
acid) [125]. Reprinted from Nostrum with permission from Express Polymer
Letters.

15
 CHAPTER-3
POLYGLYCIDOL
3.1 INTRODUCTION:
Linear poly(ethylene oxide), one polymer that has found many
applications in medicine in spite of some pros and contras, is sufficiently stable,
hydrophilic, and biocompatible; when attached to surfaces it makes them protein
repellent, and provides “stealth” properties to the poly(ethylene oxide)-modified
nanoparticles [1,2,3,4,5,6]. However, the chains of linear poly (ethylene oxide)
cannot have more than two reactive end-groups, whereas, in many instances,
polymers with similar properties, but bearing multiple functional groups, are
needed. Such multifunctional polymers are suitable for covalent immobilization
of various drugs, receptor-targeting moieties, fluorescent labels, and many other
uses.
The closest multifunctional analogue of poly(ethylene oxide)
is polyglycidol (see Scheme 1). The number of hydroxyl –CH2OH groups in the
polyglycidol chain is equal to its degree of polymerization. Thus, polymers with
high molar masses provide many options for immobilization and labelling.

Scheme 1. Poly (ethylene oxide) and polyglycidol constitutional units.

3.2 SYNTHESIS OF POLYGLYCIDOL:

3.2.1 GLYCIDOL:
Glycidol contains two reactive groups in a molecule, epoxide
and hydroxyl (Scheme 2). In anionic polymerization the epoxide group is involved
in propagation, whereas the hydroxyl one is responsible for chain transfer
reactions. Therefore, the polymerization of glycidol always leads to branched
polymers. Linear polyglycidol could be synthesized only by polymerization of the
monomer with blocked –CH2OH groups (e.g., with 1-ethoxyethyl or trityl moieties).

16
Scheme 2. Structure of glycidol and 1-ethoxyethylglycidyl ether.
There are several routes for the synthesis of glycidol
(see Scheme 3) [12,13,14,15,16,17,18,19,20,21]. Industrial production of glycidol
is based on the epoxidation of allyl alcohol with hydrogen peroxide or on the
conversion of glycerol into glycerol monochlorohydrin and its subsequent
conversion into glycidol under the action of a strong base (e.g., KOH) [12,13].
However, these processes are not environmentally friendly, producing significant
amounts of harmful waste and causing corrosion of equipment. Recently, some
researchers concentrated their attention on the much more convenient approach
based on decarboxylation of glycerol carbonate. Using tetraethylammonium
amino acid ionic liquids (TAAILs) as catalysts allows us to carry out this synthesis
in one pot [17,18,20,21].

Scheme 3. Synthetic routes to glycidol.

The glycidol molecule contains a chiral carbon atom in the
ring. Since for some applications the enantiomerically pure polyglycidol (or
polyglycidol enriched in polymeric units of one enantiomer) might be needed,
some researchers investigated the stereocontrolled synthesis of glycidol. Already
in 1991, R. M. Hanson published an extensive review on this subject [12]. The
reviewed methods included synthesis of the optically active monomers from the
optically active substrates (e.g., from D-mannitol or L-serine), syntheses by
asymmetric epoxidation, enzymatic transformation of achiral substrates, and
chiral resolution. The latter is especially interesting because it could be based on

17
the already synthesized glycidol with blocked –CH2OH groups. Using the properly
chosen lipase and hydrolysis conditions allowed synthesis of glycidol with nearly
100% enantiomeric purity (see Scheme 4) [22].

Scheme 4. Synthetic pathway to enantiomerically pure glycidol.

Synthesis of linear polyglycidol requires a monomer with
blocked –CH2OH groups. Otherwise, the unblocked groups participate in chain
transfer, which leads to the branching. Fitton et al. described synthesis of glycidol
in which the hydroxyls were blocked with 1-ethoxyethyl groups [23]. The blocked
monomer was synthesized in a simple reaction of glycidol with vinyl ethyl ether.
The process was catalyzed with p-toluenesulfonic acid (see Scheme 5).

Scheme 5. Synthetic route to 1-ethoxyethylglycidyl ether.

3.2.2 PGA POLYMER:

Mono- and difunctional potassium alkoxides and sec-
BuLi/phosphazene base were used later as initiators [25,26,27,28,29,30].
However, detailed studies of the anionic polymerization of 1-ethoxyethylglycidyl
ether revealed that in these processes propagation is accompanied by chain
transfer, which leads to polymers with decreased molar masses (see Scheme
6 [28]).

18
Scheme 6. Propagation and cain transfer in the anionic polymerization of 1-
ethoxyethylglycidyl ether.
Polymers with higher molar masses (up to 85,000 for poly(1-
ethoxyethylglycidyl ether) and 53,000 for poly(tert-butyl glycidyl ether)) were
obtained by monomer-activated anionic polymerization initiated with
tetraoctylammonium bromide or tetrabutylammonium azide initiators and a
triisobutylaluminum catalyst [29,31]. Deblocking of hydroxyl groups in the
abovementioned polymers gave polyglycidol samples with Mn = 74,000 and
30,200, respectively. The mechanism of initiation and propagation for the
polymerization of 1-ethoxyethylglycidyl ether in a process with
tetrabutylammonium azide initiator and triisobutylaluminum catalyst (monomer
activator) is shown in Scheme 7.

Scheme 7. Polymerization of 1-ethoxyethylglycidyl ether with

tetrabutylammonium azide initiator and triisobutylaluminum catalyst (monomer
activator).
Activation of the monomer molecule with Al(i-Bu)3 leads to
formation of a partial positive charge at the endocyclic –CH2– group, which
facilitates the nucleophilic attack during the initiation and propagation steps.
Polymerization of 1-ethoxyethylglycidyl ether and deblocking
of –OH groups is not the only pathway to creating linear polyglycidol. Other
monomers, like trimethylsilylglycidyl ether and t-butylglycidyl ether, could also be
used for this purpose [32]. It is worth noting that t-butylglycidyl ether is
commercially available. However, the advantage of synthesis via polymerization
of 1-ethoxyethylglycidyl ether consists is the easy deblocking of –OH groups by
removal of acetal moieties in mildly acidic conditions.
In some instances, the difference in deprotection rates for
acetal and t-butyl groups could be beneficial. For example, in Section 2.7 (on
functionalized polyglycidol and polyglycidol-containing copolymers) we discuss
the synthesis of polyglycidol derivatives with different labels, based on the
selective removal of acetal and t-butyl groups in poly(1-ethoxyethylglycidyl ether)-
b-poly(t-butylglycidyl ether).

19
3.3 APPLICATIONS:
3.3.1 BIOCOMPATIBILITY:
Biocompatibility of polymers is indispensable for using these
materials in medicine as drug carriers, implants (regardless whether permanent
or resorbable), and various elements of equipment. Thus, the issue of the
biocompatibility of polyglycidol is of primary importance.
Efficient protein adsorption, accompanied by conformational changes
resulting in the denaturation of adsorbed proteins, usually triggers undesired
effects including immune response and clot formation, and has a deleterious
influence on the biological functions of adsorbed proteins. Extensive studies
carried out in our laboratory revealed that the incorporation of polyglycidol into
the interfacial layer of the polystyrene microspheres and surfaces of carbon
glass, gold, and stainless steel flat substrates leads to a strong reduction of
protein adsorption [57,58,59,60,61,62]. However, the activation of polyglycidol
hydroxyl groups with 1,3,5-trichlorotriazine allows for efficient covalent protein
binding (see scheme8) [57,59,61,62].

Scheme 8. Attachment of protein to polyglycidol.

Studies of interactions of linear and branched polyglycidols
and polyglycidol-containing copolymers with cell cultures and living organisms
revealed that these compounds:
 do not interact with the DNA of the Chinese hamster B14 cell
line (linear and arborescent polymers with poly (ethylene oxide) and
polyglycidol units) [63];

20
  are not toxic towards peripherial blood mononuclear cells
(hyperbranched) [64];
 are hemocompatible (hyperbranched polyglycidol and
hyperbranched copolymer of glycerol and sebacic acid) [65,66];
 and are well tolerated even if injected in high doses [65].
It was also found that dendritic polyglycidol with terminal sulfate end groups
has anti-inflammatory properties [67]. These observations support the attempts
to use polyglycidols with various architectures as well as their copolymers as
materials for medical applications.
3.3.3 DIAGNOSTIC-BASED DRUG CARRIERS:
Biocompatibility, long circulation time in the blood, the
availability of many routes for functionalization, and the suitability for controlled
binding of various biomolecules makes polyglycidol and its derivatives interesting
for applications in medical diagnostics, both in vivo and in vitro.
There is great interest in contrast agents used in tissue imaging. Gd3+-loaded
hyperbranched polyglycidol with amine groups containing corona [103] and
Fe3O4 superparamagnetic particles protected by a hyperbranched pololyglycidol
coating, used to stabilize particle circulation in the blood, were found to be
suitable for Magnetic Resonance Imaging (MRI) Hyperbranched polyglycidol with
sulfated corona, labeled with indocyanine green or indotricarbocyanine dyes,
were excellent agents for near-infrared fluorescence imaging
Complex particles comprising a superparamagnetic iron oxide core coated
with fluorescent silica and protected with grafted hyperbranched polyglycidol
constitute a new contrast agent for MRI and optical imaging [108]. Tri-modal
imaging systems were also developed based on hyperbranched polyglycidol
labeled with radioactive 111In, fluorescent Alexa dye, and Gd3+ for MRI [109].
Hyperbranched polyglycidol with moieties chelating 67Ga/68Ga were studied as
reagents for positron emission tomography (PET) [110]. Gold nanorods coated
with hyperbranched polyglycidol with sulfated corona were used as a contrast
agent for optoacoustic tomography, for the monitoring of rheumatoid arthritis
[111].
Polyglycidol with immobilized glucose oxidase is an essential component of
biosensors for the detection of glucose [112].
Basinska et al. developed a new type of diagnostic test based on the changes
of electrophoretic mobility in poly(styrene/α-tertbutoxy-ω-vinylbenzyl-
polyglycidol) [113]. The test was dedicated for determination of γ-globulins
against Helicobacter pylori in the blood serum. The microspheres were
synthesized by emulsion copolymerization of styrene and α-tert-butoxy-ω-
vinylbenzyl-polyglycidol. Their interfacial layer enriched in polyglycidol allowed
the covalent immobilization of antigens complementary to antibodies
against Helicobacter pylori, the proteins that are present in the blood of infected
patients. The polyglycidol-rich interfacial layer eliminated any adventitious

21
protein adsorption, allowing only attachment of antibodies against Helicobacter
pylori by antigen–antibody interactions. Since both microspheres and antibodies
are electrically charged, the attachment of antibodies affects the mobility of
microspheres in an electric field.

22
 CHAPTER-4
METHODS OF ANALYSIS OF BIODEGRADABLE POLYMERS
4.1 CHROMATOGRAPHICAL METHODS:
Chromatographic methods are described as a process
whereby a chemical mixture transported by a gas or liquid (mobile phase) is
separated into components as a consequence of the di erential distribution of the
solutes as they flow around or over a stationary solid or liquid phase (stationary
phase). This approach is commonly used to separate, identify, and determine the
chemical components of complicated mixtures and polymers. In comparison to
other methods, the chromatographic methods are touted as a powerful and
practical tool for the separation and identification of polymers.

4.1.1 SEC and GPC:

Size exclusion chromatography (SEC) is a chromatographic
method that separates compounds in a solution based on their size and molecular
weight. This method is commonly employed to separate complex
macromolecular substances, such as polymers and proteins. Gel-filtration
chromatography is the terminology utilised when an aqueous solution (mobile
phase) is used to transport the sample through the column (stationary phase), as
opposed to the method of gel permeation chromatography (GPC), which is used
when an organic solvent is used as a mobile phase. The chromatography column
is filled with tiny, porous beads formed of agarose, dextran, or polyacrylamide
polymers. These beads’ pore sizes are used to measure the dimensions of
macromolecule samples. Because of its ability to generate accurate molecular
weight data, SEC is commonly used for polymer characterization, which is deem
as an advantage in the polymer research field.
Theoretically, the smaller molecules are retained in the pores
of the adsorbent (stationary phase) in the column. Some particles enter the pores
as the solution travels through the column. In contrast, larger particles cannot
penetrate as many pores and simply pass by the pores, thus leading to a faster
elution time. As a result, larger molecules move faster through the column than
the smaller ones. In other words, longer retention times are associated with
smaller molecules

23
 CHAPTER-5
CONCLUSION
5.1 CONCLUSION FOR POLYLACTIC ACID(PLA):
Completely degradable PLA material solves the white-
pollution problem caused by petroleum-based materials, and has become the top
priority in the sustainable development of science and technology. Because PLA
possesses problems such as brittleness, poor mechanical properties, slow
crystallization speed, and low crystallinity, it is severely restricted in many
aspects, especially with respect to blown films. In order to overcome the
shortcomings of PLA, scientists modified it using physical or chemical methods
and prepared a series of ideal materials with good biodegradability, flexibility, and
heat resistance. Along with its low price, promising research results in this area
have guaranteed and expanded the application of PLA in many fields, providing a
platform for production and manufacturing in the fields of industry, 3D printing,
advanced technology, and the biomedical field.
In the process of commercialization of polylactic acid, the
price is a key issue to be solved. To solve the problem of the price of PLA, it is
necessary to start with the production of raw materials by improving the
production e iciency of lactic acid and obtaining high-quality lactic acid at low
cost. A further improvement in the production process of lactic acid is required
due to the low-cost materials and high-performance microorganisms. It can be
seen that the optimization of the production process of lactic acid is also a
challenge for the bulk production of polylactic acid.

5.2 CONCLUSION FOR POLYGLYCIDOL:

Synthesis of polyglycidol with moderate molar mass (about
30,000) and controlled topology (linear, star-like, hyperbranched) does not pose a
problem. Many methods were developed for synthesis of various copolymers
containing units of polyglycidol, polyethers (mainly poly(ethylene oxide) and
poly(propylene oxide)), polyesters (polylactide and poly(ε-caprolactone)), and
polyolefins (styrene). These copolymers could be functionalized with alkene and
alkyne moieties, sulfate, amine, azide, and carboxyl groups. They could be used
for binding proteins and other biomolecules. Polyglycidols modified with
hydrophobic segments self-assemble into polymeric micelles, polymeric
liposomes, and other kinds of aggregates. When tethered to surfaces they modify
the surface properties, making the surfaces hydrophilic and antifouling.
Amphiphilic derivatives of polyglycidol are promising candidates for drug carriers

24
and for contrast agents useful for various kinds of tissue imaging. However, in spite
of significant achievements in this field, there are still several problems to be
solved.
Many functionalization processes and synthetic routes of drug
carriers are multistep and for large-scale pharmaceutical applications they are
probably too expensive. Thus, a further search for simpler modification routes is
still needed. Knowledge of relations between topology and chemical composition
of polyglycidol-containing copolymers and their self-organization into polymeric
micelles and other types of nanoparticles is insu icient and still requires further
studies. In spite of numerous reports on protein–polyglycidol interactions, further
investigation will be needed to give a detailed explanation of these interactions at
a molecular level. The possibility of synthesizing high molar mass polyglycidol and
polyglycidol-containing copolymers with biodegradable segments; i.e.,
copolymers with mechanical properties appropriate for use as temporary
implants replacing tendons and other elastic tissue, has been insu iciently
explored.

25
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