APPLICATIONS OF PLA - POLY (LACTIC ACID) IN TISSUE ENGINEERING AND DELIVERY SYSTEMS

APPLICATIONS OF PLA - POLY (LACTIC ACID) IN TISSUE ENGINEERING
AND DELIVERY SYSTEMS
ABSTRACT
Poly (lactic acid) is a thermoplastic derived from renewable resources and is at
present, one of the most promising biodegradable and nontoxic biopolymers. In addition
to its versatility and consequent large-scale production, PLA can be processed with a large
number of techniques.
Due to its excellent mechanical properties and biocompatibility, this polymer is
becoming largely applied in the biomedical field such as in tissue engineering for
scaffolds and in delivery systems in the form of micro and nanoparticles. Furthermore,
because it’s relatively cheap and an eco-friend, it has been considered as one of the
solutions to lessen the dependence on petroleum-based plastics and solid waste problems.
In order to maximize the knowledge and development of this polymer, it is
necessary to understand the material synthesis, proprieties, manufacturing processes,
main applications, commercialization and its market state, which will be presented in this
review.
Keywords: Poly (lactic acid), PLA, Biomaterials, Biodegradability, Applications
CONTENTS
1. Introduction
2. Poly (lactic acid)
2.1. Precursors
2.2. Synthesis
2.3. Proprieties
2.4. Processing
2.5. Biomedical Applications
2.6. Other Applications
3. Economic Potential of PLA
4. Conclusions
1. INTRODUCTION
In the last years, the progresses of our society and consequently, the
technological and scientific developments, have driven significant advances in the
discovery, improvement and production of polymers. [1]
Biodegradable polymers are derived from naturally occurring polymers that are
found in all living organisms and can be classified into two groups: the agro-polyme rs
(polysaccharides, proteins) and the biodegradable polyesters such as poly (lact ic

2 Applications of PLA - Poly (lactic acid) in tissue engineering and delivery systems
acid) (PLA), poly (hydroxyalkanoate) (PHA), aromatic and aliphatic copolyester s.
Between these biopolyesters, PLA has caught the attention of polymer scientists as a
potential biopolymer to substitute the conventional petroleum-based plastics. [2, 3]
Poly (lactic acid) or PLA belongs to the family of aliphatic polyester s
commonly made from α-hydroxyacids. This polymer has been the subject of many
investigations for over a century. In 1845, Pelouze condensed lactic acid by
distillation of water to form low molecular-weight PLA and lactide, the cyclic dimer
of lactic acid. About 50 years later, Bischoff and Walden prepared PLA from lactide,
but without success. So, in 1932, Carothers et al developed a method to polyme r ize
lactide to produce PLA, but the method was unsuitable for its commercial viabili t y
and it was limited for biomedical applications. The breakthrough occurred in 1988,
when Cargill Incorporated began an investigation into lactic acid, lactide, and PLA
and consequently, started to address the manufacturing, melt processing and cost
issues. In 1997, Cargill and The Dow Chemical Company formed Cargill Dow LLC
in order to develop and bring to full commercialization the PLA technology and
products under the trade name NatureWorks. Ever since, the increased availability of
PLA stimulated an enlarged in its research activities. [2, 4]
The most attractive advantages that distinguish PLA from the more common
polymers are renewability, biocompatibility, processability and energy saving. First of
all, PLA is a thermoplastic, high-strength and high-modulus polymer derived from
renewable and degradable resources such as corn and rice, which can help alleviate the
energy crisis as well as reduce the dependence on fossil fuels of our society. It also is
degraded by simple hydrolysis of the ester bonds, which does not require the presence of
enzymes and in turn prevents inflammatory reactions. The hydrolytic products from such
degradation process are then transformed into nontoxic subproducts that are eliminated
through normal cellular activity and urine, making it an optimal material for biomedica l
applications. Moreover, this polymer has good thermal proprieties and thus it can be
processed by film casting, extrusion, blow molding, injection molding and fiber spinning.
This thermal processability is greater than other biomaterials such as poly (ethylene
glycol) (PEG), poly (hydroxyalkanoates) (PHAs) and poly(ɛ-caprolactone) (PCL),
contributing to the PLA application in textiles and food packaging fields. Finally, PLA
production consumes 25-55% less fossil energy than petroleum-based polymers which

3
Applications of PLA - Poly (lactic acid) in tissue engineering and delivery systems
will lead to significant reductions in air and water pollution and the total amount of water
required for PLA production it is also competitive. [1]
However, confronted with many requirements for certain applications, Poly(lact ic
acid) has some disadvantages as its slow degradation rate through hydrolysis of the
backbone ester groups which can takes several years and can prevent its biomedical and
food packaging applications. Another obstacle, unless it is properly modified, is the
brittleness of this polymer, with less than 10% elongation at break; it is not suitable for
demanding mechanical performance applications. PLA is also strongly hydrophobic and
when it is applied as a tissue engineering material, because of its low affinity with cells,
it can induce an inflammatory response from the tissues and living hosts. The last
limitation is its limited gas barrier proprieties which prevent its complete access to
industrial sectors such as packaging. From this point of view and considering its high
cost, low availability and limited molecular weight, PLA has not received the attention it
deserves, and that’s why the surface modification, the introduction of other components,
or the surface energy, charge and roughness control have been examined.[1]
Actually and in the biomedical field, micro and nanoparticles are a signific ant
group of delivery systems, and the application of PLA is interesting due to its low
toxicity and hydrolytic degradability. The most important properties of these systems
are the drug release rate and the matrix degradation rate which are affected by the
particle design and the material properties. Tissue engineering is also an area of
interest for the PLA application, mainly in porous scaffolds to reconstruct matr ic es
for damaged tissues and organs. [2]
In this paper we will discuss traditional topics including the synthesis, properties,
modification and processing techniques of this promising polymer, referring the raw
materials and comparing with other biopolymers, but also its biomedical and non-biomedical
applications, the potential products on the market and the recent and future
advances, providing a comprehensive picture of PLA as a successful biomaterial in the
near future.
2. POLY (LACTIC ACID)

Lactic acid is a chiral molecule existing in L and D isomers, so the mean of poly (lactic
acid) refers to a family of polymers: pure poly-L-lactic acid (PLLA), pure poly-D-lactic
acid (PDLA), and poly-D,L-lactic acid (PDLLA).
Between these molecules, the L-isomer is a biological metabolite and is the main
fraction of PLA derived from renewable and biological sources, since the majority of
lactic acid from these types of sources exists in this form. Depending on the composition
of the optically active L- and D, L-enantiomers, PLA can crystallize in the forms of α, β,
and γ, as can be verified later. [5]
2.1.POLY (LACTIC ACID): PRECURSORS
Poly (lactic acid) belongs to the family of aliphatic polyesters with lactic acid as the
basic unit. Lactic acid (2-hydroxypropionic acid) is a chiral molecule also known as “milk
acid” and can be produced by carbohydrate fermentation or by common chemica l
synthesis, and it is the monomeric precursor of poly (lactic acid). It is a hydroxyl acid
with an asymmetric carbon atom and two optically configurations: D and L isomers.
These isomers can be produced in bacterial systems, and the mammalian organisms only
produce the L isomer. [2, 7, 9]
Biomass Resources
- Long-stored rice
- Potatoes
- Cellulose
- Raw garbage, etc.
Photosynthesis
Chemical Recycle
(Feedstock Recycle)
Purification Polymerization
CO2
H2O
Poly
(lactic acid)
Product
Biodegradation Energy Recovery
(Combustion)
Lactide
Lactic
Acid
Lactic
Fermentatio
Starch
Figure 1 - The life cycle of Poly (lactic acid). PLA starting with fermentation of starch to give lactic acid,
the dimer form lactide is obtained, which is polymerized to give high molecular weight PLA. The PLA on
hydrolysis degrades to lactic acid which is further broken to give CO2 and H2O.
Lactic acid can be produced by chemical synthesis that is based on the hydrolysis of
lactonitrile by a strong acid and a racemic mix of the two isomers (D(−) and L(+)) lactic
acid is produced. The production of lactic acid has a significant interest, because of its

5
importance in environmental issues and its low production cost from sugarcane
fermentation, decreased fossil-based feedstock dependency, reduced CO2 emission,
biocatalyst use, and high product specificity [10].
About 90% of the total lactic acid produced is made by bacterial fermentation and the
remaining portion is produced synthetically by the previous process. The fermenta t ion
processes can be classified according to the type of bacteria that is used. The carbohydrate
fermentation can be heterofermentative and it produces lactic acid with significa nt
quantities of metabolites (carbon dioxide, acetic acid, ethanol, glycerol and mannitol); or
homofermentative, with greater yields of lactic acid and lower levels of metabolites. [4, 11,
12]
The carbon source for microbial production of lactic acid can be basic sugars such as
glucose, sucrose, lactose and maltose from corn, potato from cane or beet sugar, and so
one. The processing conditions are an acid pH close to 6, a temperature around 40°C and
a low oxygen concentration. The major method of separation consists in adding CaCO3,
Ca(OH)2, Mg(OH)2 , NaOH, or NH4OH to neutralize the fermentation acid and to give
soluble lactate solutions, which are filtered to remove both the cells (biomass) and the
insoluble products. The product is then evaporated, crystallized, and acidified with
sulphuric acid to obtain the crude lactic acid.
Lactide is usually obtained by the depolymerization of low molecular weight PLA
under reduced pressure to give a mixture of L, D and meso lactide. In most of the
processes is the separation between each stereoisomer to control the final PLA structure,
based on the boiling point differences between the meso- and the L or D lactide. [2]
2.2.POLY (LACTIC ACID): SYNTHESIS
PLA synthesis starts from the lactic acid production with an intermediate step, the
formation of the lactide and ends with its polymerization. For this process there are three
main methods, polycondensation and ring opening polymerization, which are the most
common routes, and by direct methods like azeotopic dehydration, as we can see in figure
2. [5, 2]

Figure 2 - Synthesis methods for obtaining high molecular weight PLA.
The condensation polymerization is the least expensive method and includes solution
polycondensation and melts polycondensation. This method produces a low molecular
weight and brittle polymer which is unusable if there is no external agents to increase the
chain length. In polycondensation, for the removal of water produced, solvents and/or
catalysts are used under high temperatures and vacuum. To produce a variety of molecular
weights, the resultant polymer can be used with epoxides, isocyanides or peroxides. [5, 8]
This method has three phases, the removal of the free water; oligomer
polycondensation and melt condensation of high molecular weight PLA. In first and third
stages, the removal of water is the rate-determining step. For the second one, the rate
determining step is the chemical reaction, which depends on the catalyst used.
Polycondensation creates oligomers with average molecular weights several tens of
thousands and other reactions can occur, such as the formation of ring structures as
lactide, named transesterification.
The direct polycondensation of lactic acid in bulk is not applied on a large scale,
because of the competitive reaction of lactide formation and the simultaneously occurring
degradation process. In the sequential melt/solid-state polycondensation besides the three
mentioned steps (i. e., removal of the free water content, oligomer polycondensation, and
melt polycondensation) is utilized an additional fourth stage. In the fourth stage, the melt -
polycondensated PLA is cooled below its melting temperature, followed by particle
formation, which then subjected to a crystallization process. Chain extension is effective
way to achieve high molecular weight lactic acid-based polymers by polycondensat ion.
In this method the intermediate low molecular weight is to treat polymers with chain

7
extenders which link the low molecular weight pre polymer into a polymer of high
molecular weight. [5, 7]
The main vantages of polycondensation are the low costs and easy control, but the
disadvantages are the reactions to the temperature, the reaction time, catalysis, pressure
and the susceptibility to impurities from the solvent. These parameters can strongly
influence the molecular weight of the final products. [2]
In azeotopic dehydration condensation no chain extenders or adjuvants are needed
and it can yield high molecular weight PLA directly. In this method, it’s relatively easy
to remove the water formed from the reaction medium, through the reduction of the
pressure distillation of lactic acid and the removal of the condensation water. [5, 7]
The next step is the addition of the catalyst and diphenyl ether, and the attachment of
a tube packed with molecular sieves to the reaction vessel for the returning of the
refluxing solvent to the vessel by way of the molecular sieves. Then the PLA is purified.
For this method, the disadvantages are the catalyst residues which are toxic and can
cause degradation and hydrolysis, presenting many drawbacks in biomedica l
applications. [5]
The last one, Ring-Opening Polymerization (ROP) of lactide is the main and the most
usual method to synthesized PLA. This is an important and effective route to manufac ture
high molecular weight PLA and occurs by ring opening of the lactide with a catalyst. It
can be performed as a bulk polymerization, emulsion, dispersion or in solution.
The mechanisms of the ROP process can be summarized in three steps:
polycondensation, depolymerization and ring-opening polymerization. An initiator is
required to start the polymerization which has different influence on transesterifica t ion
which is decisive for the enantiomeric purity and chain architecture of the resulting
macromolecules. So this type of mechanism depends on the initiator, and it can be
cationic or anionic and coordination- insertion for high molecular weight. Different types
of initiators have been tested, but among them, stannous octoate is preferred because it
offers high reaction rate, high conversion rate, and high molecular weights, even under
rather mild polymerization conditions. [5, 8]
For this process, a complex between monomer and initiator is made and then, a
rearrangement of the covalent bonds. The monomer is inserted within the oxygen–me ta l
bond of the initiator, and its cyclic structure is thus opened through the cleavage of the
acyl–oxygen link, therefore the metal is incorporated with an alkoxide bond into the
propagating chain. This polymerization and the transesterification effect are affected by

different parameters, such as the polymerization temperature and time; the
monomer/catalyst ratio and the type of catalyst. It’s also important to mention that the
chain length is controlled by the OH impurities.
It is possible to control the ratio and sequence of D- and L-lactic acid units in the final
polymer by monitoring residence time and temperatures in combination with catalyst type
and concentration. [2]
2.3. POLY (LACTIC ACID): PROPRIETIES
The stereochemistry and thermal characteristics of PLA have direct influence on its
crystallinity, molecular characteristics, degree of chain orientation and its general
properties. [2, 5]
The two isomers of lactic acid, L-lactic acid and D-lactic acid, or the mixtures of both,
are needed for the synthesis of PLA. The homopolymer of lactic acid is a white powder
at room temperature with Tg and Tm values of about 55°C and 175°C, respectively. High
molecular weight PLA is a colorless, glossy, rigid thermoplastic material with properties
similar to polystyrene.
The two isomers of LA can produce four distinct materials: Poly (D-lactic acid)
(PDLA), a crystalline material with a regular chain structure; poly(L-lactic acid) (PLLA),
which is hemi crystalline, and likewise with a regular chain structure; poly(D,L-lac t ic
acid) (PDLLA) which is amorphous; and meso-PLA, obtained by the polymerization of
meso-lactide. PDLA, PLLA and PDLLA are soluble in common solvents including
benzene, chloroform, dioxane, etc. and degrade by simple hydrolysis of the ester bond
even in the absence of a hydrolase. [5]
The L-isomer constitutes the main fraction of PLA derived from renewable sources
since the majority of lactic acid from biological sources exists in this form. Depending on
the composition of the optically active L- and D,L-enantiomers, PLA can crystallize in
three forms (α, β and γ). The α-structure is more stable and has a melting temperature Tm
of 185 ◦C compared to the β-structure, with a Tm of 175 ◦C. [6]
PLA with PLLA content higher than 90% tends to be crystalline, while the lower
optically pure is amorphous. The melting temperature (Tm), and the glass transition
temperature (Tg) of PLA decrease with decreasing amounts of PLLA. [4, 5, 6]

9
Physical characteristics such as density, heat capacity, and mechanical and rheologica l
properties of PLA are dependent on its transition temperatures.[13] For amorphous PLA,
the glass transition temperature (Tg) is one the most important parameters since dramatic
changes in polymer chain mobility take place at and above Tg. For semicrystalline PLA,
both Tg and melting temperature (Tm) are important physical parameter for predicting
PLA behavior. [4, 5, 14] The melt enthalpy estimated for an enantiopure PLA of 100%
crystallinity (ΔH°m) is 93 J/g; it is the value most often referred to in the literature
although higher values (up to 148 J/g) also have been reported. [15]
The density of amorphous and crystalline PLLA has been reported as 1.248 g ml−1
and 1.290 g ml−1, respectively. The density of solid polylactide was reported as 1.36 g
cm−3 for l-lactide, 1.33 g cm−3 for meso-lactide, 1.36 g cm−3 for crystalline polylact ide
and 1.25 g cm−3 for amorphous polylactide. [4, 5]
In general, PLA products are soluble in dioxane, acetonitrile, chloroform, methylene
chloride, 1,1,2-trichloroethane and dichloroacetic acid. Ethyl benzene, toluene, acetone
and tetrahydrofuran only partly dissolve polylactides when cold, though they are readily
soluble in these solvents when heated to boiling temperatures. Lactid acid based polymers
are not soluble in water, alcohols as methanol, ethanol and propylene glycol and
unsubtituted hydrocarbons (e.g. hexane and heptane). Crystalline PLLA is not soluble in
acetone, ethyl acetate or tetrahydrofuran.
PLA can be tailored by formulation involving co-polymerizing of the lactide with other
lactones type monomers, a hydrophilic macromonomers (polyethylene glycol (PEG)), or
other monomers with functional groups (such as amino and carboxylic groups, etc.), and
blending PLA with other materials. [5,9] Blending can radically alter the resultant
properties, which depend sensitively on the mechanical properties of the components as
well as the blend microstructure and the interface between the phases. Polymers made
from ε-caprolactone are excellent drug permeation products. However, mechanical and
physical properties need to be enhanced by copolymerization or blending.[4, 5, 16]
PLA degrades primarily by hydrolysis, after several months exposure to moisture.
Polylactide degradation occurs in two stages. First, random non-enzymatic chain scission
of the ester groups leads to a reduction in molecular weight. In the second stage, the
molecular weight is reduced until the lactic acid and low molecular weight oligomers are
naturally metabolized by microorganisms to yield carbon dioxide and water.
The polymer degradation rate is mainly determined by polymer reactivity with water
and catalysts. Any factor which affects the reactivity and the accessibility, such as particle

size and shape, temperature, moisture, crystallinity, % isomer, residual lactic acid
concentration, molecular weight, water diffusion and metal impurities from the catalyst,
will affect the polymer degradation rate.
The in vivo and in vitro degradation have been evaluated for polylactide surgical
implants. In vitro studies showed that the pH of the solution does play a role in the in
vitro degradation, and that, an in vivo study can be used as a predictor of the in vivo
degradation of PLA.[4,5]
Table 1 - Physical and chemical properties of PLA[1]
Properties PDLA PLLA PDLLA
Solubility
All soluble in benzene, chloroform, acetonitrile, tetrahy drofuran, diexane…, but
insoluble on ethanol, methanol, and hydrocarbons
Crystalline S tructure Crystalline Hemicrystalline Amorphous
Melting Temperature
(Tm)/ ºC
~180 ~180 Variable
Glass Transition
Temperature (Tg)/ ºC
50-60 55-60 Variable
Decomposition
Temperature/ ºC
~200 ~200 185-200
Elongation at Break/ (%) 20-30 20-30 Variable
Breaking S trength/ (g/d) 4.0-5.0 5.0-6.0 Variable
Half-life in 37ºC normal
saline
4-6 months 4-6 months 2-3 months
2.4. POLY(LACTIC ACID): PROCESSING
The main conversion processes for PLA are based on melt processing. This method
implicates heating the polymer above its melting point, shaping it to the desired forms,
and cooling to stabilize its dimensions. So, the understanding of the polymer properties
such as crystallization, thermal and rheological performance is critical to optimize the
quality of the process. Examples of melt processed PLA are injection molded disposable
cutlery, thermoformed containers and cups, injection stretch blown bottles, extruded cast
and oriented films, and meltspun fibers for nonwovens, textiles and carpets [6]
In the last few years, PLA has also been managed with other type of materials, making
composites with desirable and exclusive properties.
The extrusion of PLA products is normally associated with other processing steps
such as thermoforming, injection molding, film blowing, extrusion coating, and so one,
so the properties of the polymer will be determined on the specific conditions during the
processing steps. The most important considerations during the melt processing are the

11
temperature, residence time, moisture content and atmosphere, but the major problem is
the limited thermal stability during this melting step and to overcome this obstacle and to
give new proprieties to this polymer, a variety of multiphase materials have been
developed, mixing PLA with others products. [2]
Lactide monomer is a good plasticizer for Poly (lactid acid), although it presents high
migration because of its small molecular size. Thus, oligomeric lactic acid (OLA) seems
to be a better solution, since it demonstrates low migration and high efficiency. The
integration of citrates or maleates, mainly in PLLA, improves its flexibility. These
plasticizers are miscible with PLA, but increasing the plasticizer content can increase the
crystallinity by enhancing chain mobility. Other plasticizers that are compatible with PLA
are low molecular weight polyethylene glycol (PEG), polypropylene glycol and fatty
acid. [2]
The PLA-based blends (such as starch/PLA blends), can decrease the costs without
losing its degradability and preserving the thermal and mechanical properties. Native
starch can be blended with PLA, but it remains in a separate conglomerate form in the
PLA matrix because it is composed of semi-crystalline granules, making a poor adhesion
with PLA. Thus, many experiments work with thermoplastic starch, which is produced
by the disruption of the granular starch and the transformation of its semi-crystall ine
granules into a homogeneous, rather amorphous material with the destruction of hydrogen
bonds between the macromolecules. Although this concern in plasticized starch/PLA
materials, there are some restrictions, because of the poor compatibility between the
constituents, mainly because of the PLA hydrophobic character.
It is proved that poly (lactic acid) forms miscible blends with PEG when the PLA
fraction is below 50 per cent. The PLA/PEG blend consists of two semi-misc ible
crystalline phases dispersed in an amorphous PLA matrix. PHB (polyhydroxybutyra te)
/PLA blends are miscible over the whole range of composition and both PLA/PGA and
PLA/PCL blends give immiscible components.
Developing low cost multilayer and compostable materials is also curious.
Coextrusion and compression molding are the techniques that are used. The major
problems in coextrusion concerns in the multilayer flow conditions, such as encapsulat ion
and interfacial instability phenomena.
Numerous types of fillers have also been tried with PLA, such as calcium phosphate
or talc, which demonstrates an increase in its mechanical properties. In inorganic fillers,
the greatest reinforcing effect is obtained with whiskers of potassium titanate and

aluminum borate with a high aspect ratio. Carbon or glass fibers improve the mechanica l
properties, particularly with fiber surface treatments capable of inducing strong
interactions with PLA matrix. Different organic fillers can be associated with PLA.
Biocomposites with improved mechanical properties are obtained by the association
of ligno-cellulose fillers, such as paper-waste fibers and wood flour, with PLA by
extrusion and compression moulding. [2]
2.5.POLY(LACTIC ACID): BIOMEDICAL APPLICATIONS
The biomaterials main requirements for medical applications include
biocompatibility, sterilizability, nontoxicity and effectiveness. The combination of the
biomaterial and the function for which it is projected without undesired responses is
named biocompatibility and the materials with this characteristic can be biodegradable,
if they remain temporarily in the body and disappear upon degradation or non-biodegradable,
if they stay in the body and require long-term biocompatibility. [4] The
most important advantage of biodegradable over non-degradable biomaterials is not
required removal of implants. [5]
Among the synthetic biodegradable polymers, the most common in medical
applications are the poly(α-hydroxyacid)s, including poly(glycolic acid) (PGA),
polydioxanone (PDS) and poly(lactic acid) (PLA). [5] The latter is the most promising
polymer because of its mechanical properties and it has been successfully used for many
medical implants and approved in many countries.
The application of PLA in medicine goes back to 1966 when Kulkami et al found
that PLLA had nontoxic tissue response when implanted in guinea pigs and rats. Later, in
1971, Cutright and Hunsuck reported the PLA application in orthopedic fixation and
sutures. [4]
Nowadays, the main biomedical applications of PLA are in surgical implants, drug
delivery systems and also as porous scaffolds for the growth of tissues (figure 3) and
because of its slow degradation, the polymer can be blended or copolymerized with other
components to increase the degradation rate. [5]
The degradation of PLA by hydrolytic scission of ester linkages yields lactic acids.
Lactic acid is a natural product associated with muscular construction in animals and
humans, which can be decomposed by the body’s normal metabolic pathways. In the
body, lactic acid is converted to pyruvic acid and enters the tricarboxylic acid cycle to

13
yield carbon dioxide and water. Using carbon-labeled PLA, no significant amount of
accumulation of degradation products was found in any organ; only very little was found
in feces or urine, indicating that the products were released through respiration. Since L-lactic
acid (LLA) is the naturally occurring stereoisomer of lactic acid, PLLA is more
commonly used for medical applications than poly(D-lactic acid) (PDLA), which yields
D-lactic acid (DLA).
Tissue Engineering
•Porous Scaffold for
Ti s sue Remodeling
2.5.1. Tissue Engineering
Delivery Systems
•Dosage Forms
•Sus tained Release
and Targeted
Drug,
peptide/protein
and DNA/RNA
del ivery
Other fields
•Membrane
applications
(wound covers)
•Implants and
Medical Devices
(fixation rods,
plates, pins,
s crews, sutures)
•Dermatological
Treatments (facial
l ipoatrophy and
s car rejuvenation)
The field of tissue engineering was created to improve and develop biologic a l
functions and it’s closely associated with methods to reconstruct living tissues by
combining the cells and biomaterials. This association provides a scaffold, a temporarily
supporting structure on which they can proliferate three-dimensionally and under
physiological conditions.The advantages of tissue engineering over transplantation are
that a donor is not required and there is no problem of transplant rejection. [9]
A suitable scaffold for tissue engineering use should be biocompatible and have a
good integration into host tissues without any immune response, be porous and have
appropriate pore size and distribution for removing metabolic waste and allow cell and
tissue growth. In addition, it must be biodegradable and mechanically able to support
local stress and structure.
Not all biomaterials have the capability of being used in this field, for example,
although some metals have good mechanical proprieties and consequently being used in
biomedical implants, they are not so advantageous for scaffolds because of their lack of
degradability. Ceramics are also limited and despite good osteocondutivity and therefore
mineralization, they have poor processability into porous structures.

Some linear aliphatic polyesters such as PLA and its copolymers, due to their
structure and proprieties can be used in scaffolds. These polymers are approved by the
FDA in biomedical field, but like the other materials, have some disadvantages like their
slow rate of degradability, hydrophobicity and lack of functional groups, which
conditions cells adhesion.
Poly(lactic acid), alone or in combination with other materials, provides good
support for cell growth. A fibrous scaffold has significant advantages over polymer films
in the high level of porosity needed to accommodate large number of cells. This is where
the pore diameter (interstitial space) becomes important for cell growth, vascularizat ion,
and diffusion of nutrients. [9]
PLA Three-dimensional porous scaffolds have been created for culturing differe nt
cell types, using in cell-based gene therapy for cardiovascular diseases; muscle tissues,
bone and cartilage regeneration and other treatments of cardiovascular, neurological, and
orthopedic conditions. Osteogenic stem cells seeded on scaffolds of this material and
implanted in bone defects or subcutaneously can recapitulate both developmenta l
processes of bone formation: endochondral ossification and intramembranous
ossification. Due to the high strength of PLLA mesh, it is possible to create 3D structures
such as trays and cages. [5]
Several researches have shown that the PLA-based hybrid materials are
particularly promising and they have been successfully tested in many tissues such as
bladder, bone, liver, cartilage and adipose. Chitosan/PLGA by heparin immobilization is
an example of a novel scaffold that is being clinically tested. The introduction of chitosan
into PLGA microspheres improves the attachment of biomolecules such as heparin
because of chitosan’s reactive amino group. This heparinized chitosan/PLGA scaffolds
with a low heparin loading showed a stimulatory effect on cell differentiation and may be
used in bone regeneration.
For tissue engineering, the application of three-dimensional scaffolds as synthet ic
extracellular matrices allowed the cells proliferation and secretion while the scaffold
gradually degrades. These 3D scaffolds, often consist of polymer/ceramic composites,
such as a polymeric matrix filled with bioactive glasses, glass ceramics and calcium
phosphates, that combine the advantages of the two types of materials. The polymers that
are used in the matrix can be such as chitin and chitosan and collagen or synthet ic

15
polymers such as saturated aliphatic polyesters: polylactic acid (PLA), polyglycolic acid
(PGA), polycaprolactone (PCL) and polyhydroxyalkanoates. [2]
Three-dimensional electrospun fibrous scaffolds have been also studied for bone
regeneration. Electrospinning uses an electrical charge to draw micro and nano scale
fibers from a liquid and the use of these 3D materials like microfibrous PLLA scaffolds
have reported a higher level of osteoblasts proliferation and a favorable substrate for cell
infiltration and bone formation.
In cartilage tissue engineering, collagen and hyaluronan-based matrices are among
the most used scaffolds nowadays, because of their substrates which are normally
essential elements in native articular cartilage. The PLA is used in very few cases and as
PGA/PLA copolymer under the trade name BioSeed-B and BioSeed-C by German
industry (Biotissue Technologies AG, Freiburg, Germany). [2]
However, despite these recent developments, PLA-based materials still have an
important limitation for tissue engineering which is the risk of immune response and
disease transmission. In the future, it’s expected the use of designer scaffolds with in vivo
experimentation, and coupling scaffold design with cell printing to create designer
material hybrids to optimize tissue engineering treatments.
2.5.2. Delivery Systems
Delivery systems are methods and processes of administering bioactive
compounds to achieve therapeutic effect. In contrast to many materials which have been
tested for this type of application and with the objective of minimizing the risks, PLA can
be considered a great component because of its biocompatibility, mechanical strength,
heat processability, solubility in organic solvents and ability to produce small size dosage
forms such as microcapsules, micro and nanoparticles for their permeation through
biological barriers. These capsules are composed of a polymeric wall containing an inner
core where the drug is entrapped; therefore the drug is completely inside the particle.
Nano and microspheres, however consist of a solid polymeric matrix in which the drug
can be dispersed and distributes throughout the whole particle. [17]
As in tissue engineering field, some PLA-based materials have been approved by
the FDA in delivery systems, despite having many limitations such as their poor chemica l
proprieties to improve cell interactions, the restricted sustained release of hydrophil ic
molecules like proteins, the low encapsulation efficiency and high burst release of the

encapsulated biomolecule within the first few hours or days because of the weak
interactions between the hydrophilic molecules and the polymer. To overcome these
obstacles, measures like large doses, site-specific administration and the introduction of
functional groups on these materials becomes necessary.
The drug release is controlled by drug diffusion and polymer degradation and this
type of delivery system involves binding fragments specific to a tumor-associated surface
antigen, with a ligand binding to its corresponding receptor on the tumor cell surface,
which can be attached on the surface of the PLA-based materials. Furthermore, these
types of materials that can display a physiochemical response to changes in their
environment are considered a potential drug and gene delivery systems.
For genetic diseases, PLGA nanoparticles have been explored with the aim to
overcome the major obstacle in the use of nucleic acids, the low delivery efficiency of the
therapeutic DNA to the diseased site. The nanoparticles of PLGA can be manipulated to
escape the degradative endosomal lumen because of their physical proprieties.
In the context of incorporation of monomeric substrates on PLA-based materia ls,
PEG is considered one of the most promising polymers and it has being employed in
several commercial applications (Ocaspar and Neulasta). This incorporation contributes
to modify the polymeric matrix by adding a hydrophilic part that can change the
physicochemical properties of hydrophobic PLA/PLGA segments, obtaining particles
that exhibit long circulation properties. Considering the available hydrophilic polymers,
PEG has been found to be particularly effective, probably due to its chain flexibilit y,
electrical neutrality and absence of functional groups which avoids undesired interactions
with biological components in vivo, forming a protective coating on the particle surface.
Another valid alternative to the use of the PEG, is the polysaccharide CS whose
OH groups supply and hydrophilic character to nano and microparticles. CS has been
recognized for its mucoadhesivity, biodegradability and ability to enhance the penetration
of large molecules across mucosal surfaces. These are other reasons to be an eligible
alternative to the PEG. The addition of CS to the system is usually accompanied by the
incorporation of lecithin to the organic phase, where the polymer is dissolved. The real
objective of this procedure is to promote interactions between polymer and CS that will
be facilitated by the ionic interaction between the negatively charged surfactant (lecithi n)
and the positively charged CS molecules. Many studies concluded that there is no
formation of nanoparticles when the CS acts alone, so the best choice seems to be a

17
mixture with PVA in order to obtain not only cationic particle but also with uniform size
and spherical shape.
To summarize, according to the available references it is clear that the most widely
employed substrates to induce changes in the properties of PLA-based nano and
microparticles are PVA, PEG and CS. [17]
The surface modification of PLA-based nano and microparticles is another
strategy widely utilized in order to generate materials able to interact with polar
substrates. In this context, special attention deserves the incorporation of magnetic
compounds (based on iron oxides) into PLA-based nano- and microparticles that lead to
‘‘magnetic nano- and microparticles’’ useful for the magnetic drug targeting. The aim of
the drug targeting is to carry the desired amount of drug to the required target and release
it at a controlled rate. Among the ways to control the targeting specificity, there is a
possibility to use the magnetically-guided particles as drug carriers. By application of an
external magnetic field, magnetic particles could be retained within a target organ for a
given period of time limiting the spreading of the particles in the general circulation. For
this purpose, the magnetic particles should be entrapped into a particulate biodegradable
polymer matrix to improve the drug loading and the release profile.
The incorporation of Zn to nano and microparticles formulation has also been
reported. Zn increased the encapsulation efficiency of bethamethasone phosphate in the
nanoparticles by formation of a water-insoluble complex with the drug, favouring the
formation of nanoparticles by interaction with a carboxyl group in the PLA-based
molecule. They also pointed out that the presence of Zn delayed the degradation of the
matrix polymer and enlarged the size of the resultant particles, which is suitable for
intravenous administration and accumulation in inflammatory sites. [17]
PLA-based materials that are used for drug delivery have mostly been in the form
of injectable microspheres or implant systems requiring complicated fabrication
processes with organic solvents which can denature components being encapsulated.
They have also low transfection efficiencies in vitro and the animal tests and clinical trials
are reduced. In the latest developments, hybrid versions of this material have been
potentiated, but many issues still remain like the presence of surfactants or stabilizers in
the microparticles necessary to achieve antigen binding and colloidal stability.
2.5.3. Other Biomedical Applications

As we saw earlier, PLA is a polymer of great versatility, thus it has been explored
for another biomedical applications such as wound covers, implants and medical devices
(fixation rods, plates, pins, screws, sutures) and dermatological treatments (facial
lipoatrophy and scar rejuvenation).
In wound treatment, the immobilization of drugs or antibacterial agents within the
nanofibers by electrospinning or the electrospinning of polymers with intrins ic
antibacterial and wound-healing properties is one of the best solutions. The most common
materials for this application are silver nanoparticles and chitosan because of their high
intrinsic activity against a broad spectrum of bacteria.
For fracture fixation, metals are still the most popular materials. However, there
are disadvantages such as stress shielding, accumulation in tissues, hypersensitivit y,
growth restriction, pain, corrosion, and interference with imaging techniques. In order to
lessen all these drawbacks, PLA has been a target of many studies because of its
satisfactory strength during the healing of bone tissue and degradation. [5]
As mentioned previously, the degradation product, lactic acid, can be decomposed
by the body. However, LA is a relatively strong acid and its accumulation at the impla nt
site, due to the “burst” release by the bulk degradation of PLA, will result in lowering of
local pH and can trigger an inflammation response. Inflammation that lasts for more than
1 year has been observed in some cases. Another study revealed that particles smaller
than 2 mm released by degradation have caused a foreign body reaction resulting in
detrimental effects in bone tissue. Some research has been targeted at attempting to
neutralize the acidic degradation products by adding agents such as calcium carbonates
and/or calcium phosphates to the PLLA implants. In
Addition, many studies have been conducted on development of a new range of initia tors
and catalysts based on metals that are more biocompatible, including magnesium and
calcium.
The applications of PLA as fixation rods, plates, pins, screws, sutures, and so one
in orthopedics and dentistry is also increasing. Surgical sutures are wound closure
filaments fabricated in various shapes. The basic requirement of sutures is that they hold
tissues in place until natural healing of a wound provides sufficient tissue strength. PLA
has been approved by the Federal Drug Administration (FDA, USA) for use as a suture
material because of features that offer crucial advantagesAn example of a commercia l

19
product in this type of clinical applications is the VICRYL suture material, based on
PGA/PLA copolymers.
Because of its slow degradation rate, PLLA fibers are not suitable for sutures, but
in applications that require long retention of the strength, such as ligament and tendon
reconstruction, and stents for vascular and urological surgery, PLLA fibers are the
preferred material. PLLA fibers were used clinically to augment ruptured knee ligame nts
in early 1990. The anterior cruciate ligament (ACL) connects bones of the knee joint and
is the most commonly injured ligament during sporting activities or trauma. Since a
completely torn ACL cannot be repaired by itself, reconstructive surgery using autografts,
such as patellar tendons (part of the tendon in the front of the knee) or hamstring tendons,
needs to be carried out. However, if enough material is not available, polymer ic
biomaterials such as polyethylene and polypropylene are used. PLLA fibers have been
utilized for this application and showed similar improvement in tendon reconstruction
compared to polypropylene in an animal model. PLLA fibers are also utilized in the form
of biodegradable stents in cardiovascular and urological surgery. [5]
When the progression of the bone healing, it is necessary that the bone is subjected
to a gradual increase in stress and this is possible only if the plate loses rigidity in in vivo
environment. A solution is the introduction of resorbable polymers as PLA reinforced
with non-resorbable materials (such as carbon and polyamide fibers). Carbon fibers/PLA
composites have high mechanical proprieties before implantation, but they lose them too
quickly in vivo. [2]
In the dermatological treatments field, lipodystrophy is associated with the usage
of highly active antiretroviral therapy (HAART) containing protease inhibitors or
nucleoside reverse transcriptase inhibitors for HIV patients. Sculptra [poly(L-lactic acid)]
was the first injectable facial “volumizer” in the treatment of this syndrome and it acts
with the stimulation of the fibroblastic activity, generating connective tissue fibers. PLA
can also treat scars due to acne, traumas, surgeries and sutures. For example, PLLA can
be applied in the form of injectable microspheres to filling in facial reconstructive
surgery. These microspheres can also been used as an embolic material in transcatheter
arterial embolization, which is an effective method to manage arteriovenous fistula and
malformations, massive hemorrhage, and tumors. [5]
2.6.POLY(LACTIC ACID): OTHER APPLICATIONS

Currently, in addition to the recent market in biomedicine, PLA-based materia ls
are also applied in the textile (mainly in Japan) and the packaging (such as food
packaging) market.
Poly (lactic acid) is considered an economically material for packaging and it is
the most important market in biodegradable packaging. One of the first companies to use
PLA as packaging material was Danone in yoghurt cups and during the last years, the
application of this material has increased all across USA, Japan and Europe, mainly in
the fresh products packaging. Presently, this polymer can be found in containers, drinking
cups, wrappings for sweets, lamination films, blister packages, water bottles and
cardboards. For this market the mainly disadvantages are the limited mechanica l
proprieties and heat resistance. [2]
3. ECONOMIC POTENTIAL OF PLA
Recently, poly (lactic acid) has gained much popularity among the biodegradable
plastics that are available in the market. In the future, it is expected that the increasing
awareness regarding the environmental issues by the use of conventional plastics cause
an increase in the PLA and Lactic Acid market.
Statistically, the global market of Lactic Acid is dominated by North America,
accounting for 35.8% of the overall market in 2010. Europe and Asia-Pacific are the
second and third largest markets for lactic acid; accounting for 29.9% and 29.2% of the
overall market respectively in 2010. Industrial applications are the largest for lactic acid,
accounting for 42.4%. Industrial applications have surpassed food and beverages as a
leading application for the consumption of lactic acid. This has primarily been a result of
strong growth in the PLA and solvents markets for which lactic acid is the primary raw
material. [26]
Some researchers estimate the global capacity of this biopolymer in the next few
years. It is expected that Europe will be the most dominant market and Asia-Pacific, the
fastest growing market in the next five years, due to its significant domestic demand. [26]
A challenge for industries that produce this material is to increase the skills and
alternatives in relation to costs efficiency. However, this market has some restrictions on

21
the supply due to the shortage of major suppliers on a global platform and more high-quality
L-lactic acid is needed. [26]
Especially in the Asia-Pacific region, the market players are increasing their
production capacities, mainly because their abundance of raw materials such as
sugarcane, sugar beet and tapioca for the lactic acid production. In 2011, the Lactic Acid
total capacity in China reaches 385,000t/year and its output comes to 165,500 tonnes, and
in the same year, the output of corn and glucose is 184,000,000 tonnes and 1,900,000
tonnes, respectively. [25, 26]
The PLA market is forecasted for many geographic regions such as North America,
Europe, Asia-Pacific, and some key growth regions such as Brazil. The major producing
countries are U.S., U.K., China and Japan. In terms of volumes, revenue, developme nts,
strategies and major applications of this biopolymer, the major companies that in the
coming years will continue to lead are NatureWorks LLC (U.S.), Purac (The
Netherlands), Pyramid Bioplastics Guben GmBH (Germany), Archer Daniels Midland
Company (U.S.), and Henan Jindan (China).[26]
Besides this, several U.S. companies have built demonstration-scale plants and have
recognized the environmentally products and processes, so they have strategies for major
large-scale plants in the future. Some novel processes are also being developed for
simplistic production of lactic polymer feedstock from lactic acid and a variety of
polymers and copolymers with many potential applications could be resulting as these
products and processes are brought on-stream. These new technologies, can give at the
manufacturing costs and economics of lactic acid and its derivatives an attractive potential
in large-scale systems. [27]
4. CONCLUSIONS
Throughout this review work, it was possible to concluded that poly (lactic acid) has
several and desirable properties, including biocompatibility, renewabilit y,
biodegradability, transparency, and thermoplasticity, making it an ideal biomaterial for
numerous biomedical applications.
Furthermore, since the discovery of this polymer, scientists can decrease the
environmental concerns that are associated with the conventional polymers applications.
Among some drawbacks of this biopolymer, the major concern in the previous years
was its costs compared with other polymers, but nowadays it’s possible to reduce these

prices by optimizing the lactic acid and PLA manufacturing processes and because of the
increasing demand, the price is currently lower.
The next objectives of many polymer scientists are to extent and prove to some
companies based on petrochemicals, the advantages of the PLA such as the catalysts with
good biocompatibility, the excellent stereo selectivity and low toxicity, but also to
improve and overcome its drawbacks such as its slow degradation rate, poor ductility, and
hydrophobicity. For these disadvantages, some modifications of the poly (lactic acid)
bulk and surface proprieties are being explored.
Fortunately, promising results have been testified, but in the present, these
conclusions cannot be generalized to the most of biomedical applications because most
of these experiments were carried out in vitro. However these advances give the chance
to increase some studies about the associations between the proprieties and functionalit ies
of this polymer with the biological systems such as cell adhesion, biological responses
and biodegradability, which can develop PLA biomedical applications in some areas such
as in tissue engineering (scaffolds) and in delivery systems (micro and nanoparticles).
Thus, according to the reported characteristics, we can conclude that PLA is one
of the most highly versatile biodegradable polymers synthesized from renewable
resources for biomedical devices applications and from the environmental viewpoint,
the proprieties of this biopolymer are well suited for many applications where
recycling, reuse and recovery of products are not possible. As PLA is obtained by the
lactic acid, which is found in some raw materials based on the agricultural feedstock,
the increase of its use will certainly create a positive impact on the global agricultura l
economy and in the environment.
Depending on the type of application that is required, the technology for the PLA
processing can be different, but all the converting processes of PLA consists on melt
processing and the most important technique for creating a homogeneous PLA melt
is the extrusion. Other important parameter in order to obtain a reliable final product
is the rigorous control of the material properties and surroundings in which it’s
processed, since the polymer is very sensitive to changes on the outer conditions.
To finalize, thanks to this polymer, novel and economical technologies are being
explored and improved with large expectations of revolutionizing the world of
biomedicine and a wide range of products can be marketed in the future, with a great
success.

23
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InTech, DOI: 10.5772/23927.
[2] Averous L. (2008). Polylactic Acid: Synthesis, Properties and Applications, Belgacem
N. and Gandini A. (Eds), Elsevier Publication. Accessed: 1 Oct. 2012.
http://www.biodeg.net/fichiers/Polylactic%20Acid%20Synthesis%20Properties%20and
%20Applications.pdf
[3] Balakrishnan H., Hassan A., Imran M., Wahit M. U. (2012). Toughening of Polylactic
Acid Nanocomposites: A Short Review, Polymer-Plastics Technology and Engineer ing,
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[4] Auras, R., Lim, L.T., Selke, S.E.M., Tsuji, H. (2010). Poly (lactic acid): Synthesis,
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[5] Lasprilla, A.J.R., Martinez, G.A.R., Lunelli, B.H., Jardini, A.L., Filho, R. M. (2012).
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[6] Lim, L.T., Auras, R., Rubino, M. (2008). Processing technologies for poly(lactic
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[7] Zhu, R. (2011). Preparation of Maleic Anhydride Grafted Poly (lactic acid) (PLA) and its
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[8] Kaur, P. (2011). Kinetic Studies on Polymerization of Poly(Lactic Acid) Using
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[10] Lunelli, B.H., Andrade, R.R., Atala, D.I.P., Wolf, Maciel M.R., Maugeri, Filho. F.,
Maciel R. (2010). Production of lactic acid from sucrose: strain selection, fermentation,
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[11] Garvie, E.L. (1980). Bacterial lactate dehydrogenases. Microbiol Rev 1980;44:106–39
[12] Hofvendahl, K., Hahn-Hägerdal, B. (2000). Factors affecting the fermentative lactic acid
production from renewable resources. Enzyme Microb Technol 2000; 26:87–107

[13] Henton, D.E., Gruber, P., Lunt, J., Randall, J. (2005). Polylactic acid technology. In:
Mohanty AK, editor. Natural Fibers, Biopolymers and Biocomposites. CRC Press; 2005. p. 528–
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[14] Bouapao, L., Tsuji, H., Tashiro, K., Zhang, J., Hanesaka, M. (2009). Crystallization,
spherulite growth, and structure of blends of crystalline and amorphous poly(lactide)s. Polymer
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[15] Södergard, A., Stolt, M. Properties of lactic acid based polymers and their correlation with
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[16] Broz, M.E., VanderHart, D.L., Washburn, N.R. (2003 ). Structure and mechanical properties
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[17] Lassalle V., Ferreira M.L. (2007). PLA Nano- and Microparticles for Drug Delivery:
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[25] Global Industry Analysts, Inc, (April 2012). Lactic Acid - Global Strategic Business
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