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Critical Reviews in Therapeutic Drug Carrier Systems, 29(1), 163 (2012)
0743-4863/12/$35.00 2012 Begell House, Inc. www.begellhouse.com 1
Scaffold: A Novel Carrier for Cell and Drug DeliveryTarun Garg,* Onkar Singh, Saahil Arora & R.S.R. Murthy
Department of Pharmaceutics, ISF College of Pharmacy, Moga (Punjab), India 09501223252(M)
*Address all correspondence to: Tarun Garg; Tel.: 09829752244; [email protected].
ABSTRACT: Scaffolds are implants or injects, which are used to deliver cells, drugs, and genes into the body. Different forms of polymeric scaffolds for cell/drug delivery are avail-able: (1) a typical three-dimensional porous matrix, (2) a nanofibrous matrix, (3) a thermosen-sitive sol-gel transition hydrogel, and (4) a porous microsphere. A scaffold provides a suitable substrate for cell attachment, cell proliferation, differentiated function, and cell migration. Scaffold matrices can be used to achieve drug delivery with high loading and efficiency to specific sites. Biomaterials used for fabrication of scaffold may be natural polymers such as alginate, proteins, collagens, gelatin, fibrins, and albumin, or synthetic polymers such as polyvinyl alcohol and polyglycolide. Bioceramics such as hydroxyapatites and tricalcium phosphates also are used. Techniques used for fabrication of a scaffold include particulate leaching, freeze-drying, supercritical fluid technology, thermally induced phase separation, rapid prototyping, powder compaction, sol-gel, and melt moulding. These techniques allow the preparation of porous structures with regular porosity. Scaffold are used successfully in various fields of tissue engineering such as bone formation, periodontal regeneration, repair of nasal and auricular malformations, cartilage development, as artificial corneas, as heart valves, in tendon repair ,in ligament replacement, and in tumors. They also are used in joint pain inflammation, diabetes, heart disease, osteochondrogenesis, and wound dressings. Their application of late has extended to delivery of drugs and genetic materials, including plasmid DNA, at a controlled rate over a long period of time. In addition, the incorporation of drugs (i.e., inflammatory inhibitors and/or antibiotics) into scaffolds may be used to prevent infec-tion after surgery and other disease for longer duration. Scaffold also can be used to provide adequate signals (e.g., through the use of adhesion peptides and growth factors) to the cells, to induce and maintain them in their desired differentiation stage, and to maintain their survival and growth. The present review gives a detailed account of the need for the development of scaffolds along with the materials used and techniques adopted to manufacture scaffolds for tissue engineering and for prolonged drug delivery.
KEY WORDS: scaffold, tissue engineering, implants, prolonged drug delivery, tissue regen-eration, graft surgery
I. INTRODUCTION
Tissue engineering aims to replace or facilitate the regrowth of damaged or diseased tis-sue by applying a combination of biomaterials, cells and bioactive molecules.1 Every day thousands of clinical procedures are performed to replace or repair tissues in the human body that have been damaged through disease or trauma. The damaged tissue is replaced by using donor graft tissues (autografts, allografts, or xenografts), but the main problems
-
Critical Reviews in Therapeutic Drug Carrier Systems
2 Garg et al.
associated with this are a shortage of donors or donor sites, transmission of disease, rejec-tion of grafts, donor site pain and morbidity, the volume of donor tissue that can be safely harvested, and the possibility of harmful immune responses.2 Compared with replacing damaged tissues with grafts, tissue engineering, or regenerative medicine, there are aims to regenerate damaged tissues by developing biological substitutes that restore, maintain, or improve tissue function.3,4 In the last 2 decades, the research and development among the scientific community in this emerging field of tissue engineering and regenerative medicine has progressed at a rapid rate.5 Biodegradable polymeric scaffolds for tissue en-gineering have received much attention because they provide a temporal and spatial en-vironment for cellular growth and tissue in-growth.68 Scaffold is the central component that is used to deliver cells, drugs, and genes into the body. The definition of the scaffold is categorized into 2 main categories: (1) a cell delivery scaffold and (2) a drug deliv-ery scaffold. When cells are implanted or seeded into an artificial structure capable of supporting three-dimensional (3D) tissue formation, these structures typically are called cell delivery scaffolds, and when drugs are loaded into a 3D artificial porous structure capable of high drug loading efficiency and sustained release of a drug for longer dura-tion, they typically are called drug delivery scaffolds.9 Different forms of polymeric scaffolds for cell/drug delivery are available: (1) a typical 3D porous matrix, which is a highly porous and well interconnected open pore structure that allows high cell seed-ing density and tissue in-growth, as shown in (Fig. 1A); (2) a nanofibrous matrix that is prepared by electrospinning or self-assembly would provide a better resemblance of the physiological environment (Fig. 1B)8,10; (3) a thermosensitive sol-gel transition hydrogel (Fig. 1C); and (4) a porous microsphere (Fig. 1D). These are already widely utilized as sustained protein-release formulations and have been applied in tissue engineering for the potential use as a cell delivery carrier or supportive matrix.11,12
Of the polymeric scaffolds listed above, a typical 3D porous matrix and nanofibrous matrix are the implantable forms and a thermosensitive sol-gel transition hydrogel and
Figure 1. Different forms of polymeric scaffolds for cell/drug/gene delivery: three-dimensional porous matrix (A); nanofiber mesh (B); hydrogel (C); and microsphere (D).
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Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 3
porous microsphere are the injectable forms. Tissue engineering technologies are based on this biological triad and involve the successful interaction between three compo-nents: (1) the scaffold that holds the cells together to create the tissues physical form; (2) the cells that create the tissue; and (3) the biological signalling molecules, such as growth factors, that direct the cells to express the desired tissue phenotype (Fig. 2).13
Scaffold for tissue engineering (cell delivery) should posses the following:1. Mechanical properties that are sufficient to shield cells from tensile forces with-
out inhibiting biomechanical cues 2. Desired volume, shape, and mechanical strength8 3. Acceptable biocompatibility 4. A highly porous and well-interconnected open pore structure to allow high cell
seeding density and tissue in-growth5. Bioadsorption at predetermined time period 6. Biocompatible chemical compositions and their degradation products, causing
minimal immune or inflammatory responses14 7. Physical structure to support cell adhesion and proliferation, facilitating cell
cell contact and cell migration15 Scaffold for drug delivery should posses the following:1. Homogenous drug dispersion throughout the scaffold 2. Ability to release the drug at a predetermined rate 3. Drug binding affinity that is sufficiently low to allow the drug released to be stable
when incorporated in the scaffold at a physiological temperature 4. Stable physical dimension, chemical structure, and biological activity over a
prolonged period of time. There is a significant challenge in the design and manufacture of scaffolds that pos-
sess all of the above requirements and the ability to control the release kinetics of drug or growth factors over the period of treatment or tissue regeneration.9
Figure 2. The tissue engineering triad.
-
Critical Reviews in Therapeutic Drug Carrier Systems
4 Garg et al.
II. PROPERTIES OF SCAFFOLD MATRICES IN CELL/DRUG DELIVERY
Scaffolds play a critical role in tissue engineering. The function of scaffolds is to direct the growth of cells either seeded within the porous structure of the scaffold or migrating from surrounding tissue. The majority of mammalian cell types are anchorage-depen-dent, meaning they will die if an adhesion substrate is not provided. Scaffold matri-ces can be used to achieve cell delivery with high loading and efficiency to specific sites. Therefore, the scaffold must provide a suitable substrate for cell attachment, cell proliferation, differentiated function, and cell migration1619 to permit the transport of nutrients, waste, and biological signalling factors to allow for cell survival. The ma-trix material should be biodegrade at a controllable rate that approximates the rate of natural tissue regeneration and should provoke a minimal immune and/or inflamma-tory response in vivo.13 Tissue engineering scaffolds are meant to be colonized by cells and should transmit the chemical and physical cues necessary to ensure adequate tissue growth. Synthetic polymer scaffolds may be used to deliver proteins and growth factors with or without cells locally to enhance tissue repair and regeneration.9 An ideal tissue engineering scaffold should fulfill the following 11 requirements.20
II.A. Biocompatibility
The scaffold should possess acceptable biocompatibility and toxicity profiles.16 Bio-compatibility is the ability of the scaffold to perform in a specific application without eliciting a harmful immune or inflammatory reaction.13 If the scaffold is nontoxic and degradable, new tissue will eventually replace it, whereas if it is nontoxic and biologi-cally active, the scaffold will integrate with the surrounding tissue. However, if the scaf-fold is biologically inactive, it may be encapsulated by a fibrous capsule; in the worst case, when the scaffold is toxic, rejection of the scaffold and localized death of the sur-rounding tissue can occur.21
II.B. Biodegradability
The scaffold material should be biodegradable. Its degradation products should not be toxic and should be eliminated easily from the implantation site by the body,13 eliminat-ing the need for further surgery to remove it.22 The scaffolds degradation rate should be adjusted to match the rate of tissue regeneration so that it has disappeared completely once the tissue is repaired.16
II.C. Mechanical Properties
Mechanical properties of the scaffold should match those of the tissue at the implanta-tion site, or the mechanical properties at least should be sufficient to shield cells from damaging compressive or tensile forces without inhibiting appropriate biomechanical cues15,23 and to survive under physiological conditions. Immediately after implantation,
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Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 5
the scaffold should provide a minimal level of biomechanical function that should im-prove progressively until normal tissue function has been restored, at which point the construct should have fully integrated with the surrounding host tissue.13
II.D. Structure
It should have a reproducible microscopic and macroscopic structure with a high surface:volume ratio suitable for cell/drug attachment.16
II.E. Interface Adherence
Interface adherence is how cells or proteins attach to a scaffolds surface. The scaffold should support cell adhesion and proliferation, facilitating cellcell contact and cell mi-gration.15
II.F. Porosity
Porous structures allow for optimal interaction of the scaffold with cells.13 Specifically, pore size determines the efficiency at which cells seed into the scaffold24; small pores prevent the cells from penetrating the scaffold, whilst large pores prevent cell attach-ment due to a reduced area and, therefore, available ligand density.13 The scaffold should have an adequate porosity; this includes the magnitude of the porosity, the pore size distribution, and its interconnectivity. This also will allow cell in-growth and vasculari-sation and promote metabolite transport.16 A scaffold with an open and interconnected pore network and a high degree of porosity (>90%) is ideal for the scaffold to interact and integrate with the host tissue.25
II. G. Nature
Mimicking the native extracellular matrix (ECM), an endogenous substance that sur-rounds cells, allows them to bind into tissues and provide signals that aid cellular devel-opment and morphogenesis.15,26
II.H. Processability
The scaffold should possess relatively easy processability and malleability into the de-sired shape, according to the need. They should be capable of being produced into a sterile product.
II.I. Loading Capacity Release Kinetics
Loading capacity release kinetics is defined as the amount of drug that can be mixed into the scaffold. The scaffold should have a maximum loading capacity so the drug is
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Critical Reviews in Therapeutic Drug Carrier Systems
6 Garg et al.
released continuously for longer duration after insertion into the body. The drug needs to be dispersed homogenously throughout the scaffold or in discrete areas and must avoid an initial burst effect. The drug release from the scaffold needs to be controlled to allow the appropriate dose of drug to reach the cells over a given period of time.
II.J. Binding Affinity
Binding affinity is defined as how tightly the drug binds the scaffold; this binding affin-ity must be sufficiently low to allow release of the drug; however, low binding affinity would lead to dose dumping, which eventually may produce toxic effects.
II.K. Stability
The stability of the incorporated drug/cell at physiological temperature with respect to physical, chemical, and biological activity is to be assessed. They should posses di-mensional stability, chemical stability, and biological activity over a prolonged period of time.9
III. DESIGN STRATEGIES FOR CELL AND DRUG DELIVERY SYSTEMS
Although prefabricated scaffolds are most widely used for tissue regeneration as well as drug delivery purposes, different forms of polymeric scaffolds for cell/drug delivery are also available. These forms can be classified as (1) a typical 3D porous matrix, (2) a nanofibrous matrix, (3) a thermosensitive sol-gel transition hydrogel, and (4) a porous microsphere. Of these, the typical 3D porous matrix and nanofibrous matrix are the implantable forms and the thermosensitive sol-gel transition hydrogel and the porous microsphere are the injectable forms. Injectable scaffold materials formed in situ have received much attention recently because they can be administered using a syringe needle15 and thus avoid surgery. To mimic the topological and microstructural characteristics of the ECM, a biomaterial must have a high degree of porosity, a high surface:volume ratio, a high degree of pore interconnection, appropriate pore size, and geometry control.27 These properties can be well controlled in an injectable scaffold. Some of the drug/cell delivery systems and their design strategies are given in the fol-lowing sections.
III.A. Hydrogel-Based Systems
Hydrogel matrices are physically or chemically cross-linked, water-soluble polymers, which swell to form a gel like substance on exposure to water.28 Hydrogels are appealing for biological applications because of their high water content and biocompatibility.29 Hydrogels can be made from naturally occurring polymers such as collagen, chitosan, and gelatine or synthetic polymers such as poly(ethylene glycolide) and poly vinyl alco-hol. Growth factors are released from hydrogels through diffusion of the growth factor
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Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 7
through the highly hydrophilic scaffold, mechanical stimulation, or hydrolytic degrada-tion of the scaffold28 or upon swelling in response to an environmental stimulus. For example, gelatin and dextran can be fabricated as an interpenetrating polymer hydrogel for drug delivery and can exhibit an intelligent property of degradation in response to dual stimuli.30 Release behavior can be regulated by controlling the chemical and physi-cal properties of the gels from a few days to several months.31 Above critical concentra-tions, these hydrogels show a sol state at room temperature, but change into a gel state at body temperature15; hydrogels can be administered in a minimally invasive manner and therefore they are used in tissue engineering strategies as a potential cell and protein delivery vehicle.27 Additional advantages of hydrogels are that they may protect drugs, peptides, and especially proteins against the potentially harsh environment in the vicin-ity of the release site; they enable enhanced residence times, sustained delivery, and/or targeted drug delivery29; and they have significant potential in wound healing applica-tions, though pore size and degradation properties must be optimized.27 For example, in-jectable poly(N-isopropylacrylamide) physical hydrogels encapsulating cells have been prepared for cartilage and nerve regeneration.32,33 Pluronic/heparin composite hydrogels delivering growth factor also have been studied to induce angiogenesis.34 Photo cross-linked poly(ethylene glycol) (PEG)based hydrogels have been utilized for delivery of chondrocytes and osteoblasts.3537 Bone morphogenic protein introduced into the hydro-gel material (temperature-sensitive chitosan-polyol salt combination) has been effective in promoting de novo bone and cartilage formation in vivo.38 Poly(lactic acidglycolic acid) (PLGA) grafted with PEG and PEG grafted with PLGA hydrogels capable of sus-tained insulin delivery and cartilage repair were synthesized.39 Pluronic copolymers at a higher concentration (more than 20% [w/v]) have been used to encapsulate chondro-cytes and produce engineered cartilage.40
III.B. Microsphere- and Microparticle-based Systems
Microspheres and microparticles have attracted attention as carrier matrices in both the biomedicine and bioengineering fields and could satisfy the need of delivering biomol-ecules such as growth factors, genes, and cells.41 Prior to injection, the porous structure (30 m) would allow sufficient cell seeding in and out of the matrix. After injection in vivo, the porous matrix would permit infiltration of cells and ingrowth of tissue from the host, facilitating the regeneration process.15 Microparticles also can be used as inject-able scaffolds to support cell growth and proliferation directly and as vehicles of growth factor, and to enhance cell proliferation and expansion simultaneously.27 Microsphere-based technology has an application for tissue engineering as well as gene therapy. Gene delivery has several potential advantages, such as the inherent stability of plasmid DNA, reduced fabrication costs, extended shelf-life, a more economical use , and application in skin repair.42 Application is pellets incorporated with basic fibroblast growth factorloaded microspheres into alginate porous scaffolds to enhance vascularization after im-plantation in the rat peritoneum. Chitosan scaffolds loaded with basic fibroblast growth factor contained in gelatin microparticles were effective in accelerating wound closure
-
Critical Reviews in Therapeutic Drug Carrier Systems
8 Garg et al.
of pressure ulcers.43 Biodegradable PLGA microspheres have been studied for delivery of chondrocytes for cartilage engineering.15 Nanofabricated particles could offer better delivery properties to direct cell fate and to regulate processes such an angiogenesis and cell migration.27
III.C. Membrane-based Systems
Human skin is considered the gold standard for treatment of skin wounds. However, skin grafts are not always the perfect solution. They are limited in terms of the conditions needed for tissue availability, graft rejections, and conformability with the surround-ing tissue with respect to thickness and pigmentation.44,45 Current strategies for wound dressings have been aimed at the development of the bilayer-structured membrane, with incorporation of growth factors into these matrices for improved healing. For example, gelatin hydrogel containing epidermal growth factorloaded microspheres has an en-hanced effect on re-epithelization, improving the healing of the wound area. Antibiotics should be incorporated into the membranes to prevent infections because sustaining a sufficient drug concentration at the site of infection is important for the treatment of an infected wound. For example, a bilayered membrane combines silver sulphadiazine and a laminin-modified collagen membrane, which was shown to facilitate the dermal wound healing process.46
IV. BIOMATERIALS FOR SCAFFOLD FABRICATION
A number of different categories of biomaterials are commonly used as scaffold for cell and drug delivery.
IV.A. Natural Polymers
Natural polymers include alginate, proteins, collagens, gelatin, fibrins, albumin, elsinan, pectin (pectinic acid), galactan, curdlan, gellan, levan, emulsan, dextran, pullulan, gluten, elastin, fibroin, hyarulonic acid, cellulose, starch, chitosan (chitin), scleroglucan, heparin, silk, chondroitin 6-sulfate, and polyhydroxyalkanoates. They can be used as biomateri-als for cell/drug/gene delivery purposes. Advantages of natural polymers include their biocompatibility, commercial availability, easy processing, and they more closely mimic the natural ECM of tissues; however, limitations are short supply, expense, batch-to-batch variation, and susceptibility to cross-contamination.47 Different natural polymers and their properties, advantages, disadvantages, and applications are described in Table 1.
IV.B. Synthetic Polymers
Synthetic polymers are largely divided into two categories: biodegradable and nonbio-degradeable. Biodegradable polymers are polyglycolide, polylactide and its copolymer poly(lactide-co-glycolide), polyphosphazene, polyanhydride, poly(propylene fuma-
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Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 9
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
atio
ns
A.1
A.1
.1Pr
otei
n-or
igin
C
olla
gen4
858
Col
lage
n is
a m
ajor
pro
tein
co
mpo
nent
of t
he E
CM
that
in
tera
cts
with
cel
ls in
con
nec-
tive
tissu
es a
nd tr
ansd
uces
es
sent
ial s
igna
l for
the
regu
la-
tion
cell
anch
orag
e, m
igra
tion,
pr
olife
ratio
n, d
iffer
entia
tion,
an
d su
rviv
al.
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d bi
ocom
patib
ility
Lo
w a
ntig
enic
ity
Hig
h m
echa
nica
l stre
ngth
Abi
lity
to b
e cr
oss-
linke
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ood
cell
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gniti
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Vira
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prio
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mbi
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xten
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rate
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egra
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ster
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rtific
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kin,
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liga
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tebr
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isc,
gen
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ascu
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orth
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dru
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yA
.1.2
Gel
atin
576
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Gel
atin
is a
den
atur
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rote
in
obta
ined
by
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and
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oces
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olla
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in w
ater
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repa
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hydr
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thro
ugh
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ical
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oss-
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ith w
ater
-so
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Bio
degr
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and
bio
-co
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phy
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Lo
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rger
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cula
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psul
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l dr
ug d
eliv
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A.1
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ilk fi
broi
n57,
58,6
365
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der s
ilk is
an
intri
guin
g bi
omat
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l tha
t is
light
wei
ght,
extre
mel
y st
rong
and
ela
s-tic
, and
exh
ibits
mec
hani
cal
prop
ertie
s co
mpa
rabl
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the
best
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thet
ic fi
bers
pro
duce
d by
mod
ern
tech
nolo
gy.
Silk
wor
m B
omby
x m
ori
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to w
eave
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ajor
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po-
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e fib
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and
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ater
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ber B
ioco
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low
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iver
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ound
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ssin
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s, a
nter
ior c
ruci
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TAb
le 1
. Pro
pert
ies,
Adv
anta
ges,
Dis
adva
ntag
es a
nd A
pplic
atio
ns o
f Nat
ural
bio
mat
eria
ls U
sed
as S
caffo
lds
for C
ell a
nd D
rug
Del
iver
y
-
Critical Reviews in Therapeutic Drug Carrier Systems
10 Garg et al.
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
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A.1
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brin
27,5
7,58
,64,
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a p
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atrix
pr
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om fi
brin
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-vi
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une-
com
patib
le
carr
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or d
eliv
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of a
ctiv
e bi
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ecul
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peci
ally
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ls.
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in n
atur
ally
con
tain
site
s fo
r cel
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, and
has
bee
n in
vest
igat
ed a
s a
subs
trate
fo
r cel
l adh
esio
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prea
ding
, m
igra
tion,
pro
lifer
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ibrin
ha
s ha
emos
tatic
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mot
actic
an
d m
itoge
nic
prop
ertie
s.
Indu
ce im
prov
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cellu
lar i
nter
actio
n, U
sed
as a
ce
ll ca
rrie
r to
man
y ce
ll ty
pes,
su
ch a
stra
chea
l epi
thel
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ells
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urin
e em
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nic
stem
cel
ls,
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ench
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geni
tor c
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, ke
ratin
ocyt
es a
nd u
roth
eliu
m
cells
Rap
id d
egra
datio
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ifficu
lt to
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ntai
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in
tegr
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Inst
able
, Lo
w m
echa
nica
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fnes
s
Bon
e an
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artil
age,
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ular
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Ski
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Car
diov
ascu
lar,
Spin
al c
ord
inju
ry, I
nter
verte
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al d
isc,
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ondr
al,
Tiss
ue s
eala
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Perip
hera
l ner
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ener
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n,
sept
al c
hond
rocy
tes
A.1.
5el
astin
57,7
274
Elas
tin is
syn
thes
ized
by
vasc
ular
sm
ooth
mus
cle
cells
an
d se
cret
ed a
s a
tropo
elas
tin
mon
omer
that
is s
olub
le, h
ydro
-ph
obic
, and
non
glyc
osyl
ated
. El
astin
is a
pot
ent r
egul
ator
of
vasc
ular
sm
ooth
mus
cle
cell
activ
ity, r
egul
atio
ns im
porta
nt
for p
reve
ntin
g fib
roce
llula
r pa
thol
ogy.
Con
fers
ela
stic
ityPr
ecis
e m
olec
ular
wei
ght
Low
pol
y-di
sper
sity
Bio
com
pat-
ibilit
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esis
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ontro
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adat
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rine
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ular
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ooth
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cle
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tivity
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omes
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lubl
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ncre
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mpe
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es in
solu
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and
aggr
e-ga
te a
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ritic
al te
mpe
ratu
re
Dru
g de
liver
y, c
ardi
ovas
cu-
lar,
bloo
d ve
ssel
repl
ace-
men
ts, v
ascu
lariz
atio
n in
bo
ne re
gene
ratio
ns
A.1
.6S
oybe
an57
,75
Ric
h in
pro
tein
s (4
050
%),
carb
ohyd
rate
s (2
630
%),
and
lipid
s (2
030
%).
Abu
ndan
t R
enew
able
Inex
pens
ive
Env
ironm
ent f
riend
ly B
iode
-gr
adea
ble
App
licat
ion
of s
oy-b
ased
po
lym
ers
in th
is fi
eld
is s
till v
ery
narr
ow
Gro
wth
fact
or,
cell
and
drug
del
iver
y, in
the
food
in
dust
ry, c
ompu
ter c
asin
gs,
elec
troni
c ch
ip p
acka
ging
TAb
le 1
. (co
ntin
ued)
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 11
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
atio
ns
A.2
.A
.2.1
Poly
sacc
harid
e po
lym
ers
Chi
tosa
n57,
58,7
678
A fu
lly/p
artia
lly d
eace
ty-
late
d fo
rm o
f chi
tin. D
egre
e of
de
acet
ylat
ion
of c
omm
erci
al
chito
san
is u
sual
ly b
etw
een
70%
and
95%
, and
the
mo-
lecu
lar w
eigh
t bet
wee
n 10
and
10
00 k
Da.
Chi
tosa
n ex
hibi
ts
a pH
-sen
sitiv
e be
havi
or a
s a
wea
k po
ly-b
ase
beca
use
of
the
larg
e qu
antit
ies
of a
min
o gr
oups
on
its c
hain
.
Bio
logi
cally
rene
wab
leB
iode
grad
able
and
bio
com
-pa
tible
Non
antig
enic
and
non
toxi
cB
iofu
nctio
nal
Inex
pens
ive
Add
ition
al c
ontro
l ove
r chi
to-
san
s fin
al p
rope
rty
Indu
ces
rapi
d bo
ne re
gene
ra-
tion
at in
itial
sta
ges
Bon
e fo
rmat
ion
afte
r im
plan
ting
thes
e m
atric
es o
ccur
s ov
er a
lo
ng p
erio
d (s
ever
al m
onth
s or
ye
ars)
.
Bon
e an
d ca
rtila
ge, n
erve
, sk
in,
perio
dont
al b
one,
os
teoc
hond
ral,
vasc
ular
iza-
tion,
wou
nd d
ress
ing,
dr
ug d
eliv
ery,
enc
apsu
la-
tion
of c
ells
, sut
ures
A.2
.2St
arch
57,7
981
Sta
rch
is s
tore
d as
inso
lubl
e gr
anul
es c
ompo
sed
of
am
y-la
se (2
030
%) a
nd a
myl
opec
-tin
(70
80%
).P
hysi
cal p
rope
rties
of s
tarc
h ar
e gr
eatly
influ
ence
d by
the
amou
nt o
f wat
er p
rese
nt.
Deg
rada
tion
prod
ucts
are
ol
igo
sacc
harid
es th
at c
an
be re
adily
met
abol
ized
to
prod
uce
ener
gy.
Inhe
rent
bio
degr
adab
-ility
O
verw
helm
ing
Abu
ndan
ce
Ren
ewab
ility
Ext
rem
ely
diffi
cult
to p
roce
ss
Brit
tle
Sem
icry
stal
line
nativ
e st
arch
gr
anul
es s
truct
ure
is e
ither
de-
stro
yed,
reor
gani
zed,
or b
oth.
Bon
e, v
ascu
lariz
atio
n, d
rug
deliv
ery
incl
udin
g ca
ncer
th
erap
y, n
asal
adm
inis
tra-
tion
of in
sulin
A.2
.3A
lgin
ate1
3,57
,58,
82
Orig
inat
es fr
om s
eaw
eed
and
is s
truct
ural
ly s
imila
r to
natu
ral
GA
Gs.
It is
an
anio
nic
poly
mer
w
ith c
arbo
xyl e
nd g
roup
s is
a
good
muc
oadh
esiv
e ag
ent
with
a h
igh
degr
ee o
f sw
ellin
g an
d sh
rinki
ng d
urin
g ca
tioni
c cr
oss-
link
ing.
Bio
com
patib
le
Sim
ple
gela
tion
met
hods
Res
ista
nce
to a
cid
cond
ition
Poo
r mec
hani
cal p
rope
rties
U
ncon
trolle
d de
grad
atio
n ki
net-
ics
Dru
g lo
ss b
y le
achi
ng
Bon
e an
d ca
rtila
ge, v
as-
cula
rizat
ion,
inte
rver
tebr
al
disc
, liv
er a
nd p
ancr
eas,
drug
del
iver
y, e
ncap
sula
-tio
n of
cel
ls, s
utur
es,
wou
nd d
ress
ings
, per
iph-
eral
ner
ve re
gene
ratio
n,ge
ne e
xpre
ssio
n
TAb
le 1
. (co
ntin
ued)
-
Critical Reviews in Therapeutic Drug Carrier Systems
12 Garg et al.
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
atio
ns
A.2
.4H
yalu
roni
c ac
id57
,58,
838
8
This
is a
maj
or m
acro
mol
ecu-
lar c
ompo
nent
of t
he E
CM
.H
yalu
rona
n is
a n
atur
ally
oc-
curr
ing,
non
sulfa
ted
glyc
os-
amin
o-gl
ycan
and
a m
ajor
m
acro
mol
ecul
ar c
ompo
nent
of
the
inte
r-ce
llula
r mat
rix o
f m
ost c
onne
ctiv
e tis
sues
suc
h as
car
tilag
e, v
itreo
us o
f hu-
man
eye
, um
bilic
al c
ord,
and
sy
novi
al fl
uid.
Bio
com
patib
leE
asily
func
tiona
lized
Goo
d ce
ll re
cogn
ition
Eas
ily a
nd c
ontro
llabl
y pr
o-du
ced
in a
larg
e sc
ale
thro
ugh
mic
robi
al fe
rmen
tatio
n
Poo
r mec
hani
cal p
rope
rties
E
xpen
se o
f pre
serv
atio
n an
d st
orag
e in
a c
ryo-
freez
er.
Adi
pose
, car
tilag
e, b
one,
ne
rves
, ski
n, v
ascu
lariz
a-tio
n, s
pina
l cor
d, o
steo
-ch
ondr
al, d
rug
deliv
ery,
de
rmal
, nas
al, p
ulm
onar
y,
lipos
ome
mod
ified
, im
plan
t-ab
le d
eliv
ery
devi
ces
for
gene
del
iver
y, d
rug
targ
et-
ing,
cho
ndro
gene
sis
A.2
.5C
hond
roiti
n su
lpha
te57
,89,
90
This
is th
e m
ost p
hysi
olog
i-ca
lly im
porta
nt G
AG
s.B
ioch
arac
teris
tics
of G
AG
s in
clud
e th
e bi
ndin
g an
d m
odul
atio
n of
gro
wth
fact
ors
and
cyto
kine
s, th
e in
hibi
tion
of p
rote
ases
, and
the
invo
lve-
men
t in
adhe
sion
, mig
ratio
n,
prol
ifera
tion,
and
diff
eren
tia-
tion
of c
ells
.
Non
imm
unog
enic
Deg
rade
s to
non
toxi
c ol
igo-
sacc
harid
esS
hock
abs
orbe
r
Rea
dily
wat
er-s
olub
le n
atur
e A
pplic
atio
n as
a s
olid
-sta
te d
rug
deliv
ery
vehi
cle
It is
usu
al to
car
ry o
ut a
cro
ss-
linki
ng tr
eatm
ent w
ith p
olym
ers,
su
ch a
s ch
itosa
n, g
elat
in, c
ol-
lage
n, h
yalu
rona
n, p
oly(
viny
l al
coho
l), to
pro
duce
mor
e st
able
m
ater
ials
.
Car
tilag
e an
d bo
ne, v
as-
cula
rizat
ion,
hea
rt va
lve,
ki
dney
, dru
g de
liver
y,
cent
ral n
ervo
us s
yste
m,
skin
A.2
.6D
extr
an57
,91
93
Dex
tran
is a
bra
nche
d, h
igh
mol
ecul
ar w
eigh
t pol
ymer
of
D-g
luco
se, p
rodu
ced
by
diffe
rent
bac
teria
l stra
ins
by
dext
rans
ucra
se e
nzym
efro
m s
ucro
se.
Bio
degr
adab
le a
nd b
ioco
m-
patib
leR
educ
es a
ggre
gatio
n an
d ad
hesi
vene
ssR
eadi
ly a
vaila
ble
in a
wid
e ra
nge
of m
olec
ular
wei
ghts
al
ong
with
sev
eral
der
ivat
ives
Cos
t O
ver h
ydra
tion
Ana
phyl
axis
R
isks
of c
oagu
latio
nab
norm
aliti
es
Bon
e, b
lood
sub
stitu
tes,
plas
ma
expa
nder
s,
drug
del
iver
y, g
uide
d ce
ll an
d ax
onal
rege
nera
tion,
ca
rtila
ge ti
ssue
eng
inee
ring
TAb
le 1
. (co
ntin
ued)
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 13
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
atio
ns
A.2
.7A
gar5
7,58
,94,
95
Aga
r for
ms
ther
mor
ever
s-ib
le g
els
diss
olve
d in
wat
er.
The
visc
oela
stic
pro
perti
es o
f ag
aros
e ge
ls d
ecre
ase
with
a
decr
ease
in th
e de
gree
of d
e-su
lfatio
n of
its
nativ
e po
lysa
c-ch
arid
e ag
ar.
Bio
com
patib
leB
iode
grad
eabl
eD
ifficu
lt to
pro
cess
Diffi
cult
to o
btai
n fro
m re
sour
c-es
Car
tilag
e an
d bo
ne,
hear
t, ne
rve,
pan
crea
s,in
terv
erte
bral
dis
c, c
orne
a,
wou
nds
A.2.
8C
arra
geen
ans9
610
1
Extra
cted
from
red
mar
ine
al-
gae,
can
form
a th
erm
orev
ers-
ible
gel
at r
oom
tem
pera
ture
. D
ue to
the
stro
ng io
nic
natu
re,
carra
geen
ans
exhi
bit a
hig
h de
gree
of p
rote
in re
activ
ity.
Thix
otro
pic
natu
re H
ighl
y fle
x-ib
lem
olec
ules
Hig
h m
eltin
g te
mpe
ra-tu
reW
hen
a ge
l-ind
ucin
g re
agen
t is
not
pre
sent
in th
e re
actio
n m
ixtu
re, d
isso
lutio
n of
the
gel w
ill oc
cur
Dru
g de
liver
y,in
the
food
indu
stry
,bo
ne ti
ssue
eng
inee
ring
A.2.
9G
ella
n gu
m57
,92
This
is p
rodu
ced
byPs
eudo
mon
as e
lode
a. It
s ab
le
to fo
rm tr
ansp
aren
t gel
s, in
its
nativ
e or
hig
h ac
yl fo
rm, a
nd
two
acyl
sub
stitu
ents
D-a
ceta
te
and
D-g
lyce
rate
are
pre
sent
Res
ista
nt to
hea
t and
aci
dTh
e hi
gh a
cyl f
orm
pro
duce
s tra
nspa
rent
, sof
t, el
astic
, and
fle
xibl
e ge
ls
Low
acy
l for
m p
rodu
ces
firm
, no
nela
stic
brit
tle
Food
indu
stry
, dru
g de
-liv
ery,
oph
thal
mol
ogy,
as
adju
vant
s an
d as
veh
icle
s fo
r dru
g de
liver
y
A2.
10C
ellu
lose
57,1
021
04
Cel
lulo
se is
the
mos
t abu
n-da
nt o
rgan
ic p
olym
er in
the
wor
ld. I
ts h
ighl
y co
hesi
ve,
hydr
ogen
-bon
ded
stru
ctur
e gi
ves
cellu
lose
fibe
rs e
xcep
-tio
nal s
treng
th a
nd m
akes
th
em w
ater
inso
lubl
e de
spite
thei
r hyd
ro-
phili
city
.
Rea
dily
ava
ilabl
e Lo
w c
ost
Eas
ily c
onve
rted
into
der
iva-
tives
S
tabi
lizes
the
stru
ctur
e P
orou
s B
ioco
mpa
tible
Poo
r deg
rada
tion
in v
ivo
Nee
ds m
ore
time
to re
gene
rate
Car
tilag
e an
d bo
ne,
card
iac,
adh
esio
n ba
rrie
r, he
mos
tat,
cell
cultu
re
TAb
le 1
. (co
ntin
ued)
-
Critical Reviews in Therapeutic Drug Carrier Systems
14 Garg et al.
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
s
Adv
anta
ges
Dis
adva
ntag
esA
pplic
atio
ns
A2.
11G
alac
tose
105
Gal
acto
se is
reco
gniz
ed b
y m
amm
alia
n he
pato
cyte
s th
roug
h an
asi
alog
lyco
prot
ein
rece
ptor
lead
ing
to re
gula
tion
of a
deg
rada
tive
path
way
in
glyc
opro
tein
hom
eost
asis
.
Impr
oved
cel
l atta
ch-m
ent,
viab
ility
, and
met
abol
ic fu
nc-
tions
Less
sta
ble
Live
r, bo
ne, c
artil
age
A2.
12H
epar
in15
Hep
arin
is a
hig
hly
sulfa
ted
GA
G c
onst
itutin
g th
e E
CM
Hep
arin
bin
ding
pre
serv
e th
e st
abili
ty a
nd b
iolo
gica
l act
ivity
of
the
grow
th fa
ctor
s
Whe
n ce
lls a
re im
bibe
d in
this
sc
affo
ld, t
he re
quire
a lo
nger
du
ratio
n fo
rgr
owth
Sus
tain
ed re
leas
e of
gr
owth
fact
ors,
bone
,ca
rtila
geE
CM
, ext
race
llula
r mat
rix; G
AG
, gly
cosa
min
ogly
cans
.
TAb
le 1
. (co
ntin
ued)
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 15
rate), polycyanoacrylate, polycaprolactone, polydioxanone, and polyurethanes. Non-biodegradeable polymers include polyvinyl alcohol, polyhydroxyethymethacrylate, and poly(N-isopropylacrylamide). Advantages of this scaffold are easily controlled physi-cochemical properties and quality, no immunogenicity, processing with various tech-niques, and consistent supply of large quantities.13 Different synthetic polymers and their properties, advantages, disadvantages, and applications are described in Table 2.
IV.C. Bioceramics
Melting inorganic raw materials to create an amorphous or crystalline solid body is known as bioceramics, and these porous final products are used mainly for scaffolds. Bioceramics classified as (1) nonresorbable (relatively inert), for example alumina, zir-conia, and silicon nitride; and (2) bioactive or surface active (semi-inert), for example glass ceramics such as dense hydroxyapatites [9CaOCa (OH)23P2O5], and biodegrad-able or resorbable (noninert) such as calcium phosphates, aluminium calcium phos-phates, coralline, tricalcium phosphates (3CaOP2O5), zinc calcium phosphorus oxides, zinc sulphate calcium phosphates, ferric calcium phosphorus oxides, and calcium alu-minates.13 Bioceramics polymers and their properties, advantages, disadvantages, and applications are described in Table 3.
IV.D. Composites
Because of some of the problems associated with using scaffolds synthesised from a single-phase biomaterial (poor mechanical properties and biocompatibility of natural and synthetic polymers and poor degradability of bioceramics), a number of research-ers have developed composite scaffolds comprising two or more phases to combine the advantageous properties of each phase. Combinations of (1) syntheticsynthetic, (2) syntheticnatural and (3) naturalnatural polymers have ability to tailor mechanical, degradation, and biological properties but compromise the best qualities of individual polymers with properties of the overall scaffold.13 Composite polymers and their proper-ties, advantages, disadvantages, and applications are described in Table 4.
V. SCAFFOLD FABRICATION TECHNIQUES
In the body, cells and tissue are organized into 3D architecture. To engineer these func-tional tissue and organs, scaffolds have to be fabricated by different methodologies to facilitate the cell distribution and guide their growth into 3D space. The conventional methods include fiber mesh, fiber bonding, melt molding, solvent casting/particulate leaching, gas foaming/particulate leaching, phase separation, and high-pressure process-ing. Electrospinning also has been utilized in producing a nanofibrous 3D matrix, and rapid prototyping technologies have enabled solid free-form fabrication directly from a computer-aided design (CAD) model.15 Many different techniques that are used to fabri-cate scaffolds for tissue engineering are summarized in the following sections.
-
Critical Reviews in Therapeutic Drug Carrier Systems
16 Garg et al.
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
B.1
.B
.1.1
Bio
degr
adab
le p
olym
erPo
ly(la
ctic
aci
d),
poly
(gly
colic
aci
d), a
nd c
o-po
lym
ers9
,13,
57,1
06,1
07
The
lact
ic a
nd g
lyco
lic a
cid
poly
mer
s ar
e th
e m
ost w
idel
y us
ed s
ynth
etic
pol
yest
ers
for
abso
rbab
le im
plan
ts,
drug
del
iver
y, a
nd ti
ssue
eng
i-ne
erin
g. M
echa
nica
l deg
rada
-tio
n pr
oper
ties
can
be tu
ned
by v
aryi
ng p
olym
er s
egm
ents
.
Goo
d bi
ocom
patib
ility
Exc
el-
lent
wid
e ra
nge
of b
iode
gra-
detio
n ra
teG
ood
bior
esor
ptio
n
Poo
r wet
ting
prop
ertie
s re
sult
in
poor
dis
tribu
tion
of c
ell d
yrin
g se
edin
gD
egra
datio
n pr
oduc
ts a
re C
O2
and
H2O
, cre
atin
g lo
cal a
cidi
c co
nditi
onIn
flam
mat
ory
resp
onse
is p
os-
sibl
e P
oor s
tiffn
ess
and
com
pres
sion
stre
ngth
Bar
rier m
embr
anes
, dru
g de
liver
y, o
rthop
edic
app
lica-
tions
, gui
ded
tissu
e re
gen-
erat
ion
(in d
enta
l), s
tent
s,
stap
les,
sut
ures
, tis
sue
engi
neer
ing
B.1
.2Po
ly(e
thyl
ene
glyc
ol)9,
13,1
08,1
09
Use
d as
an
inje
ctab
le g
el,
mec
hani
cal d
egra
datio
n pr
op-
ertie
s ca
n be
tune
d by
var
ying
po
lym
er s
egm
ents
.
Bio
com
patib
le a
nd n
onto
xic
Hyd
roph
ilic
Ens
ures
uni
form
and
den
se
cell
seed
ing
Poo
r cel
l adh
esio
nP
oor m
echa
nica
l pro
perit
ies
Poo
r stif
fnes
s
Adi
pose
, bon
e , n
erve
car
ti-la
ge, l
iver
, hea
rt
B.1
.3Sy
nthe
tic p
olye
ster
s (P
lA, P
lGA
) and
col
lage
n bl
ends
57,5
8,11
0,11
1
The
spon
ges
of s
ynth
etic
po
lym
er w
ere
imm
erse
d in
a
colla
gen
sol u
nder
vac
uum
(to
fill
the
pore
with
col
lage
d so
lutio
n), t
hen
lyop
hiliz
ed a
nd
cros
slin
ked
by tr
eatm
ent w
ith
glut
aral
dehy
de.
Hig
h m
echa
nica
l stre
ngth
D
esire
d sh
ape
and
degr
ada-
tion
rate
Goo
d bi
ocom
patib
ility
and
cel
l in
tera
ctio
n
Sys
tem
ic o
r loc
al re
actio
ns
caus
ed b
y ac
idic
deg
rada
tion
prod
ucts
Adi
pose
, bon
e, n
erve
, car
ti-la
ge, m
uscl
es
Tabl
e 2.
Pro
pert
ies,
Adv
anta
ges,
Dis
adva
ntag
es, a
nd A
pplic
atio
ns o
f Syn
thet
ic B
iom
ater
ials
Use
d as
Sca
ffol
ds fo
r C
ell a
nd
Dru
g D
eliv
ery
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 17
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
B.1
.4B
.1.4
.1A
lipha
tic/a
rom
atic
deg
rad-
able
pol
yest
ers
PPFs
111,
113
Line
ar p
olye
ster
with
a re
peat
-in
g un
it co
ntai
ns 2
est
er b
onds
an
d on
e un
satu
rate
d ca
rbon
ca
rbon
dou
ble
bond
.H
ydro
lysi
s of
the
este
r bon
d al
low
s P
PF
to d
egra
de, a
nd
degr
adat
ion
prod
ucts
of P
PF
have
bee
n sh
own
to b
e pr
i-m
arily
fum
aric
aci
d an
d pr
opyl
-en
e gl
ycol
.
Bio
com
patib
le a
nd b
iode
-gr
adea
ble
Ove
rcom
es th
e lim
itatio
n of
hy
drop
hobi
city
Slo
wer
deg
rada
tion
Min
imal
enc
apsu
latio
nLa
cks
mec
hani
cal s
treng
th
Orth
opae
dic,
bon
e,ca
rtila
ge, d
rug
deliv
ery
B.1
.4.2
PeT
Pb
T114
,115
Offe
rs th
e po
ssib
ility
of
man
ipul
atin
g hy
drop
hilic
ity
whi
ch is
an
impo
rtant
fact
or in
ce
ll ad
hesi
on a
nd g
row
th b
y ve
rifyi
ng th
e P
ET
cont
ent o
f th
e po
lym
er.
Bio
com
patib
le a
nd b
iode
-gr
adea
ble
Exc
elle
nt c
ell a
dhes
ion
Har
d to
pro
cess
and
con
trol
Arti
ficia
l ski
n,bo
ne ti
ssue
eng
inee
ring
B.1
.4.3
PHA
s57,
116
120
Phy
sica
l pro
perti
es in
clud
e no
nlin
ear o
ptic
al a
ctiv
ity
and
piez
oele
ctric
ity; i
.e.,
the
capa
city
of a
mat
eria
l to
suffe
r el
ectri
c po
lariz
atio
n du
e to
m
echa
nica
l stre
ss.
Bio
degr
adab
le a
nd h
ighl
y bi
ocom
patib
le T
herm
opla
stic
m
ater
ials
Hig
h br
ittle
ness
Pro
gres
sive
deg
ener
atio
nTi
ssue
eng
inee
ring,
dru
g de
liver
y, c
ardi
ac ti
ssue
en
gine
erin
g
B.1
.4.4
Pol
y(gl
ycer
ol s
ebac
ate)
121
123
This
pol
ymer
cla
ss c
an fo
rm
elas
tom
eric
and
toug
h bi
oma-
teria
ls. S
uppo
rts th
e gr
owth
of
a va
riety
of c
ells
, inc
ludi
ng fi
-br
obla
sts,
hep
atoc
ytes
, sm
ooth
m
uscl
e, e
ndot
he-li
al, c
ardi
ac
mus
cle,
and
Sch
wan
n ce
lls.
Bio
com
patib
le a
nd b
iode
grad
-ab
leH
igh
yiel
d Fa
bric
atio
n
Less
sta
ble
Live
r, ca
rdia
c
TAb
le 2
. (co
ntin
ued)
-
Critical Reviews in Therapeutic Drug Carrier Systems
18 Garg et al.
TAb
le 2
. (co
ntin
ued)
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
B.1
.5.
B.1
.5.1
Am
ine
grou
p co
ntai
ning
po
lym
ers
PAA
124
Con
tain
s te
rtiar
yam
ino
and
amid
o gr
oups
that
ar
e re
gula
rly a
rran
ged
alon
g th
eir p
olym
er c
hain
.
Hig
hly
vers
atile
C
ontro
lled
degr
ee o
f cro
ss-
linki
ng
Hig
hly
hydr
ophi
lic N
onto
xic
Inco
rpor
ates
pep
tide
or p
ro-
tein
stru
ctur
e
Hig
h de
grad
atio
n ra
teD
rug
deliv
ery,
cel
l del
iver
y,
orth
oped
ic, p
rote
in a
nd
pept
ide
deliv
ery
B.1
.5.2
N-s
ucci
nim
idyl
tar-
tara
te m
ono-
amin
epo
ly(e
thyl
eneg
lyco
lbl
ock
poly
(D,L
-lact
ic
acid
)125,
126
This
dib
lock
cop
olym
er
cons
ists
of a
bio
degr
ade-
able
lipo
phili
c po
lym
er b
lock
an
d a
hydr
ophi
lic b
lock
to
limit
or s
uppr
ess
the
nons
pe-
cific
ads
orpt
ion
proc
ess
and
conc
omita
nt d
isad
vant
ageo
us
side
effe
cts.
Bio
com
patib
leC
ontro
labl
e su
rface
com
posi
-tio
n C
ontro
labl
e ce
ll be
havi
or
Con
trola
ble
unde
sire
d pr
otei
n ad
sorp
tion
Diffi
cult
to p
roce
ss a
nd c
ontro
lD
rug
deliv
ery,
cel
l del
iver
y,
orth
oped
ic, b
one
B.1
.5.3
Poly
(dep
sipe
ptid
e-co
-lac-
tide)
127,
128
Has
pos
itive
or n
egat
ive
char
ges
exhi
bitin
g hi
gher
cel
l at
tach
men
t abi
lity.
Hig
h le
vel o
f con
trolla
ble
biod
egra
debi
lity
Con
trol o
f the
inte
ract
ion
with
liv
ing
cells
Diffi
cult
to m
aint
ain
stab
ility
for
long
er d
urat
ion
Dru
g de
liver
y, c
ell d
eliv
ery,
or
thop
edic
, bon
e, p
rote
in
and
pept
ide
deliv
ery
B.1
.6Po
ly(u
reth
ane)
s129
131
Tiss
ue-e
ngin
eere
d co
nstru
cts
mus
t exh
ibit
tissu
e-lik
e fu
nc-
tiona
lpr
oper
ties,
incl
udin
g m
e-ch
anic
al b
ehav
ior c
ompa
tible
to
the
nativ
e tis
sues
they
are
in
tend
ed to
repl
ace.
Goo
d m
echa
nica
l pro
perty
B
ioco
mpa
tibili
ty c
hara
cter
is-
tics
Con
trol o
f fibe
r dia
met
er, p
o-ro
sity
, and
deg
rada
tion
rate
Sm
all p
ore
size
sR
econ
stru
ctio
n of
bla
dder
m
uscl
e, e
ndot
heliu
m, v
as-
cula
r epi
thel
ial,
carti
lage
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 19
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
B.1
.7Pl
uron
ic F
-127
(PeO
PPO
Pe
O)13
213
4
Cop
olym
er o
f PE
O a
nd P
PO
. P
luro
nic
F-12
7 is
bio
com
pat-
ible
hyd
roge
l with
sur
fact
ant
prop
ertie
s.
Stim
ulat
ed c
hond
rocy
te p
ro-
lifer
atio
n Im
prov
ed c
artil
age
mat
rix d
e-po
sitio
n in
term
s of
his
tolo
gy
and
bioc
hem
istry
Diffi
cult
to m
aint
ain
stab
ility
Car
tilag
e, a
s sc
affo
ld fo
r cel
l gr
owth
or a
s gr
owth
sup
-po
rting
filli
ng m
ater
ial
B.1
.8TD
P135
TDP
s w
ith a
n et
hyl e
ster
R
grou
p ha
ve b
een
show
n to
ha
ve fa
vora
ble
load
bea
ring
prop
ertie
s as
wel
l as
good
bo
ne a
ppos
ition
in v
ivo.
Suf
ficie
nt m
echa
nica
l stre
ngth
fo
r loa
d be
arin
g bo
ne fi
xatio
nTD
Ps
degr
ade
mai
nly
thro
ugh
carb
onat
e-hy
drol
ysis
to fo
rm 2
al
coho
ls a
nd C
O2,
so a
uto-
cata
lytic
deg
rada
tion
and
toxi
c ef
fect
s to
the
loca
l env
iron-
men
t pro
blem
s ar
e re
mov
ed
Deg
rade
s to
o sl
owly
(in v
itro)
Loss
in m
echa
nica
l stre
ngth
in
vivo
Orth
oped
ic s
caffo
ldap
plic
atio
ns
B.1
.9Po
lyor
thoe
ster
s136
Deg
rade
s th
roug
h th
e hy
dro-
lysi
s of
the
surfa
ce. B
y ad
ding
va
ryin
g am
ount
s of
lact
ide
segm
ent,
the
degr
adab
ility
of
thes
e po
lym
ers
can
be e
asily
tu
ned
from
15
100
days
.
Rat
e of
bre
akdo
wn
are
easi
ly
cont
rolle
dP
oor m
echa
nica
l pro
perti
esO
rthop
edic
, dru
g de
liver
y sy
stem
s, s
tent
s
B.1
.10
Poly
phos
phaz
enes
137,
138
Due
to th
e fle
xibl
e P
N b
ack-
bone
of p
olyp
hosp
h-az
enes
, re
sear
cher
s ha
ve a
sses
sed
the
scop
e of
this
pol
ymer
with
re
gard
s to
bot
h ha
rd a
nd s
oft
tissu
e en
gine
erin
g.
Bio
com
patib
le
Sup
ports
ost
eoge
nic
cell
grow
th (i
n vi
tro)
By
alte
ring
the
side
gro
ups,
ch
arac
teris
tics
such
as
crys
talli
nity
,deg
rada
bil-
ity, a
nd
hydr
opho
bici
ty c
an b
e va
ried
Deg
rada
tion
prod
ucts
of N
H3,
phos
phat
e, a
nd a
min
o ac
id
caus
e lit
tle h
arm
in v
ivo
Dru
g de
liver
y,sk
elet
al re
cons
truct
ion,
bone
rege
nera
tion,
wou
nd
dres
sing
,bl
ood
cont
actin
g de
vice
s
B.1
.11
Poly
anhy
drid
es13
9
Sur
face
ero
sion
pro
perti
esB
ioco
mpa
tible
, S
uppo
rt os
teog
enic
cel
l gr
owth
(in-
vitro
)
Mec
hani
cal s
treng
th m
uch
low
er th
an th
at o
f bon
eD
rug
deliv
ery,
Bon
e tis
sue
engi
neer
ing
TAb
le 2
. (co
ntin
ued)
-
Critical Reviews in Therapeutic Drug Carrier Systems
20 Garg et al.
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
B.1
.12
Poly
pyrr
ole1
40,1
41
Poly
pyrro
le h
as b
een
inve
sti-
gate
d as
a c
ondu
ctiv
e po
lym
er
that
cou
ld a
llow
sig
nal t
rans
-du
ctio
n to
take
pla
ce w
hile
the
nerv
e ce
lls a
re g
row
ing.
Its a
bilit
y to
be
easi
ly d
oped
so
its
wet
abi
lity
and
char
ge
dens
ity c
an b
e va
ried
to b
est
mim
ic n
eura
l stru
ctur
e
Hig
h co
st
Diffi
cult
proc
essi
ngLa
ck o
f mec
hani
cal s
tabi
lity
afte
r do
ping
Diffi
cult
to fa
bric
ate
Ner
ve ti
ssue
eng
inee
ring,
drug
del
iver
y,ce
ll de
liver
y,bo
ne ti
ssue
eng
inee
ring
B.1
.13
Poly
eth
er e
ster
am
ides
136
This
pol
ymer
is m
ade
up o
f a
soft
PEG
seg
men
t con
nect
ed
to a
har
d di
este
rdi
amid
e se
g-m
ent t
hrou
gh a
n et
her b
ond.
Ora
l and
par
ente
ral a
dmin
istra
-tio
nD
ifficu
lt to
fabr
icat
eH
igh
cost
Diffi
cult
proc
essi
ng
Test
ed fo
r tox
icity
B.2
.B
.2.1
Non
biod
egra
deab
le p
oly-
mer
sPo
lyvi
nyl a
lcoh
ol (P
VA)14
2 H
ydro
phili
c po
lym
er p
rodu
ced
by h
ydro
lysi
s of
pol
yvin
yl
acet
ate.
The
PVA
with
a
high
deg
ree
of h
ydro
lysi
s is
no
t sol
uble
in w
ater
at r
oom
te
mpe
ratu
re b
ut is
sol
uble
at
elev
ated
tem
pera
ture
s (u
su-
ally
abo
ve 7
0C
).
Mec
hani
cal s
tabi
lity
and
flex-
ibili
tyLi
mite
d du
rabi
lity
Deg
rada
tion
rate
not
con
trol-
labl
e
Cho
ndro
cyte
s, d
rug
deliv
-er
y, b
one
tissu
e en
gine
erin
g
B.2
.2PH
eMA
143
PH
EM
A is
a p
olym
er th
at
form
s a
hydr
ogel
in w
ater
.
Bio
com
patib
leH
igh
purit
yIn
duce
s hy
pers
ensi
tivity
reac
-tio
ns in
hum
ans
Brit
tle
Bon
e, c
artil
age,
drug
del
iver
y, c
onta
ct le
ns,
endo
vasc
ular
sur
gery
B.2
.3Po
ly(N
-isop
ropy
lacr
yl-
amid
e)14
3
Tem
pera
ture
sen
sitiv
e an
d ha
s a
sim
ulta
neou
sly
hydr
ophi
lic
and
hydr
opho
bic
stru
ctur
e th
at
dem
onst
rate
s a
low
crit
ical
so
lutio
n te
mpe
ratu
re a
t abo
ut
32o C
.
Mec
hani
cal s
tabi
lity
and
flex-
ibili
tyB
ioco
mpa
tible
Hig
h pu
rity
Diffi
cult
to m
aint
ain
stab
ility
for
long
er d
urat
ions
Text
ile in
dust
ry, m
edic
ine,
en
viro
nmen
tal fi
elds
, con
-tro
lled
drug
del
iver
y
PAA
, pol
y(am
ido
amin
e); P
BD
, pol
y(bu
tyle
ne te
reph
thal
ate)
; PE
O, p
olye
thyl
ene
oxid
e; P
ET,
pol
y(et
hyle
nete
reph
tala
te);
PH
A, p
olyh
ydro
xyal
kano
-at
e; P
HEM
A, p
olyh
ydro
xyet
hym
etha
cryl
ate;
PLA
, pol
y(la
ctic
aci
d); P
LGA,
pol
y(la
ctic
aci
dgl
ycol
ic a
cid)
; PPF
, pol
y(pr
opyl
ene
fum
arat
e); P
PO,
poly
prop
ylen
e ox
ide;
PVA
, pol
y vi
nyl a
lcoh
ol; T
DP,
tyro
sine
-der
ived
pol
ycar
bona
te.
TAb
le 2
. (co
ntin
ued)
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 21
Tabl
e 3.
Pro
pert
ies,
Adv
anta
ges,
Dis
adva
ntag
es,
and
App
licat
ions
of
Bio
cera
mic
s B
iom
ater
ials
Use
d as
Sca
ffol
ds f
or C
ell
and
Dru
g D
eliv
ery
Scaf
fold
N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
C.1
.C
.1.1
Cal
cium
pho
spha
te b
ased
Hyd
roxy
apat
ite58
,144
Fo
und
natu
rally
as
a co
mpo
-ne
nt o
f min
eral
phas
e of
bon
e.
Exc
elle
nt b
ioco
mpa
tibili
ty A
d-eq
uate
mec
hani
cal s
treng
thG
ood
oste
ocon
duct
ivity
Non
reso
rbab
leS
low
ly d
egra
dabl
eB
rittle
P
oor m
echa
nica
l pro
perti
es
Bon
e re
gene
ratio
n, b
one
and
carti
lage
, hea
rt an
d ne
rve,
ar
tifici
al s
kin,
liga
men
t and
de
ntal
, ren
al g
lom
erul
ar ti
ssue
, in
terv
erte
bral
dis
cC
.1.2
Tric
alci
um p
hosp
hate
145,
146
Com
posi
tiona
l sim
ilarit
y to
the
min
eral
pha
se o
f bon
e.
Exc
elle
nt b
ioco
mpa
tibili
ty A
d-eq
uate
mec
hani
cal s
treng
thB
iode
grad
able
G
ood
oste
ocon
duct
ivity
Poo
r mec
hani
cal p
rope
rties
S
low
ly d
egra
dabl
e (in
the
case
of c
ryst
allin
e st
ruc-
ture
)B
rittle
Bon
e an
d ca
rtila
ge, h
eart
and
nerv
es, a
rtific
ial s
kin,
liga
men
t an
d de
ntal
, ren
al g
lom
erul
ar
tissu
e, in
terv
erte
bral
dis
c, g
eni-
tour
inar
y tra
ct, v
ascu
latu
re,
wou
nd c
losu
re, c
ardi
ovas
cula
r, dr
ug d
eliv
ery,
ost
eoge
nic
dif-
fere
ntia
tion
C.2
bio
activ
e gl
asse
s an
d gl
ass
cera
mic
s (b
iogl
ass,
pho
s-ph
ate
glas
s)57
,106
Sho
w th
e ca
pabi
lity
to b
ond
to
both
bon
e an
d so
ft tis
sue
and
to s
timul
ate
bone
gro
wth
.
Goo
d bi
ocom
patib
ility
and
oste
ocon
duct
ivity
Tailo
rabl
e re
sorp
tion
Goo
d an
giog
enet
icA
dequ
ate
mec
hani
cal s
treng
th
Slo
wly
deg
rada
ble
(cry
stal
-lin
e st
ruct
ures
)B
rittle
(am
orph
ous
stru
c-tu
re).
Adi
pose
, car
tilag
e, b
one,
ne
rve,
ski
n, v
ascu
lariz
atio
n,
spin
al c
ord,
ost
eoch
ondr
al,
drug
del
iver
y
-
Critical Reviews in Therapeutic Drug Carrier Systems
22 Garg et al.
Tabl
e 4.
Pro
pert
ies,
Adv
anta
ges,
Dis
adva
ntag
es, a
nd A
pplic
atio
ns o
f Com
posi
te B
iom
ater
ials
Use
d as
Sca
ffol
ds fo
r C
ell a
nd D
rug
Del
iver
ySc
affo
ld N
o.Po
lym
ers
and
Prop
ertie
sA
dvan
tage
sD
isad
vant
ages
App
licat
ions
D.1
Pol
ymer
-Cer
amic
13,5
8,14
7,14
8
Nat
ural
or s
ynth
etic
pol
ymer
s co
mbi
ned
with
cer
amic
s ar
e of
ten
used
for b
one
tissu
e en
gine
erin
g ap
plic
atio
ns.
Abi
lity
to ta
ilor m
echa
nica
l de
grad
a-tio
n an
d its
bio
logi
cal
prop
ertie
s
Fabr
icat
ion
tech
niqu
es
can
be c
ompl
ex
Bon
e an
d ca
rtila
ge, n
erve
, sk
in,
perio
dont
al b
one,
ost
eo-
chon
dral
, vas
cula
rizat
ion,
w
ound
dre
ssin
g, d
rug
deliv
ery
D.2
Pol
ymer
P
olym
er58
,147
,148
Com
bina
tions
of (
1) s
ynth
etic
sy
n-th
etic
, (2)
syn
thet
ic
natu
ral a
nd
(3) n
atur
aln
atur
al p
olym
ers
are
poss
ible
.
Goo
d bi
ocom
patib
ility
Goo
d os
teoc
ondu
ctiv
ity
Tailo
rabl
e de
grda
tion
rate
Im
prov
ed m
echa
nica
l pro
per-
ties
Com
prom
ise
betw
een
bes
t qu
aliti
es o
f ind
i-vi
dual
com
pone
nts
with
ov
eral
l sca
ffold
pro
perti
es
Bon
e an
d ca
rtila
ge, h
eart
and
nerv
es, a
rtific
ial s
kin,
lig
amen
t and
den
tal,
rena
l gl
omer
ular
tiss
ue, i
nter
ver-
tebr
al d
isc,
gen
itour
inar
y tra
ct, v
ascu
latu
re,
wou
nd c
losu
re, c
ardi
ovas
-cu
lar
PCL,
pol
ycap
rola
cton
e; P
EG, p
oly(
ethy
lene
gly
col);
PG
A, p
olyg
lyco
lic a
cid;
PLG
A, p
oly(
lact
ic a
cid
glyc
olic
aci
d); P
LA, p
oly(
lact
ic a
cid)
; PLL
A,
poly
- l-la
ctic
aci
d.
-
Volume 29, Number 1, 2012
A Novel Carrier for Cell and Drug Delivery 23
V.A. EMULSIFICATION/FREEzE-DRYING METHOD
The freeze-drying technique is use for fabrication of porous scaffolds. This technique is based upon the principle of sublimation. Scaffolds are generally prepared by dissolving/suspending polymers/ceramics in water or in an organic solvent followed by emulsifica-tion with a water phase. After pouring this mixture into a mold, solvents are removed by freeze-drying and porous structures are obtained (Fig. 3).150,151
Freeze-drying is conducted by freezing the material