Jurnal

Critical Reviews in Therapeutic Drug Carrier Systems, 29(1), 163 (2012)
Scaffold: A Novel Carrier for Cell and

Drug Delivery
Tarun 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; tarun.garg9@gmail.com.
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 available: (1) a typical three-dimensional porous matrix, (2) a nanofibrous matrix, (3) a thermosensitive 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 infection 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 regeneration, graft surgery
I. INTRODUCTION
Tissue engineering aims to replace or facilitate the regrowth of damaged or diseased tissue 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
0743-4863/12/$35.00 2012 Begell House, Inc. www.begellhouse.com
Garg et al.
associated with this are a shortage of donors or donor sites, transmission of disease, rejection 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 engineering have received much attention because they provide a temporal and spatial environment 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 delivery 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 duration, they typically are calleddrug 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 seeding 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).
Critical Reviews in Therapeutic Drug Carrier Systems
A Novel Carrier for Cell and Drug Delivery
porous microsphere are the injectable forms. Tissue engineering technologies are based
on this biological triad and involve the successful interaction between three components: (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 without 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-growth
5. 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 possess 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.
Volume 29, Number 1, 2012
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-dependent, meaning they will die if an adhesion substrate is not provided. Scaffold matrices 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 matrix material should be biodegrade at a controllable rate that approximates the rate of
natural tissue regeneration and should provoke a minimal immune and/or inflammatory 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 Biocompatibility 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 biologically active, the scaffold will integrate with the surrounding tissue. However, if the scaffold 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 surrounding 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 eliminating 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 implantation 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,
the scaffold should provide a minimal level of biomechanical function that should improve 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 migration.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 attachment 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 vascularisation 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 surrounds cells, allows them to bind into tissues and provide signals that aid cellular development and morphogenesis.15,26
II.H. Processability
The scaffold should possess relatively easy processability and malleability into the desired 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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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 affinity 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 dimensional 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 following 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 alcohol. Growth factors are released from hydrogels through diffusion of the growth factor
through the highly hydrophilic scaffold, mechanical stimulation, or hydrolytic degradation 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 physical properties of the gels from a few days to several months.31 Above critical concentrations, 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 vicinity of the release site; they enable enhanced residence times, sustained delivery, and/or
targeted drug delivery29; and they have significant potential in wound healing applications, though pore size and degradation properties must be optimized.27 For example, injectable 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 crosslinked poly(ethylene glycol) (PEG)based hydrogels have been utilized for delivery of
chondrocytes and osteoblasts.3537 Bone morphogenic protein introduced into the hydrogel 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 sustained insulin delivery and cartilage repair were synthesized.39 Pluronic copolymers at
a higher concentration (more than 20% [w/v]) have been used to encapsulate chondrocytes 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 biomolecules 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 injectable scaffolds to support cell growth and proliferation directly and as vehicles of growth
factor, and to enhance cell proliferation and expansion simultaneously.27 Microspherebased 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 factor
loaded microspheres into alginate porous scaffolds to enhance vascularization after implantation in the rat peritoneum. Chitosan scaffolds loaded with basic fibroblast growth
factor contained in gelatin microparticles were effective in accelerating wound closure
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 surrounding 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 enhanced 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 biomaterials 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-tobatch 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 nonbiodegradeable. Biodegradable polymers are polyglycolide, polylactide and its copolymer
poly(lactide-co-glycolide), polyphosphazene, polyanhydride, poly(propylene fuma-
Biodegradability and biocompatibility in physiological

environments
Low antigenicity
Easy to process into a range
of shapes, including sponges
and injectable hydrogels
Environmentally safe
Biodegradable material Used
as a textile fiber Biocompatibility
Slow degradability Excellent
mechanical properties
Used for surgical sutures
Gelatin5762
Gelatin is a denatured protein
obtained by acid and alkaline
processing of collagen.
Insoluble in water to prepare
hydrogel through chemical
cross-linking, with watersoluble carbodiimides and
glutaraldehyde.
Silk fibroin57,58,6365
Spider silk is an intriguing
biomaterial that is light weight,
extremely strong and elastic, and exhibits mechanical
properties comparable to the
best synthetic fibers produced
by modern technology.
Silkworm Bombyx mori
produces silk to weave its
cocoon, and its major components are fibroin and sericin.
A.1.2
A.1.3
Advantages
Good biocompatibility
Low antigenicity
High mechanical strength
Ability to be cross-linked
Good cell recognition
Polymers and Properties
Protein-origin
Collagen4858
Collagen is a major protein
component of the ECM that
interacts with cells in connective tissues and transduces
essential signal for the regulation cell anchorage, migration,
proliferation, differentiation,
and survival.
Scaffold
No.
A.1
A.1.1
Spider silk production very low

High brittleness
Poor mechanical properties

Brittle
Viral and prion conta-mination

High cost when derived by
recombinant technologies
Difficult to process
Extent and rate of degradability
is difficult to control
All sterilization methods incur
some degree of alteration
Disadvantages
Bone and cartilage, liver,

wound dressing, angiogenesis, anterior cruciate
ligament
Bone, cartilage, heart,

nerve, artificial skin,
skin regeneration, ligament,
dental, renal glomerular
tissue, adipose, intervertebral disc, genitourinary
tract, vasculature, wound
closure, cardiovascular,
reconstruction of blood
vessels, orthopaedic, tissue augmentation, drug
delivery
Bone and cartilage, artificial
skin,adipose, osteochondral, hemostatic device,
neurosurgery, thoracic
surgery, ocular surgery,
capsule coating for oral
drug delivery
Applications
Table 1. Properties, Advantages, Disadvantages and Applications of Natural Biomaterials Used as Scaffolds for Cell and Drug
Delivery

9
A.1.6
A.1.5
Induce improved
cellular interaction, Used as a
cell carrier to many cell types,
such as
tracheal epithelial cells,
murine embryonic stem cells,
mesenchymal progenitor cells,
keratinocytes and urothelium
cells
Fibrin27,57,58,64,6671
Fibrin is a protein matrix
produced from fibrinogen, providing an immune-compatible
carrier for delivery of active
biomolecules, specially cells.
Fibrin naturally contain sites
for cell binding, and has been
investigated as a substrate
for cell adhesion, spreading,
migration, proliferation. Fibrin
has haemostatic, chemotactic
and mitogenic properties.
Elastin57,7274
Elastin is synthesized by
vascular smooth muscle cells
and secreted as a tropoelastin
monomer that is soluble, hydrophobic, and nonglycosylated.
Elastin is a potent regulator of
vascular smooth muscle cell
activity, regulations important
for preventing fibrocellular
pathology.
Soybean57,75
Rich in proteins (4050%),
carbohydrates (2630%), and
lipids (2030%).
Abundant
Renewable
Inexpensive
Environment friendly Biodegradeable
Confers elasticity
Precise molecular weight
Low poly-dispersity Biocompatibility
Resistance to fatigue
Controlled degradation
Potent autocrine regulator of
vascular smooth muscle cells
activity
Advantages
Table 1. (continued)
Scaffold
No.
A.1.4
Application of soy-based
polymers in this field is still very
narrow
Becomes insoluble after increase

in temperature
Becomes insoluble and aggregate at a critical temperature
Rapid degradation,
Difficult to maintain structural
integrity,
Instable,
Low mechanical stiffness
Disadvantages
Growth factor, cell and

drug delivery, in the food
industry, computer casings,
electronic chip packaging
Drug delivery, cardiovascular, blood vessel replacements, vascularization in

bone regenerations
Bone and Cartilage,

Vascularisation, Skin,
Cardiovascular,
Spinal cord injury, Intervertebral disc, Osteochondral,
Tissue sealant,
Peripheral nerve generation,
septal chondrocytes
Applications
10
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A.2.3
A.2.2
Scaffold
No.
A.2.
A.2.1

Uncontrolled degradation kinetics
Drug loss by leaching
Biocompatible
Simple gelation
methods
Resistance to acid condition
Induces rapid bone regeneration at initial stages

Bone formation after implanting
these matrices occurs over a
long period (several months or
years).
Extremely difficult to process

Brittle
Semicrystalline native starch
granules structure is either destroyed, reorganized, or both.
Biologically renewable
Biodegradable and biocompatible
Nonantigenic and nontoxic
Biofunctional
Inexpensive
Additional control over chitosans final property
Polysaccharide polymers
Chitosan57,58,7678
A fully/partially deacetylated form of chitin. Degree of
deacetylation of commercial
chitosan is usually between
70% and 95%, and the molecular weight between 10 and
1000 kDa. Chitosan exhibits
a pH-sensitive behavior as a
weak poly-base because of
the large quantities of amino
groups on its chain.
Starch57,7981
Starch is stored as insoluble
granules composed of amylase (2030%) and amylopectin (7080%).
Physical properties of starch
are greatly influenced by the
amount of water present.
Degradation products are
oligo saccharides that can
be readily metabolized to
produce energy.
Alginate13,57,58,82
Originates from seaweed and
is structurally similar to natural
GAGs. It is an anionic polymer
with carboxyl end groups is
a good mucoadhesive agent
with a high degree of swelling
and shrinking during cationic
crosslinking.
Disadvantages
Inherent biodegradab-ility
Overwhelming Abundance
Renewability
Advantages
Bone and cartilage, vascularization, intervertebral

disc, liver and pancreas,
drug delivery, encapsulation of cells, sutures,
wound dressings, peripheral nerve regene ration,
gene expression
Bone, vascularization, drug

delivery including cancer
therapy, nasal administration of insulin
Bone and cartilage, nerve,

skin, periodontal bone,
osteochondral, vascularization, wound dressing,
drug delivery, encapsulation of cells, sutures
Applications

11
A.2.6
A.2.5
Hyaluronic acid57,58,8388
This is a major macromolecular component of the ECM.
Hyaluronan is a naturally occurring, nonsulfated glycosamino-glycan and a major
macromolecular component
of the inter-cellular matrix of
most connective tissues such
as cartilage, vitreous of human eye, umbilical cord, and
synovial fluid.
Chondroitin sulphate57,89,90
This is the most physiologically important GAGs.
Biocharacteristics of GAGs
include the binding and
modulation of growth factors
and cytokines, the inhibition
of proteases, and the involvement in adhesion, migration,
proliferation, and differentiation of cells.
Dextran57,9193
Dextran is a branched, high
molecular weight polymer
of D-glucose, produced by
different bacterial strains by
dextransucrase enzyme
from sucrose.
Scaffold
No.
A.2.4
Disadvantages
Biodegradable and biocompatible

Reduces aggregation and
adhesiveness
Readily available in a wide
range of molecular weights
along with several derivatives
Nonimmunogenic
Degrades to nontoxic oligosaccharides
Shock absorber
Cost
Over hydration Anaphylaxis
Risks of coagulation
abnormalities
Readily water-soluble nature

Application as a solid-state drug
delivery vehicle
It is usual to carry out a crosslinking treatment with polymers,
such as chitosan, gelatin, collagen, hyaluronan, poly(vinyl
alcohol), to produce more stable
materials.

Biocompatible
Expense of preservation and
Easily functionalized
storage in a cryo-freezer.
Good cell recognition
Easily and controllably produced in a large scale through
microbial fermentation
Advantages
Bone, blood substitutes,

plasma expanders,
drug delivery, guided cell
and axonal regeneration,
cartilage tissue engineering
Cartilage and bone, vascularization, heart valve,

kidney, drug delivery,
central nervous system,
skin
Adipose, cartilage, bone,

nerves, skin, vascularization, spinal cord, osteochondral, drug delivery,
dermal, nasal, pulmonary,
liposome modified, implantable delivery devices for
gene delivery, drug targeting, chondrogenesis
Applications
12
Garg et al.
A2.10
A.2.9
A.2.8
Agar57,58,94,95
Agar forms thermoreversible gels dissolved in water.
The viscoelastic properties of
agarose gels decrease with a
decrease in the degree of desulfation of its native polysaccharide agar.
Carrageenans96101
Extracted from red marine algae, can form a thermoreversible gel at room temperature.
Due to the strong ionic nature,
carrageenans exhibit a high
degree of protein reactivity.
Gellan gum57,92
This is produced by
Pseudomonas elodea. Its able
to form transparent gels, in its
native or high acyl form, and
two acyl substituents D-acetate
and D-glycerate are present
Cellulose57,102104
Cellulose is the most abundant organic polymer in the
world. Its highly cohesive,
hydrogen-bonded structure
gives cellulose fibers exceptional strength and makes
them water
insoluble despite their hydrophilicity.
Scaffold
No.
A.2.7
Readily available
Low cost
Easily converted into derivatives
Stabilizes the structure
Porous
Biocompatible
Resistant to heat and acid

The high acyl form produces
transparent, soft, elastic, and
flexible gels
Thixotropic nature Highly flexible

molecules
Biocompatible
Biodegradeable
Advantages
Cartilage and bone,

heart, nerve, pancreas,
intervertebral disc, cornea,
wounds
Applications
Food industry, drug delivery, ophthalmology, as

adjuvants and as vehicles
for drug delivery
Cartilage and bone,

cardiac, adhesion barrier,
hemostat, cell culture
Low acyl form produces firm,

nonelastic brittle
Poor degradation in vivo

Needs more time to regenerate
High melting tempera-ture

Drug delivery,
When a gel-inducing reagent
in the food industry,
is not present in the reaction
bone tissue engineering
mixture, dissolution of the gel will
occur
Difficult to process
Difficult to obtain from resources
Disadvantages

13
Improved cell attach-ment,

viability, and metabolic functions
Advantages
Heparin15
Heparin binding preserve the
Heparin is a highly
stability and biological activity
sulfated GAG constituting the of the growth factors
ECM
ECM, extracellular matrix; GAG, glycosaminoglycans.
A2.12
Galactose105
Galactose is recognized by
mammalian hepatocytes
through an asialoglycoprotein
receptor leading to regulation
of a degradative pathway in
glycoprotein
homeostasis.
Scaffold
No.
A2.11
When cells are imbibed in this

scaffold, the require a longer
duration for
growth
Less stable
Disadvantages
Sustained release of
growth factors,
bone,
cartilage
Liver, bone, cartilage
Applications
14
Garg et al.
15
rate), polycyanoacrylate, polycaprolactone, polydioxanone, and polyurethanes. Nonbiodegradeable polymers include polyvinyl alcohol, polyhydroxyethymethacrylate, and
poly(N-isopropylacrylamide). Advantages of this scaffold are easily controlled physicochemical properties and quality, no immunogenicity, processing with various techniques, 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, zirconia, and silicon nitride; and (2) bioactive or surface active (semi-inert), for example
glass ceramics such as dense hydroxyapatites [9CaOCa (OH)23P2O5], and biodegradable or resorbable (noninert) such as calcium phosphates, aluminium calcium phosphates, coralline, tricalcium phosphates (3CaOP2O5), zinc calcium phosphorus oxides,
zinc sulphate calcium phosphates, ferric calcium phosphorus oxides, and calcium aluminates.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 researchers 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 properties, 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 functional 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 processing. 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 fabricate scaffolds for tissue engineering are summarized in the following sections.
B.1.3
B.1.2
Scaffold
No.
B.1.
B.1.1
Good biocompatibility Excellent wide range of biodegradetion rate
Good bioresorption
Biodegradable polymer
Poly(lactic acid),
poly(glycolic acid), and copolymers9,13,57,106,107
The lactic and glycolic acid
polymers are the most widely
used synthetic polyesters for
absorbable implants,
drug delivery, and tissue engineering. Mechanical degradation properties can be tuned
by varying polymer segments.
Poly(ethylene glycol)9,13,108,109
Used as an injectable gel,
mechanical degradation properties can be tuned by varying
polymer segments.
Synthetic polyesters
(PLA, PLGA) and collagen
blends57,58,110,111
The sponges of synthetic
polymer were immersed in a
collagen sol under vacuum
(to fill the pore with collaged
solution), then lyophilized and
crosslinked by treatment with
glutaraldehyde.
Poor cell adhesion
Poor mechanical properities
Poor stiffness
Poor wetting properties result in

poor distribution of cell dyring
seeding
Degradation products are CO2
and H2O, creating local acidic
condition
Inflammatory response is possible
Poor stiffness and
compression strength
Disadvantages
High mechanical strength

Systemic or local reactions
Desired shape and degradacaused by acidic degradation
tion rate
products
Good biocompatibility and cell
interaction
Biocompatible and nontoxic

Hydrophilic
Ensures uniform and dense
cell seeding
Advantages
Adipose, bone, nerve, cartilage, muscles
Adipose, bone , nerve cartilage, liver, heart
Barrier membranes, drug

delivery, orthopedic applications, guided tissue regeneration (in dental), stents,
staples, sutures, tissue
engineering
Applications
Table 2. Properties, Advantages, Disadvantages, and Applications of Synthetic Biomaterials Used as Scaffolds for Cell and
Drug Delivery
16
Garg et al.
B.1.4.4
B.1.4.3
B.1.4.2
Scaffold
No.
B.1.4
B.1.4.1
Aliphatic/aromatic degradable polyesters

PPFs111,113
Linear polyester with a repeating unit contains 2 ester bonds
and one unsaturated carbon
carbon double bond.
Hydrolysis of the ester bond
allows PPF to degrade, and
degradation products of PPF
have been shown to be primarily fumaric acid and propylene glycol.
PET PBT114,115
Offers the possibility of
manipulating hydrophilicity
which is an important factor in
cell adhesion and growth by
verifying the PET content of
the polymer.
PHAs57,116120
Physical properties include
nonlinear optical activity
and piezoelectricity; i.e., the
capacity of a material to suffer
electric polarization due to
mechanical stress.
Poly(glycerol sebacate)121123
This polymer class can form
elastomeric and tough biomaterials. Supports the growth of
a variety of cells, including fibroblasts, hepatocytes, smooth
muscle, endothe-lial, cardiac
muscle, and Schwann cells.
Biocompatible and biodegrad- Less stable

able
High yield Fabrication
High brittleness
Progressive degeneration
Hard to process and control
Biocompatible and biodegradeable

Excellent cell adhesion
Biodegradable and highly

biocompatible Thermoplastic
materials
Slower degradation
Minimal encapsulation
Lacks mechanical strength
Disadvantages
Biocompatible and biodegradeable

Overcomes the limitation of
hydrophobicity
Advantages
Liver, cardiac
Tissue engineering, drug

delivery, cardiac tissue
engineering
Artificial skin,
Orthopaedic, bone,
cartilage, drug delivery
Applications

17
B.1.6
B.1.5.3
B.1.5.2
Scaffold
No.
B.1.5.
B.1.5.1
Poly(urethane)s129131
Tissue-engineered constructs
must exhibit tissue-like functional
properties, including mechanical behavior compatible
tothe native tissues they are
intended to replace.
Amine group containing

polymers
PAA124
Contains tertiary
amino and amido groups that
are regularly arranged along
their polymer chain.
N-succinimidyl tartarate mono-amine
poly(ethyleneglycol
block poly(D,L-lactic
acid)125,126
This diblock copolymer
consists of a biodegradeable lipophilic polymer block
and a hydrophilic block to
limit or suppress the nonspecific adsorption process and
concomitant disadvantageous
side effects.
Poly(depsipeptide-co-lactide) 127,128
Has positive or negative
charges exhibiting higher cell
attachment ability.
Good mechanical property

Biocompatibility characteristics
Control of fiber diameter, porosity, and degradation rate
High level of controllable

biodegradebility
Control of the interaction with
living cells
Biocompatible
Controlable surface composition
Controlable cell behavior
Controlable undesired protein
adsorption
Highly versatile
Controlled degree of crosslinking
Highly hydrophilic Nontoxic
Incorporates peptide or protein structure
Advantages
Small pore sizes
Difficult to maintain stability for

longer duration
Difficult to process and control
High degradation rate
Disadvantages
Reconstruction of bladder
muscle, endothelium, vascular epithelial, cartilage
Drug delivery, cell delivery,

orthopedic, bone, protein
and peptide delivery

orthopedic, bone

orthopedic, protein and
peptide delivery
Applications
18
Garg et al.
Polyphosphazenes137,138
Due to the flexible PN backbone of polyphosph-azenes,
researchers have assessed
the scope of this polymer with
regards to both hard and soft
tissue engineering.
Polyanhydrides139
Surface erosion properties
B.1.10
B.1.11
Polyorthoesters136
Degrades through the hydrolysis of the surface. By adding
varying amounts of lactide
segment, the degradability of
these polymers can be easily
tuned from 15100 days.
Stimulated chondrocyte proliferation

Improved cartilage matrix deposition in terms of histology
and biochemistry
Pluronic F-127 (PEOPPO

PEO)132134
Copolymer of PEO and PPO.
Pluronic F-127 is biocompatible hydrogel with surfactant
properties.
TDP135
TDPs with an ethyl ester R
group have been shown to
have favorable load bearing
properties as well as good
bone apposition in vivo.
Biocompatible,
Support osteogenic cell
growth (in-vitro)
Biocompatible
Supports osteogenic cell
growth (in vitro)
Sufficient mechanical strength

for load bearing bone fixation
TDPs degrade mainly through
carbonate-hydrolysis to form 2
alcohols and CO2, so autocatalytic degradation and toxic
effects to the local environment problems are removed
Rate of breakdown are easily
controlled
Advantages
B.1.9
B.1.8
Scaffold
No.
B.1.7
By altering the side groups,

characteristics such as
crystallinity,degradability, and
hydrophobicity can be varied
Degradation products of NH3,
phosphate, and amino acid
cause little harm in vivo
Mechanical strength much
lower than that of bone
Degrades too slowly(in vitro)

Loss in mechanical strength in
vivo
Difficult to maintain stability
Disadvantages
Drug delivery,
Bone tissue engineering
Drug delivery,
skeletal reconstruction,
bone regeneration, wound
dressing,
blood contacting devices
Orthopedic, drug delivery

systems, stents
Orthopedic scaffold
applications
Cartilage, as scaffold for cell

growth or as growth supporting filling material
Applications

19
Advantages
Disadvantages
Applications
Its ability to be easily doped

High cost
Nerve tissue engineering,
Polypyrrole140,141
so its wet ability and charge
Difficult processing
drug delivery,
Polypyrrole has been investiLack of mechanical stability after cell delivery,
gated as a conductive polymer density can be varied to best
mimic neural structure
doping Difficult to fabricate
that could allow signal transduction to take place while the
nerve cells are growing.
B.1.13
Poly ether ester amides136
Oral and parenteral administra- Difficult to fabricate
Tested for toxicity
This polymer is made up of a
tion
High cost
soft PEG segment connected
Difficult processing
to a hard diesterdiamide segment through an ether bond.
Mechanical stability and flex- Limited durability
Chondrocytes, drug delivB.2.
Nonbiodegradeable polyibility
Degradation rate not controlery, bone tissue engineering
B.2.1
mers
lable
Polyvinyl alcohol (PVA)142
Hydrophilic polymer produced
by hydrolysis of polyvinyl
acetate. The PVA with a
high degree of hydrolysis is
not soluble in water at room
temperature but is soluble at
elevated temperatures (usually above 70C).
B.2.2
PHEMA143
Biocompatible
Induces hypersensitivity reacBone, cartilage,
PHEMA is a polymer that
High purity
tions in humans
drug delivery, contact lens,
forms a hydrogelin water.
Brittle
endovascular surgery
Mechanical stability and flex- Difficult to maintain stability for Textile industry, medicine,
B.2.3
Poly(N-isopropylacrylibility
longer durations
environmental fields, conamide)143
trolled drug delivery
Temperature sensitive and has Biocompatible
High purity
a simultaneously hydrophilic
and hydrophobic structure that
demonstrates a low critical
solution temperature at about
32oC.
PAA, poly(amido amine); PBD, poly(butylene terephthalate); PEO, polyethylene oxide; PET, poly(ethyleneterephtalate); PHA, polyhydroxyalkanoate; PHEMA, polyhydroxyethymethacrylate; PLA, poly(lactic acid); PLGA, poly(lactic acidglycolic acid); PPF, poly(propylene fumarate); PPO,
polypropylene oxide; PVA, poly vinyl alcohol; TDP, tyrosine-derived polycarbonate.
Scaffold
No.
B.1.12
20
Garg et al.
Table 3. Properties, Advantages, Disadvantages, and Applications of Bioceramics Biomaterials Used as Scaffolds for Cell and
Drug Delivery
Scaffold Polymers and Properties
Advantages
Disadvantages
Applications
No.
Excellent biocompatibility AdNonresorbable
Bone regeneration, bone and
C.1.
Calcium phosphate based
equate mechanical strength
Slowly degradable
cartilage, heart and nerve,
C.1.1
Hydroxyapatite58,144
Found naturally as a compo- Good osteoconductivity
Brittle
artificial skin, ligament and
nent of mineral
Poor mechanical properties dental, renal glomerular tissue,
phase of bone.
intervertebral disc
C.1.2
Tricalcium phosphate145,146
Excellent biocompatibility AdPoor mechanical properties Bone and cartilage, heart and
Compositional similarity to the equate mechanical strength
Slowly degradable (in the
nerves, artificial skin, ligament
mineral phase of bone.
Biodegradable
case of crystalline strucand dental, renal glomerular
Good osteoconductivity
ture)
tissue, intervertebral disc, geniBrittle
tourinary tract, vasculature,
wound closure, cardiovascular,
drug delivery, osteogenic differentiation
Slowly degradable (crystal- Adipose, cartilage, bone,
C.2
Bioactive glasses and glass Good biocompatibility
and osteoconductivity
line structures)
nerve, skin, vascularization,
ceramics (bioglass, phosTailorable resorption Good
Brittle (amorphous strucspinal cord, osteochondral,
phate glass)57,106
ture).
drug delivery
Show the capability to bond to angiogenetic
both bone and soft tissue and Adequate mechanical strength
to stimulate bone growth.
21
Polymer-Ceramic 13,58,147,148
Natural or synthetic polymers
combined with ceramics are often
used for bone tissue engineering
applications.
Bone and cartilage, nerve,

skin,
periodontal bone, osteochondral, vascularization,
wound dressing, drug
delivery
D.2
Polymer Polymer58,147,148
Good biocompatibility
Compromise between
Bone and cartilage, heart
Combinations of (1) synthetic syn- Good osteoconductivity
best qualities of indiand nerves, artificial skin,
thetic, (2) synthetic natural and
Tailorable degrdation rate
vidual components with
ligament and dental, renal
(3) naturalnatural polymers are
Improved mechanical proper- overall scaffold properties glomerular tissue, interverpossible.
ties
tebral disc, genitourinary
tract, vasculature,
wound closure, cardiovascular
PCL, polycaprolactone; PEG, poly(ethylene glycol); PGA, polyglycolic acid; PLGA, poly(lactic acidglycolic acid); PLA, poly(lactic acid); PLLA,
poly-l-lactic acid.
D.1
Ability to tailor mechanical

Fabrication techniques
degrada-tion and its biological can be complex
properties
Table 4. Properties, Advantages, Disadvantages, and Applications of Composite Biomaterials Used as Scaffolds for Cell and Drug
Delivery
Scaffold No.
Advantages
Disadvantages
Applications
22
Garg et al.
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 emulsification 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 and then reducing the surrounding pressure by applying a vacuum and adding enough heat to allow the frozen water
in the material to sublime directly from the solid phase to the gas phase. This technique
is applied to a number of different polymers including silk proteins, PEG, poly-l-lactic
acid (PLLA), PLGA/poly(propylene fumarate) blends.152,153
Emulsification/freeze-drying allows for faster preparation of highly porous structures with high pore interconnectivitys.18,19 The main advantage of this technique is that
it requires neither high temperature nor a separate leaching step. Its disadvantages, however, are limited to small pore size154 (porosity is often irregular) and a long processing
time.155 The pore size can be controlled by optimizing the freezing rate and pH; a fast
freezing rate produces smaller pores.
Yannas et al.149 prepared collagen scaffolds by freezing a dispersion or solution of
collagen and then freeze drying. Preparation of PLGA scaffolds of pore sizes of up to
200 m with 95% porosity was reported by Whang et. al.156
V.B. Particulate Leaching Method
Particulate leaching methods are split into two categories: (1) solvent castingparticulate leaching, and (2) melt moldingparticulate leaching.13 In solvent castingparticulate
Figure 3. Fabrication of scaffold using the emulsification/freeze-drying method.
24
Garg et al.
leaching, a polymer dissolved in a solvent is mixed with salt particles in a mold; the
solvent is then evaporated to make a polymer monolith embedded with the salt particles,
which are then removed by washing the scaffold with water, resulting in the formation
of a porous scaffold (Fig. 4).157 In melt moldingparticulate leaching, the polymer is cast
into a mold with the embedded solid porogen. The polymer is set by applying heat and
pressure, and again the porogen is leached away by washing the resulting product with
water to yield a porous polymer scaffold (Fig. 4).158
The solvent casting and particulate leaching method, first developed by Mikos et al,159 was
used primarily to manufacture composite scaffolds160,161 later the method found applications in
the creation of porous scaffolds for the growth of endothelial cells. PLGA, poly(lactic acid)
(PLA), collagen, poly(ortho ester), or small intestine submucosaimpregnated PLGA scaffolds
have been fabricated successfully into a biodegradeable sponge structure with more than 93%
porosity and a desired pore size of 1000 m.162
The advantages of the solvent casting method are that it is a simple and fairly reproducible and does not require sophisticated apparatus. A highly porous (up to 93%) scaffold of
pore diameters up to 500 m with ease of control of porosity and geometry can be prepared
using this technique.163 The pore size can be controlled by controlling the amount of porogen added and the size and shape of the porogen.164 Complex geometries such as tube, nose,
and specific organ types can be fabricated as nanocomposite hybrid scaffolds.
Advantages include large range of pore sizes, independent control of porosity and pore
size, ability to tailor crystallinity, and highly porous structures.165 Nevertheless, this method
suffers from major drawbacks because of the long period of soaking in water required to
leach all of the salt particles. This leaching period is particularly detrimental to the manu-
Figure 4. Fabrication of scaffold using the particulate leaching method.
25
facture of controlled release scaffolds because a high percentage of the drug payload can
be lost.9 The method also produces thin membranes with a dense surface skin layer that
might contain residual salt particles used during the process. Efforts have resulted in the
production of thin scaffolds with open-cell morphology with high porosity.15 The other disadvantages include limited membrane thickness (3 mm), limited mechanical properties, the
presence of residual porogen and solvents, limited interconnectivity, and poor control over
internal architecture.165 If an organic solvent is used and is not completely removed, it can
damage the cells seeded on the scaffold. Efforts have been made to overcome the problem
of thin membrane formation and to prepare a thick 3D scaffold using PLLA or PLGA porous membranes laminated into multilayer structures with various shapes.15
V.C. Gas Foaming Method
A gas foaming method was developed by Nam et al166 using an effervescent salt as
a gas foaming agent. Sieved effervescent salt particles (ammonium bicarbonate) in the
form of a polymer gel paste was cast in a mold and subsequently immersed in hot water.
The evolution of ammonia and carbon dioxide gas, along with the leaching out of ammonium bicarbonate particulates from the solidifying polymer matrix, resulted in the
formation of pores with high interconnectivity (Fig. 5).167
Foaming techniques use gaseous porogens that are produced by chemical reactions
during polymerization or are generated by the escape of gases during a temperature
increase or drop in pressure; this causes a decrease in solubility of the carbon dioxide
within the polymer, and as the carbon dioxide gas tries to escape it causes the nucleation
and growth of bubbles, resulting in a porous microstructure.24
Nam et al.168 synthesised PLA scaffolds using ammonium bicarbonate, which acted
as both a gas foaming agent and a solid salt porogen.13 The gas foaming/salt leaching
method was further improved for preparing porous PLGA scaffolds by adding another
salt, citric acid, into the aqueous solution.167 The porosity and mechanical strength could
be controlled by adjusting the extent of an acidbase gas evolving reaction between the
two salts.15 The gas foaming process is used to fabricate highly porous foams without the
use of organic solvents. Organic solvents may leave residues behind that can have toxic
Figure 5. Fabrication of scaffold using the gas foaming method.
26
Garg et al.
effects in vitro and may cause inflammation in vivo. Gas foaming yields high porosities
(up to 93%) and varying the temperature, pressure, and rates of parameter reductions
can modulate pore sizes. The significant advantage is no loss of bioactive molecules in
the scaffold matrix, given that there is no need for the leaching process and no residual
organic solvent.34 Porosities as high as 90% with pore sizes from 200 to 500 m are
attained using this technique.16 The disadvantage of this technique is the presence of
skimming film layers on the scaffold surface, resulting in the process to remove this skin
layer, and poor interconnectivity of the porosity.
V.D. Supercritical Fluid Technology
Supercritical fluid technology, also known as high-pressure processing, uses a gas such
as carbon dioxide (CO2) in a supercritical state at high pressure. The dry polymer is dissolved in supercritical carbon dioxide to form a single-phase polymer/gas solution. The
pressure is then reduced to create thermodynamic instability of the dissolved CO2 and
results in nucleation and growth of gas cells to generate pores within the polymer matrix
(Fig. 6).15
This approach has the particular advantage of preserving protein drug activity during manufacture because of the avoidance of high temperatures or the presence of aqueous/organic interfaces.169 Mooney et al.170 utilized this technique to fabricate highly
porous sponges of PLGA. Solid disks of PLGA prepared by compression molding or
solvent casting were saturated with CO2 by applying high pressure and then reducing it
to produce a macroporous structure of uniform porous structure and higher mechanical
strength. Some disadvantages of this method are nonporous external surface and closed
pore structure165 and insufficient interconnectivity of pores within the matrix. To overcome this problem, Harris et al.171 modified this technique by combining it with the particulate leaching method. A PLGA/sodium chloride mixture was compression molded
into solid disks, exposed to high-pressure CO2, and immersed in water to leach out the
Figure 6. Fabrication of scaffold using supercritical fluid technology.
27
salt. The process led to the formation of a highly interconnected porous network with no
sign of a nonporous surface.15
V.E. Electrospinning
Electrospinning is a process whereby electrical charge is used to form a mat of fine fibers. The apparatus using this method was patented by J.F.Cooly as early as 1902. In this
technique the polymer solution is passed under mechanical pressure through a high voltage (1020 kV). The droplet of polymer solution obtained sprouts followed by solvent
evaporation, leading to the formation of fine fibers that mat in to porous scaffold (Fig. 7).
Electrospinning is the most widely used method for fabrication of nonwoven nanofiber matrices. Various materials can be electrospun into nanofiber-like biodegradable
polymers such as PLGA and polycaprolactone, poly(ethylene oxide), polyvinyl alcohol,
collagen, silk protein, and other peptides.172174
Li et al.172 developed a novel PLGA nanofibrous mesh with fiber diameter ranging
from 500 to 800 nm and pores that were well interconnected.15 The main advantages of
this technique are that it can produce the scaffold with a main structural feature suitable for
growth of the cell and subsequent tissue organization.175177 It can produce ultrafine fibers
with special orientation, high surface area, and high aspect ratio that have control over
pore geometry, all of which are favorable for better cellular growth in vitro and in vivo.
The other advantage of this technique is its simplicity, high efficiency, and sheets;
cylindrical shapes can be fabricated with this technique but the electrospinning method
Figure 7. Fabrication of scaffold using the electrospinning method.
28
Garg et al.
primarily results in a two-dimensional mesh structure with a nanoscale pore size, which
is not sufficient for cell seeding and infiltration.15 Cell seeding is the main problem of
the electrospinning method. This is overcome by sacrificial biopolymer or cryospinning,
which allows creation of a hole of a desired size in electrospun matrices.178
V.F. Sol-Gel Technique
Scaffolds are prepared by dissolving inorganic metal salts or metal organic compounds
in a solvent, where a series of hydrolysis and polymerization reactions allow the formation of a colloidal suspension (sol); after casting the sol into a mold a wet gel is formed,
and with further drying and heat treatment the gel is converted into dense ceramic or
glass articles (Fig. 8).179
Sol-geltechniques have become popular recently because of their highchemical homogeneity, low processing temperatures, and the possibility of controlling the size and
morphology of particles. The sol-gelderived materials provideexcellent matrices for a
variety of organic and inorganic compounds.One of the most important features of doped
sol-gel materialsis their ability to preserve chemical and physical propertiesof the dopants. The advantages of sol-gel technology can be used for construction of biomedical
sensors, laser materials, or for delayed drug delivery.180 The disadvantages are the high
cost of raw materials; large shrinkage during processing; residual fine pores, hydroxyl,
and carbon; and a health hazard from the long processing time of the organic solution.
V.G. Melt Molding Technique
Scaffolds are prepared by melting polymers/ceramics in the presence of porogens (such
as sodium chloride and sugar crystals); once the mixture has cooled, porosity is achieved
by dissolving the porogens in water. Finally, the porous scaffolds are usually lyophilized
(Fig. 9).181
Figure 8. Fabrication of scaffold using the sol-gel method.
29
Figure 9. Fabrication of scaffold using the melt molding method.
In 1995, Thompson et al.181 used the compression molding principle: a Teflon mold
was used with PLGA and gelatin microspheres of a specific diameter; the mold was
heated above the glass-transition temperature of PLGA while pressure was applied to
the mixture. This treatment causes the PLGA particles to bond together. Once the mold
is removed, the gelatin component is leached out by immersion in water, and the scaffold is then dried. The advantage of this technique is independent control of porosity
and pore size, macroshape control, and pore interconnectivity and geometry, which is
important for the exchange of nutrients/waste from pore to pore. The disadvantage is the
high temperature required for nonamorphous polymers and residual porogens.165
V.H. Powder Compaction
Scaffolds are prepared by compressing the polymers/ceramics using projectiles or punch
and dies; the velocity of compaction of the projectile or punch and dies is adjusted to
achieve powder consolidation with the desired porosity. The process can include sintering as an alternative to use uniaxial or isostatic pressing (Fig. 10).182
V.I. Thermally Induced Phase Separation
Thermally induced phase separation (TIPS) was first applied to PLA scaffolds by Schugens et al,183 and later several other researchers applied this technique to prepare composite scaffolds. It consists of inducing a solidliquid or liquidliquid phase separation.
This is done by dissolving the polymer in a solvent and quenching the solution at a certain temperature. The quenching induces a phase separation into a polymer-rich phase
and a polymer-poor phase. In particular, TIPS uses thermal energy as the latent solvent
to induce phase separation. The solvent must then be removed from the phase-separated
solutions either by freeze-drying or solvent extraction. The solvent leaves behind microstructural foam (Fig. 11A, B).
30
Garg et al.
Figure 10. Fabrication of scaffold using the powder compaction method.
The main advantage of the phase separation method is that pore morphology and
orientation can be tailored by altering the thermodynamic and kinetic parameters of
the processing, and it is a highly porous structure and permits incorporations of bioactive agents (hydrophilic or hydrophobic).165 It can combine easily with other fabrication
technology (particulate leaching) to design 3D structures with controlled pore morphology. It can be combined with rapid prototyping to create nanofibrous scaffolds for tissue
engineering applications.184 Its disadvantages include the use of potentially toxic solvents, poor control over internal architecture, and limited range of pore sizes.63 However, tThe latter disadvantage, however, actually may be beneficial for certain biomedical
and industrial applications such as nerve regeneration, filtration membranes, mechanically damping materials, and packaging.185,186 Nam and Park187 used the TIPS technique
to obtain scaffolds with a macroporous structure with an open cellular morphology. The
coarsening process was used to increase the size of phase-separated droplets, thus en-
Figure 11. (A) Fabrication of scaffold using liquidliquid phase separations. (B) Fabrication of scaffold
using liquidsolid phase separations.
31
larging the pores (~100 m). The resultant scaffolds also had pores with a uniform size
distribution and porosity of more than 90%.15
The phase separation method is divided into freeze drying, freeze thawing, freeze
immersion precipitation, and emulsion freeze drying. Phase separation by freeze drying
can be induced by a polymer solution with an appropriate concentration by rapid freezing. The solvent used is then removed by freeze drying, resulting in a porous structure
as a portion of the solvent. Collagen scaffolds with varying pore sizes were developed
using a collagenglycosaminoglycan blend (90120 m) and chitosan scaffolds (1250
m) by varying the freezing condition. In addition, scaffold structures of synthetic polymers such as PLA and PLGA have been made successfully using this method, with more
than 90% porosity and 15- to 250-m sizes. The freeze thawing technique induces phase
separation between a solvent and a hydrophilic monomer upon freezing, followed by the
polymerization of the hydrophilic monomer by means of ultraviolet irradiation and removal of the solvent by thawing. This leads to the formation of macroporous hydrogel.
The freeze immersion precipitation method is quite similar to the freeze thawing technique except the polymer solution is first cooled before being immersed in a nonsolvent
and then the solvent is vaporized to form a porous scaffold structure.
The emulsion freeze drying method is also useful for the fabrication of porous structures. In this case, a mixture of polymer solution and nonsolvent are thoroughly sonicated, quickly frozen in liquid nitrogen at 198C, and then freeze dried. Formation of
sponge-structured injectable gel scaffolds also have been reported.188 Injectable, gelforming scaffolds provide several advantages such as the following:
1. They can fill any shape of defect because of their good flow property
2. Loading capacity to various types of bioactive molecules and cells by simple
mixing,
3. They do not contain residual solvents that may be present in a performed
scaffold
4. They do not require surgical procedure for placement16
V.J. Fiber Bonding
The fiber bonding method was first developed by Cima et al,190 who produced scaffolds
made of polyglycolic acid (PGA) polymer. They took advantage of the fact that PGA
was available as sutures and thus in the shape of long fibers. Mikos et al191 improved
the structural stability of the constructs developing a fiber-bonding technique in which
the PGA fibers are joined at their cross-linking points by sintering above their melting
point temperature. For example, PGA fibers have been bonded by embedding in PLLA
solution, cooling, and subsequent removal of PLLA.189 The scaffolds were fabricated by
bonding a collagen matrix to PGA polymers with threaded collagen fiber stitches.192 The
main advantage of the fiber-bonding technique is the high surface area:volume ratio,
which makes them ideal for tissue engineering applications and high porosity, which
provides more surface area for cell attachment and sufficient space for the regeneration
of ECM.165,193 Disadvantages are poor mechanical integrity, residual organic solvents,
32
Garg et al.
lack of structural stability, that they can be used only to make small membranes, all the
materials cannot be used for all the processes, membrane porosity is difficult to control,
and morphology.
V.K. Fiber Mesh
The fiber mesh technique for scaffold fabrication consists of individual fibers either
woven or interwoven into a 3D pattern of variable pore size.194 It is prepared by the deposition of a polymer solution over a nonwoven mesh of another polymer followed by
subsequent evaporation.195 PGA is the first biocompatible and biodegradable polymer to
be spun into fiber and used as a synthetic suture thread. The main advantage of this technique is the rapid diffusion of nutrient that is favorable for cell survival and growth and
for high cell attachment because of the large surface area.196 One of the main drawbacks
of this technique is a lack of structural stability. This problem can be overcome by hot
drying of PLLA fibers to improve crystallinity and structure orientation.
V.L. Rapid Prototyping
Rapid prototyping (RP) also is known as solid free form (SFF) fabrication. RP or SFF
fabrication technologies currently are being used by investigators to manufacture scaffolds for use in tissue engineering.197200 RP utilizes a CAD model to construct a 3D
architecture in a layer-by-layer manner with precise control of morphological characteristics as well as chemical composition and mechanical properties201 SFF fabrication
or RP technologies use layer manufacturing techniques to create 3D scaffolds directly
from computer-generated files. There are a few techniques that come under this group,
including stereolithography (SLA), selective laser sintering (SLS), fused depositional
modeling (FDM), and 3D printing (3DP).All the techniques share the same principle:
powders or liquids are solidified one layer at a time to gradually build a 3D scaffold. The
layering is controlled by CAD programs in which the scaffold architecture is designed
and modelled. Data collected from computed tomography (CT) or magnetic resonance
imaging (MRI) scans may also be used to create CAD models that are specific to the tissue to be regenerated.202 The main advantages of these techniques are reduced lead times
to produce prototype components, improved ability to visualize the part geometry due to
its physical existence, earlier detection and reduction of design errors, and increased capability to compute manufacturing properties of components and assemblies. The main
limitations of these techniques are their resolution limit (50300 m, depending on the
technique), which makes it difficult to design scaffolds with fine microstructures;203 use
of toxic binders; and poor feature symmetry.
SFF methods are based on the premise that a material in either powdered or liquid
form is solidified one layer at a time. It is thus an additive process unlike traditional
methods of manufacturing, which are subtractive. Each layer is created as defined by a
computer-generated file. Once the layer is complete, the build platform is indexed down
by one layer of thickness and the process is repeated. The systems that fall under rapid
33
prototyping technique are (1) SLA, (2) SLS, (3) FDM; (4) 3DP, (5) organ printing, and
(6) membrane lamination.
1. Stereolithography
In this technique, raw material is converted in a photo-curable monomer by a laser beam
and partially constructed in layers of thickness. An ultraviolet laser solidifies part of the
cross-section and platform is lowered, and part of the cross-section is computed at the
current height. The completed part is removed and breaks off supporting structures, which
are then cured in an oven. Polymerization occurs by the exposure of liquid resin to a laser.
Advantages of this technique are that it is relatively easy to remove support materials and
easy to achieve small features. The disadvantage, however, is mainly that the technique is
limited by the development of photopolymerisable liquid monomer material.
2. Selective Laser Sintering
The SLS technique involves moving laser beam sinters with heat-fusible powders into
areas corresponding to the CAD geometry model one layer at a time to build the solid
part. After each layer is completed, a new layer of loose powders is spread across the
surface. The powders are gradually bonded by the laser beam into a solid mass that
forms the 3D part of the geometry. In areas that are not sintered, the powders are loose
and can be poured out of the completed part. Advantages of the technique include high
porosity, achievable pore sizes of 45 to 200 m, high surface area:volume ratio, complete pore interconnectivity, good compressive strengths, a wide range of materials, and
free from solvents. However, high processing temperatures and difficulty removing materials trapped in small inner features are some disadvantages.165
3. Fused Deposition Modeling
FDM uses a moving nozzle to extrude a fiber of polymeric material (x- and y-axis control)
from which the physical model is built layer by layer. The model is lowered (z-axis control) and the procedure is repeated. The fiber must also produce external structures to support overhanging or unconnected features that need to be manually removed. Advantages
of the technique include high porosity, achievable pore sizes of 250 to 1000 m, complete
pore interconnectivity, macro shape control, independent control of porosity and pore size,
good compressive strengths, solvent free, and no materials are trapped in small features.165
High processing temperatures, limited range of materials, inconsistent pore opening in x,
y and z directions, support structures required for irregular shapes are a few disadvantages.
4. Three-Dimensional Printing
This technology was invented at the Massachusetts Institute of Technology by Bredt et
al.204 In this technique, an ink-jet printer head deposits drops of binder (starch, plaster-
34
Garg et al.
ceramic powder) on the layer of powder spread on the platform. The binder dissolves
and joins adjacent powder particles. A new layer of powder is deposited above the previous layer, and the powder is shaken to get a 3DP.63 The technique has advantages such as
a low heat effect on raw materials, easy processing, achievable pore sizes of 45 to 500
m, high porosity, high surface area:volume ratio, independent control of porosity and
pore size, and a wide range of materials. Use of toxic organic solvents, lack of mechanical strength, and materials trapped in small inner features that are difficult to remove
are some disadvantages, particularly when the technique is applied to drug/cell delivery.
5. Organ Printing (Mironov)
Organ printing can be defined as layer-by-layer additive robotic biofabrication of 3D
functional, living macrotissues and organ constructs using tissue spheroids as building
blocks. This technique is similar to that with an ink-jet printer except here thermo-responsive print gels containing cells are sprayed onto the solidifying thin layer of polymer
solution. Organ printing involves three sequential steps: (1) preprocessing or development of blueprints for organs; (2) processing or actual organ printing; and (3) postprocessing or organ conditioning and accelerated organ maturation. Organ printing could
dramatically enhance and transform the field of tissue engineering by enabling largescale industrial robotic biofabrication of living human organ constructs with built-in
perfusable intraorgan branched vascular trees. Thus, organ printing is a new emerging,
enabling technology paradigm that represents a developmental biology-inspired alternative to classic biodegradable solid scaffold-based approaches in tissue engineering. A
disadvantage of the method includes cell aggregation within a droplet, cell damage, and
limitation in the selection of materials.205
6. Membrane Lamination
Membrane lamination is prepared by solvent casting and particle leaching methods and introducing peptide and proteins layer by layer during the fabrication process. The membranes
with an appropriate shape are soaked with solvent and then stacked in 3D assemblies with
continuous pore structure and morphology.206 This method generates the porous 3D polymer
foams with defined anatomical shape because it is possible to use the computer-assisted
modeling to design a template with the desired implant shape. The disadvantages of this
technique are that layering of porous sheets results in less pore interconnectivity207,208 and
it is a time consuming process because only a thin membrane can be used in this process.
V.M. Emulsion Templating
Porous structures can be obtained by using emulsion template techniques. The internal
phase of the emulsion acts as a template for the pores whilst polymerization occurs in
the continuous phase (in which the monomer is dissolved). After polymerization, the
internal phase is removed to give a template of porous material. The resulting porous
35
microstructures are replicas of the internal phase droplets around which polymerizations
were performed. The size of the emulsion droplets is preserved, producing polymer
foams with approximately the same size and size distributions as that of the emulsion at
the point of polymerisation.209 The first reported use of emulsions as templates was for
the production of highly porous hydrophobic polymer called poly high internal phase
emulsion (HIPE). In this work, a water-in-oil type of emulsion containing styrene and
divinylbenzene was used as the external phase. The size of the cell in polyHIPE polymers was 5 to 100 m with the interconnecting pore size constituting approximately
20% to 50% of the cell diameter.210 The main advantages are a fully interconnected
open pore structure with mechanical integrity and the ability to absorb relatively large
amounts of liquid through capillary action.211
V.N. Textile Technologies
A number of textile technologies have the potential to be applied to the design and fabrication of highly porous scaffolds. Fibers provide a large surface area:volume ratio and
are therefore desirable as scaffold matrix material. These techniques include all the approaches that have been successfully employed for the preparation of nonwoven meshes
of different polymers. For example, promising results in tissue engineering of bone, cartilage, heart valves, bladder, and liver have been achieved using nonwoven mesh composed of polymer, including fibers of PGA, PGA/PDLA, and PGA/PLLA. In particular,
nonwoven polyglycolide structures have been tested for tissue engineering applications;
such fibrous structures have been found to be useful in growing different types of cells.
The principal drawbacks are related to the difficulties of obtaining high porosity and regular pore size.212 Textiles lack the structural stability and mechanical properties to withstand biomechanical loading. To improve mechanical properties, a fiber-bonding technique was developed to prepare interconnecting fiber networks with different shapes.213
V.O. Combination of Techniques
The techniques discussed earlier can be combined with each other, depending on the
exact requirements of the scaffold. For example, Whang et al.214 created an emulsion
that was quenched using liquid nitrogen, which was then freeze dried to produce porous
PLGA polymeric monoliths. A phase separation technique can easily combine with other fabrication technology (particulate leaching) to design 3D structures with controlled
pore morphology. It can be combined with rapid prototyping to create nanofibrous scaffolds for tissue engineering applications.184
VI. APPLICATION OF SCAFFOLD
Scaffold is used mainly to deliver the cell/drug/gene into the body, and application of
scaffold is mainly categorized into those three categories: (1) cell delivery, (2) DNA/
gene delivery, and (3) drug delivery. These categories are detailed in Table 5, and the
Tissue Engineering Application With

Polymer(s)/Carrier/Scaffold Structure
Bone
Collagen/hydroxylapatite224
Collagen sponge225
Collagen electrospun Nanofibers226
Gelatin (hydrogel)227
Gelatin-siloxane (porous freeze-dried
scaffolds)228
Gelatin microspheres encapsulated in
an hydrogel matrix229,230
Silk fibroin fiber scaffolds231,232
Silk fibroin hydrogel232
Fibrin gel233
Chitosan hydrogel234
Chitosan freeze-dried scaffolds235
Starch-based microparticles236
Starch-based fiber mesh scaffolds239
Alginate hydrogel240
Alginatechitosan microcapsules241
Hyaluronate gel240
Chondroitin sulfate
collagen coated discs242
Chondroitin sulfatechitosan sponges243
Dextran beads244
Dextran/gelatine hydrogel microspheres245
Agarose gel240
PLGA Scaffold246
Scaffold
No.
A.
-----Alveolar osteoblasts
Bone marrow-derived
mesenchymal stem cells (adult)
-----Osteoblast-like MC3T3-E1 cell line
Rat marrow stromal osteoblasts
Bone marrow-derived mesenchymal
stem cells
Osteoblasts
----------Rat calvarial osteoblasts
-----Osteoblasts
-----Bone marrow stromal cells
Bone marrow stromal cells
Human bone marrow cells and human
articular chondrocytes
-----Rat calvarial cells
----------Bone marrow stromal cells (transfected)
Human marrow stromal cell
Encapsulated/Seeded Cell Type
Platelet-derived growth factorBB

Recombinant human bone
morphogenetic protein-2
Insulin growth factor-I
bone morphogenetic
protein-2 gene
Dexamethasone, Ascorbate2-phosphate
-----Platelet-derived growth factor

-----Bone morphogenetic protein-2
gene
gene
Recombinant human bone
Nerve growth factor

----------Basic fibroblast growth factor
Gentamicin sulphate
-----Nonglycosylated form of bone
Platelet-derived growth factor
Corticosteroids
Active Biomolecule
In vitro and in vivo (rat,

mouse)
in vitro
In vitro and in vivo
(mice)
In vitro
In vitro
In vitro
(rabbit)
In vitro and in vivo (rat,
dog)
In vitro and in vivo (rat)
In vitro
In vitro
In vitro
In vitro
In vitro
(mouse)
(mice)
(mouse)
In vitro
(dog)
In vitro
(mouse)
(mice)
(mouse)
Experimental Trial
Table 5. Tissue Engineering Application of Polymer(s)/Carrier/Scaffold Structure With Active Biomolecule and Encapsulated/Seeded Cell
Type
36
Garg et al.
Cardiovascular
Collagen glycosamino glycans scaffold247
Fibrin gel248
Fibrin gel in a fiber-based scaffold249
Skin
Collagen gel250
Chitosan hydrogel251
Photo cross-linkable chitosan hydrogel252
Hyaluronic acid membrane253
Cartilage
Collagen sponge254
Collagen gel240
Collagen membrane255
Gelatin microspheres encapsulate in a
hydrogelinjectable matrix256
Gelatin microspheres encapsulate in a
hydrogel injectable matrix257
Porous gelatin disks (Surgifoam)258
Transglutaminase cross-linked gelatin
(hydrogel)259
Macroporous gelatine microcarrier
beads (CultiSpherG)260
Porous gelatin sponge (Gelfoam)261
Silk fibroin porous scaffolds262
Fibrincollagen gel263
Fibrin gel264266
B.
C.
D.
Fibrin gel in a PGA nonwoven mesh267

Porous fibrin gel268

Scaffold
No.
Bovine chondrocytes
Human adipose-derived
adult stem cells
Fibroblast-like NIH/3T3 cell line
Human nasal chondrocytes
Adult human mesenchymal stem cells
Mesenchymal stem cells
Embryonic chondrogenic cells
Bovine articular chondrocytes
Pig chondrocytes
Human articular chondrocytes
Rabbit articular chondrocytes
Porcine articular chondrocytes
Human adipose-derived adult stem cells
Chondrocytes
Chondrocytes
------
Melanocytes,keratinocytes
-----------
------
Human venous myofibro-blasts
Bone marrow-derived mesenchymal

stem cells
Human foreskin fibroblasts cell line
Basic fibroblast growth factor

Bone morphogenetic protein-2
gene
-----Transforming growth factor
-1, insulin growth factor1
Transforming growth factor-1
Transforming growth
factor-1
Vitronectin/fibronectin
-----------------------------------Transforming growth factor-1
plasmid
Transforming growth factor-1
------
Platelet-derived growth factor-A

and B gene
Human epidermal growth factor
Fibroblast growth factor-2-----
-----Transforming growth factor

-beta 1,insulin and plasmin
------
Active Biomolecule

(mice)
(mouse)
(rabbit)
In vitro
In vitro
In vitro
In vitro
(mice)
(rabbit)
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro

(rabbit)
(mice)
In vitro

In vitro
In vitro
Experimental Trial

37
Rabbit mesenchymal stem cells

Porcine articular chondro-cytes
Bovine articular chondro-cytes
Periostal explants
Bovine and human Chondrocytes
Alginate beads and disks258

Alginate freeze-dried sponge combined with hyaluronic acid277
Alginate hydrogel in Ethisorb210278
Chondroitin sulfatecollagen chitosan

freeze-dried scaffolds with chitosan
microspheres281
Chondroitin/gelatin hyaluronatePLGA
porous scaffolds282
Chondroitin sulfategelatinhyaluronan freeze-dried scaffolds283
Chondroitin sulfatecollagen scaffolds284
Agarose film285
Cellulose porous scaffold286
Alginate gel alone and in PGA-PLA

pads279
Alginatechitosan microcapsules241
Hyaluronic acid hydrogel280
Alginate beads272
Alginate beads273
Alginate beads274
Alginate beads275

Porcine articular chondrocytes
Human adipose-derived adult stem cells
Cattle articular chondrocytes
Rat chondrocytes
Rabbit rib chondro-progenitor cells
Human bone marrow cells and human
articular chondrocytes
Auricular chondrocytes
Rabbit articular chondrocytes
Chitosan/gelatine freeze-dried scaffolds269

Chitosan microspheres in chitosan
freeze-dried scaffolds270
Particle aggregated chitosan scaffolds271
D.

Scaffold
No.
Bone morphogenetic protein2

gene
Recombinant human osteogenic protein-1
Human platelet superna-tant
Porcine platelet-rich plasma
-----Glucose (medium)
-------------------------Transforming growth factor-1
---------------Fibroblast growth factor-2
------
Active Biomolecule
In vitro
In vitro
In vitro
In vitro
In vitro
(mice)
In vitro
(mice)
(rabbit)
(mice)
(mice)
In vitro
(rabbit)
In vitro
In vitro
(rabbit)
In vitro
Experimental Trial
38
Garg et al.

Vascularization
Collagen gel287
Collagen/heparin sulfate matrix 288
Fibrin gel containing heparin-conjugated
nanospheres289,290
Fibrin gel291
Fibrin tubes (autologous)292
Fibrin gel293
Chitosan/heparinoid injectable hydrogels294
Chitosan hydrogels295
Starch-based fiber mesh scaffolds296
Alginate beads with bioactive glass297
Hyaluronic acid (native) 298
Hyaluronic acid (Hyaff11) nonwoven
scaffold299
Chondroitin sulfate A300
Chondroitin sulphate injectable hydrogels280
Adipose
Collagen gel with gelatin microspheres301
Collagen sponge302
Gelatin microspheres incorporated in
collagen gel301
Photocured styrenated gelatin microspheres303
Gelatin microspheres incorporated in a
collagen sponge304
Hyaluronic acid spongeHyaluronic acid
coating 302
Intervertebral disc
Collagen sponge and hydrogel305,306
Fibrin gel306
Agarose gel305307
Scaffold
No.
E.
F.
G.

-----Human preadipocytes
Preadypocytes
Human intervertebral disc cells
-----Preadipocytes (human)
------
----------Human umbilical vein endothelial cells

Human umbilical vein endothelial cells
Outgrowth endothelial cells
Rat aortic smooth muscle cells
Human umbilical vein endothelial cells
-----Micro (HPMEC-ST1.6R) and Macrovascular (HUVEC) endothelial cells
Human CCD-18Co fibroblast cells adult
human dermal microvascular endothelial
cells
Human umbilical vein
endothelial cells
Human saphenous vein
endothelial cells
Porcine vascular endothelial cells
NIH 3T3 fibroblasts
Fibroblast growth factor-2

-----Fibroblast growth factor-2
Basic fibroblast growth factor,
insulin growth factor-1, insulin
--------------Transforming growth factor -1
Transforming growth factor -1
Vascular endothelial growth

factor
Vascular endothelial growth
factor
----------Fibroblast growth factor-2
Fibroblast growth factor-2
-----Vascular endothelial growth
factor
DNA
----Vascular endothelial growth
factor
Active Biomolecule

(mouse)
(mice)
(mouse)
(mice)
(mice)
(mice)
In vitro
In vitro
In vitro
In vitro
In vitro
(mouse)
In vitro
In vitro
In vitro
(mice)
(rabbit)
In vitro
In vitro
In vitro
In vitro
(mice)
Experimental Trial

39
Osteochondral
Gelatin and chemically modified hyaluronic acid hydrogel316
Fibrin glue (Tisseel) combined with plotted medical-grade PCL317
Chitosanglycerol phosphate hydrogel318
Hyaluronic acid (Hyaff11) nonwoven
mesh scaffold319
Silk fabroin microsphere impregnated
alginate scaffold320
Angiogenesis
Silk fibroin nonwoven net321,322
K.
L.
Genito-urinary tract
Collagen scaffold (fleece)314
I.
Renal glomerular tissue

Collagen vitrigel315
Tooth
Collagen sponge308
Chitosan/collagen scaffolds309
Chitosan/coral scaffolds310
Chitosan freeze-dried sponge311
Collagen scaffold312
Glycidyl methacrylated dextran/gelatin
scaffold313
H.
J.

Scaffold
No.
Endothelial cells
Rabbit bone marrowderived mesenchymal stem cells

Rabbit bone marrowderived mesenchymal cells
-----Bone marrow mesenchymal cells
Human bone marrowderived mesenchymal stem cells
Glomerular mesangial cells, epithelial

cells
Smooth muscle cells (human)
Porcine third molar cells

Human periodontal ligament cells
Human periodontal ligament cells
Fetal rat calvarial osteoblastic cells
Human dental pulp stem cell
Human periodontal ligament cell
------
----------Autologous blood
-----Growth factor: bone morphogenetic protein 2,insulin-like
growth factor 1
------
------
-----Transforming growth factor -1

plasmid
Platelet-derived growth factor
plasmid
Dentin matrix protein 1
Bone morphogenetic proteins
Active Biomolecule
In vitro

(rabbit)
(rabbit)
(rabbit)
(rabbit)
In vitro
In vitro

(mice)

(mice)
(mice)
(mice)
(mice)
Experimental Trial
40
Garg et al.

Wound dressing
Silk fibroin electrospun fiber scaffolds323
Polyurethane scaffold324
Chitosan scaffold gelatin microsphere in
collagen scaffold325
Liver
Silk fibroin/collagen scaffolds326
Oxidized alginate injectable hydrogel327
Anterior crucial ligament

Silk fibroin multifiber matrix328
Spinal cord injury

Fibrin gel and beads329,330
Fibrin scaffold331
Peripheral nerve regeneration

Fibrin gel332334
Chitosan/chitin tubular device with
PLGA microspheres335
Alginate beads336
Pancreas
Alginate beads337
Agarose sponge338
Heart valve
Chondroitin sulfatecollagen hydrogels339
Acellular aortic valve scaffold340
Scaffold
No.
M.
N.
O.
P.
Q.
R.
S.

Porcine mitral valve interstitial cells and
endothelial cells
Myofibroblast cell,
endothelial cell
Murine insulinoma TC3 cells

Pancreatic islets and insulinoma cells
Chick dorsal root ganglia cell culture

Mice neural stem cells
------
Chick dorsal root ganglia cell culture

Murine embryonic stem cells
Bone marrow-derived mesenchymal stem

cells
Hepatocytes
Rat hepatocytes
Keratinocytes and fibroblasts

------------
-----------
-----Insulin
Fibroblast growth factor, vascular endothelial growth factor,

beta-nerve growth factor
Neurotrophin-3
Epidermal growth factor
brain derived neutrophic factor
Neurotrophin-3
------
------
-----------
-----Vancomycin
Dexamethasone
Doxycycline
Active Biomolecule
In vitro
In vitro
In vitro

In vitro

In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
Experimental Trial

41
Cornea
Agarosefibrin gel343
Diabetics
PLGA scaffold344
PLG scaffolds345
Chondrogenic differentia-tion
PEG and PCL ccaffold
V.
W.
X.
Y.
Guided cell and axonal regeneration

Dextran hydrogel porous scaffolds342
U.
Tumor
PLGA microsphere in gelatin scaffold347
Hydroxyapatitechitosan nanocomposite348
346

Scaffold
No.
-----------
Rabbit chondrocytes
Islet-like cell from human embryonic stem

cell
Islet-like cell from mouse
Epithelial, stromal and

endothelial cells
Primary embryonic chick dorsal root

ganglia cells
Doxorubicin
Celecoxib
------
-----Collagen IV, fibronectin, laminin-332 growth factor
------
extracellular matrix derived

peptides
Active Biomolecule
In vitro
In vitro

(rabbit)

(mice)
(mice)

(rabbit)
In vitro
Experimental Trial
42
Garg et al.
Antibacterial effect
PLGA nanosphere incorporated into
PLLA scaffold349
-tricalcium phosphate /calcium
phosphate invert glasses/ chitosan
porous matrix350
Bioactive glass pieces351
Mesoporous bioactive glass352
Mesoporous silica-hydroxyapatite/
PLGA microspheres porous matrix353
Bioactive glass/ -cyclo-dextrin354
-tricalcium phosphate /Agarose
porous matrix355
Calcium phosphate ceramic pieces356
-tricalcium phosphate/ poly-caprolactone(PCL) porous matrix357
Hydroxyapatite/ -tricalcium phosphate/ poly(L-lactic acid) porous
matrix358
Bioactive glass pieces359
Starch/ poly(L-lactic acid) porous
matrix360
Chitosan porous matrix361
Bioactive glass/MCM-41 porous
matrix362
Silica(SBA-15) matrix
Calcium phosphatedeficient apatite
pellets
Z.
---------------------------------------------------------------------------------
Doxycycline
Gentamicin
Gentamicin
Gentamicin
Gentamicin
Tetracycline
Vancomycin
Polymyxin B
Gatifloxacin
Ciproflozacin
Silver
Dexamethasone
Dexamethasone
Ibuprofen
Alendronate
Zoledronate
Active Biomolecule
In vitro
In vitro
In vivo
In vitro
In vitro
In vivo
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
Experimental Trial
PCL, polycaprolactone; PEG, poly(ethylene glycol); PGA, polyglycolic acid; PLGA, poly(lactic acidglycolic acid); PLA, poly(lactic acid); PLLA, poly-l-lactic
acid.

Scaffold
No.

43
44
Garg et al.
cycle of reimplantation of cell/drug/gene scaffold constructs in the human body is shown

in Fig. 12.
VI.A. MATRICES/SCAFFOLD FOR CELL DELIVERY
In these, the cells with growth factor are encapsulated or seeded into the scaffold and
administered into the body. Local and sustained delivery of paracrine factors, either by
inducing or inhibiting cell proliferation, survival, migration, and/or differentiation, may
greatly enhance tissue remodelling or organogenesis.215 Growth factors can be incorporated into the scaffold matrix by bulk encapsulation, specific or nonspecific surface
adsorption, and addition of microspheres encapsulating them.15
Figure 12. Cycle of reimplantation of cell/drug/gene scaffold constructs in the human body.
45
VI.B. MATRICES/SCAFFOLD FOR DNA/GENE DELIVERY

The gene encoding a growth factor to target cells has been suggested as an effective approach for enabling continuous expression and release of the growth factor in the local
tissue site to avoid protein instability problems encountered during the harsh formulation process and the short half-life after release in the body fluid216 when growth factor
releasing scaffolds used. Polymer scaffolds have been designed to release the genetic
material continuously as naked DNA or in the form of polyplexes, thereby transfecting
to seeded cells and expressing the growth factor to stimulate morphogenesis of specific
cells to form the desired tissue.217 Nanoparticulate polyplexes composed of DNA and
polycationic-condensing agents have been incorporated within the scaffold to increase
the efficiency of gene transfection. Polycationic agents such as polyethylenimine condense the plasmid DNA into positively charged nanoparticles and enhance DNA stability, intracellular uptake, and transfection efficiency.218
When implanted in vivo, the seeded cells in the scaffold with the polyplexes exhibited a much higher level of gene expression than those with naked DNA. DNA polyplexes
were physically immobilized onto the surface of prefabricated scaffolds by adsorption
to further enhance structural stability of the DNA through the formulation process.219
VI.C. MATRICES/SCAFFOLD FOR DRUG DELIVERY
Low molecular weight drugs that control proliferation or differentiation of cells can
be incorporated into biodegradable scaffolds to induce cellular differentiation and tissue remodeling. For example, dexamethasone, a steroidal anti-inflammatory drug, was
loaded into the bulk phase of PLGA scaffolds for sustained release.220 It was observed
that sustained release of dexamethasone effectively induced differentiation of bone marrow stem cells to osteoblasts or chondrocytes.221
VII. COMMERCIAL STATUS OF SCAFFOLDS
The first bioengineered skin to receive Food and Drug Administration approval in 1998
was Apligraf (bilayered collagen gels seeded with human fibroblasts in the lower part
and human keratinocytes in the upper layer; Organogenesis, Inc. Canton, MA), used as
the dermal matrix of an artificial skin product. Revitix (a topical cosmetic product),
VCTO1 (bilayered, bioengineered skin) or Forta-Derm antimicrobial (an antimicrobial
wound dressing) are collagen-based products, also commercialized by Organogenesis,
Inc. inFUSE, marketed by Medtronic Sofamor Danek (Memphis, TN) in the United
States, is a collagen sponge that has been used as an osteoconductive carrier of bone
morphogenetic protein for spinal fusion. Collagen sponges also have been used for the
treatment of long bone fractures. Collagraft is a mixture of porous hydroxylapatite, tricalcium phosphate, and animal derived collagen I, commercialized by Angiotech Pharmaceuticals, Inc. (Vancouver, British Columbia, Canada), has been used clinically for the
treatment of long bone fractures for more than a decade. Healos bone graft replacement,
46
Garg et al.
marketed by DePuy Orthopaedics, Inc. (Warsaw, IN), is an osteoconductive matrix constructed of cross-linked collagen fibers that are fully coated with hydroxylapatite and has
been approved recently for clinical use as a bone graft substitute in spinal fusions.
Biomend is a collagen membrane conventionally used in the regeneration of periodontal tissue and is a registered trademark of Integra Lifesciences Corp. (Plainsboro,
NJ). Gelfoam is an absorbable gelatin surgical sponge used as a hemostatic device, commercialized now by Pfizer (New York, NY). Pfizer also has a commercially available
Gelfilm, an absorbable gelatine film designed for use as an absorbable gelatin implant in
neuro, thoracic, and ocular surgery. A commercially available porous, absorbable gelatine disk is Surgifoam, distributed in the United States by Ethicon Inc. (Cornelia, GA).
CultiSpher-G is a gelatin-based product in which macroporous gelatine microcarrier
beads are used as microcarrier cell cultures, marketed by Percell Biolytica AB (storp,
Sweden). CultiSpher- S is the same product with a different cross-linking procedure
conferring a higher thermal and mechanical stability. Tisseel VH consists of a two-component fibrin biomatrix with highly concentrated human fibrinogen to produce fibrin gel
from a blood sample, commercialized in the United States by Baxter (Deerfield, IL). The
CryoSeal fibrin sealant system, which enables the production of autologous fibrin sealant components from a single unit of a patients blood plasma in approximately 60 min,
is manufactured in the United States by Thermogenesis Corp. (Rancho Cordova, CA).
The Vivostat system, which is an automated system for the onsite preparation and application of patient-derived fibrin sealant or platelet-rich fibrin, has been commercialized
by Vivolution (Denmark). GeniaBeads CN are hydrogel beads made from chitosan and
have been commercialized by geniaLab (Braunschweig, Germany). The HemCon bandage, which is a chitosan bandage applied with pressure to a severe external wound, in
several minutes attracts blood cells (negatively charged surface) that merge with chitosan to form a blood clot; it has been commercialized by HemCon Medical Technologies
Inc. (Portland, OR). Alginate-based products Nu-Derm, commercialized by Johnson &
Johnson (New Brunswick, NJ); Curasorb by Kendall (Mansfield, MA); or AlgiSite by
Smith & Nephew (Continental), have been marketed widely as wound dressings. Hyalgan and Hyalubrix, commercialized by Fidia (Turin, Italy), and Artz, commercialized
by Seikagaku Corporation (Tokyo, Japan), have been used widely as lubrication and
mechanical support for the joints in osteoarthritis. Bionect, commercialized by CSC
Pharmaceutical, and Jossalind, commercialized by Hexal (Holzkirchen, Germany) have
been used widely as viscoelastic gels for surgery and wound healing. Healon is commercialized by Advanced Medical Optics (Santa Ana, CA), Opegan R is commercialized
by Seikagaku, Opelead is commercialized by Shiseido (Japan), and Orthovisc is commercialized by Anika Therapeutics (Bedford, MA); these have been used widely for implantation of artificial intraocular lens. EmbryoGlue is commercialized by Vitrolife, Inc.
(Englewood, CO) and has been used widely for in vitro fertilization. Hyaff is a benzyl
ester of hyaluronic acid that maintains the biological characteristics of the natural molecule from which it is derived and is commercialized by Fidia; it has been used widely
as a biomaterial for biomedical applications. The Integra dermal regeneration template,
which is a bilayered membrane system for skin replacement that provides a scaffold for
47
dermal regeneration, is made of a porous matrix of fibers of cross-linked bovine tendon

collagen and a glycosaminoglycan (chondroitin-6-sulfate) used for burn and reconstructive surgery; it is marketed by Integra in the United States. Viscoat is a solution of 4%
chondroitin sulfate and 3% sodium hyaluronate that is used as a surgical aid in anterior
segment procedures, including cataract extraction and intraocular lens implantation; it
is commercialized by Alcon Laboratories (Hemel Hempstead, England). Gelrite, a novel
ophthalmic vehicle, gels in the presence of mono- or divalent cations present in the lacrimal fluid. Natrosol 250HX, distributed by Hercules (Wilmington), and geniaBeads MC,
marketed by geniaLab, are used in pharmaceutical formulations for various purposes:
low-viscosity grades are used as tablet binders in immediate-release dosage forms, and
medium- and high-viscosity grades are used in sustained-release matrix formulations.
Commercially available poly--hydroxybutyrate homopolymer BIOPOLGO4 is commercialized by ICI Biological Products (Angiotech Pharmaceuticals, Inc. in Canada) in
the form of compression-molded sheets 0.5 mm thick. Similarly, ICI commercialized
BIOPOLP05, the copolymer poly(- hydroxybutyrate-co--hydroxyvalerate) containing 24% hydroxyvalerate, used as polyhydroxybutyrates, which have been studied to
some extent for tissue engineering applications, mainly for scaffold materials in combination with ceramic materials, as a vehicle for drug delivery, and as a material for cardiac tissue engineering.119 Commercialized scaffold products and their major research
applications are described in Table 6.
VIII. CONCLUSIONS AND FUTURE STUDIES
Scaffolds have been well investigated with respect to the material requirement, properties, and technology for the production of scaffolds. The field of biomaterials has played
a crucial role in the development of tissue-engineered products. In spite of this, few
scaffolds are available commercially, particularly for cell/drug delivery. Most of the
scaffolds studied are still in the investigation stage and are yet to be approved for clinical
use. Looking into convenience and practicability, there is immense scope in developing
injectable gel-sol scaffolds because they are easy to use, versatile, and involve the use
of safe adjuvants; many of them are already listed in the Generally Recognized as Safe
list or even have been approved by the Food and Drug Administration. New biodegradable polymers need to be developed to meet all requirements for surgically implantable
scaffolds. New approaches targeting cell/drug delivery are the need of the hour, particularly for tissue regeneration, postsurgical management, cancer, and congenital malformations. Scaffolds provide adequate signals (e.g., through the use of adhesion peptides
and growth factors) to the cells, induce and maintain them in their desired differentiation
stage, and are necessary for their survival and growth. Thus, equal effort should be made
in developing strategies of how to incorporate adhesion peptides and growth factors into
the scaffolds to influence cell behavior and to establish the concentrations and distributions required for successful outcomes. At present, there is a vast amount of research
being performed worldwide on all aspects of tissue engineering/regenerative medicine.
As the field progresses, one of the key challenges will be to try to mimic more accurately
48
Garg et al.
Table 6. Commercialized Scaffold Products and Their Major Research Applications

Scaffold Commercialized Scaffold Products Current Major Research Application
1
Apligraf
An artificial skin product
2
Revitix
Topical cosmetic product
3
VCTO1
Bilayered bioengineered skin
4
Forta-Derm
Antimicrobial wound dressing
5
inFUSE
An osteoconductive carrier of bone morphogenetic protein for spinal fusion
6
Collagraft
Treatment of long bone fractures
7
Healos
Used as a bone graft substitute in spinal fusions
8
Biomend
Used in the regeneration of periodontal tissue
9
Gelfoam
Used as a hemostatic device
10
Gelfilm
In neuro, thoracic, and ocular surgery
11
CultiSpher-G
Used as microcarrier cell culture
12
CryoSeal
The production of autologous fibrin sealant
components from a single unit of a patients
blood plasma
13
Vivostat
Platelet-rich fibrin
14
HemCon
Forming a blood clot
15
Nu-Derm, AlgiSite, Curasorb
Wound dressings
16
Hyalgan, Hyalubrix, Artz
Used as a lubrication and mechanical support for the joints in osteoarthritis
17
Bionect, Jossalind
Used as a viscoelastic gel for surgery and
wound healing
18
Orthovisc,Opegan R,Opelead, Healon Used for implantation of artificial intra-ocular lens.
19
EmbryoGlue
Used for in vitro fertilization
20
Hyaff
Used as a biomaterial for biomedical applications
21
Integra
Dermal regeneration
22
Viscoat
Used as a surgical aid in anterior segment
procedures including cataract extraction
and intraocular lens implantation
23
Natrosol, geniaBeads MC
Tablet binders
24
BIOPOLP05
As a vehicle for drug delivery and as a material for cardiac tissue engineering
the sophistication of the natural ECM in synthetic substitutes. As more advanced biomaterials and bioreactors are developed, and as research leads to more knowledge of the
cell signalling mechanisms required to trigger the chain of tissue development, we will
approach our goal of reducing the number of patients waiting for donor tissues.
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Critical Reviews in Therapeutic Drug Carrier Systems, 29(1), 163 (2012)

Scaffold: A Novel Carrier for Cell and

0743-4863/12/$35.00 2012 Begell House, Inc. www.begellhouse.com

Figure 1. Different forms of polymeric scaffolds for cell/drug/gene delivery: three-dimensional

Critical Reviews in Therapeutic Drug Carrier Systems

A Novel Carrier for Cell and Drug Delivery

Figure 2. The tissue engineering triad.

Volume 29, Number 1, 2012

II. PROPERTIES OF SCAFFOLD MATRICES IN CELL/DRUG DELIVERY

Critical Reviews in Therapeutic Drug Carrier Systems

A Novel Carrier for Cell and Drug Delivery

Volume 29, Number 1, 2012

Critical Reviews in Therapeutic Drug Carrier Systems

A Novel Carrier for Cell and Drug Delivery

Volume 29, Number 1, 2012

Critical Reviews in Therapeutic Drug Carrier Systems

Biodegradability and biocompatibility in physiological

Polymers and Properties

Volume 29, Number 1, 2012

Spider silk production very low

Poor mechanical properties

Viral and prion conta-mination

Bone and cartilage, liver,

Bone, cartilage, heart,

A Novel Carrier for Cell and Drug Delivery

Polymers and Properties

Becomes insoluble after increase

Growth factor, cell and

Drug delivery, cardiovascular, blood vessel replacements, vascularization in

Bone and Cartilage,

Critical Reviews in Therapeutic Drug Carrier Systems

Volume 29, Number 1, 2012

Poor mechanical properties

Induces rapid bone regeneration at initial stages

Extremely difficult to process

Polymers and Properties

Bone and cartilage, vascularization, intervertebral

Bone, vascularization, drug

Bone and cartilage, nerve,

A Novel Carrier for Cell and Drug Delivery

Polymers and Properties

Biodegradable and biocompatible

Readily water-soluble nature

Poor mechanical properties

Bone, blood substitutes,

Cartilage and bone, vascularization, heart valve,

Adipose, cartilage, bone,

Critical Reviews in Therapeutic Drug Carrier Systems

Volume 29, Number 1, 2012

Polymers and Properties

Resistant to heat and acid

Thixotropic nature Highly flexible

Cartilage and bone,

Food industry, drug delivery, ophthalmology, as

Cartilage and bone,

Low acyl form produces firm,

Poor degradation in vivo

High melting tempera-ture

A Novel Carrier for Cell and Drug Delivery

Improved cell attach-ment,

Polymers and Properties

When cells are imbibed in this

Liver, bone, cartilage

Critical Reviews in Therapeutic Drug Carrier Systems