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Critical Reviews™ in Therapeutic Drug Carrier Systems, 29(1), 1–63 (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

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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.6–8 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 called “drug delivery scaffolds.”9 Different forms of polymeric
scaffolds for cell/drug delivery are available: (1) a typical 3D porous matrix, which is
a highly porous and well interconnected open pore structure that allows high cell 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

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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 tissue’s 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

Biodegradability The scaffold material should be biodegradable.B. the scaffold must provide a suitable substrate for cell attachment. new tissue will eventually replace it. cell proliferation. meaning they will die if an adhesion substrate is not provided. the scaffold will integrate with the surrounding tissue. PROPERTIES OF SCAFFOLD MATRICES IN CELL/DRUG DELIVERY Scaffolds play a critical role in tissue engineering. Biocompatibility The scaffold should possess acceptable biocompatibility and toxicity profiles.13 If the scaffold is nontoxic and degradable. waste. Mechanical Properties Mechanical properties of the scaffold should match those of the tissue at the implantation site. The majority of mammalian cell types are anchorage-dependent. and biological signalling factors to allow for cell survival. if the scaffold is biologically inactive.16 Biocompatibility is the ability of the scaffold to perform in a specific application without eliciting a harmful immune or inflammatory reaction. Therefore. 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.22 The scaffold’s degradation rate should be adjusted to match the rate of tissue regeneration so that it has disappeared completely once the tissue is repaired. II.4 Garg et al.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. rejection of the scaffold and localized death of the surrounding tissue can occur.C. Its degradation products should not be toxic and should be eliminated easily from the implantation site by the body.16 II. when the scaffold is toxic. it may be encapsulated by a fibrous capsule.A. Immediately after implantation.13 eliminating the need for further surgery to remove it.23 and to survive under physiological conditions.9 An ideal tissue engineering scaffold should fulfill the following 11 requirements.20 II. whereas if it is nontoxic and biologically active. 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. differentiated function.21 II. Critical Reviews™ in Therapeutic Drug Carrier Systems . Synthetic polymer scaffolds may be used to deliver proteins and growth factors with or without cells locally to enhance tissue repair and regeneration. and cell migration16–19 to permit the transport of nutrients. or the mechanical properties at least should be sufficient to shield cells from damaging compressive or tensile forces without inhibiting appropriate biomechanical cues15. in the worst case. Scaffold matrices can be used to achieve cell delivery with high loading and efficiency to specific sites. However.

The scaffold should have a maximum loading capacity so the drug is Volume 29.D.13 Specifically. Number 1.13 II.26 II.A Novel Carrier for Cell and Drug Delivery 5 the scaffold should provide a minimal level of biomechanical function that should improve progressively until normal tissue function has been restored. and its interconnectivity. pore size determines the efficiency at which cells seed into the scaffold24.15 II. Porosity Porous structures allow for optimal interaction of the scaffold with cells.25 II.16 II. the pore size distribution.F.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. facilitating cell–cell contact and cell migration.H. Interface Adherence Interface adherence is how cells or proteins attach to a scaffold’s surface. This also will allow cell in-growth and vascularisation and promote metabolite transport. The scaffold should support cell adhesion and proliferation. They should be capable of being produced into a sterile product. an endogenous substance that surrounds cells.13 The scaffold should have an adequate porosity.I. II. G. available ligand density. this includes the magnitude of the porosity. Nature Mimicking the native extracellular matrix (ECM). Loading Capacity Release Kinetics Loading capacity release kinetics is defined as the amount of drug that can be mixed into the scaffold. at which point the construct should have fully integrated with the surrounding host tissue. therefore. Structure It should have a reproducible microscopic and macroscopic structure with a high surface:volume ratio suitable for cell/drug attachment. allows them to bind into tissues and provide signals that aid cellular development and morphogenesis. 2012 . small pores prevent the cells from penetrating the scaffold. according to the need.15. Processability The scaffold should possess relatively easy processability and malleability into the desired shape.E. whilst large pores prevent cell attachment due to a reduced area and.

which eventually may produce toxic effects.K. and biological activity over a prolonged period of time. a biomaterial must have a high degree of porosity. chemical. Stability The stability of the incorporated drug/cell at physiological temperature with respect to physical. different forms of polymeric scaffolds for cell/drug delivery are also available. and (4) a porous microsphere. DESIGN STRATEGIES FOR CELL AND DRUG DELIVERY SYSTEMS Although prefabricated scaffolds are most widely used for tissue regeneration as well as drug delivery purposes. and gelatine or synthetic polymers such as poly(ethylene glycolide) and poly vinyl alcohol. Injectable scaffold materials formed in situ have received much attention recently because they can be administered using a syringe needle15 and thus avoid surgery. II.27 These properties can be well controlled in an injectable scaffold. chitosan. appropriate pore size. They should posses dimensional stability. released continuously for longer duration after insertion into the body. chemical stability. II. (2) a nanofibrous matrix. Binding Affinity Binding affinity is defined as how tightly the drug binds the scaffold. These forms can be classified as (1) a typical 3D porous matrix. III. (3) a thermosensitive sol-gel transition hydrogel. and geometry control. 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. To mimic the topological and microstructural characteristics of the ECM. The drug needs to be dispersed homogenously throughout the scaffold or in discrete areas and must avoid an initial burst effect. which swell to form a gel like substance on exposure to water. and biological activity is to be assessed.J.29 Hydrogels can be made from naturally occurring polymers such as collagen.9 III. water-soluble polymers. however. this binding affinity must be sufficiently low to allow release of the drug.28 Hydrogels are appealing for biological applications because of their high water content and biocompatibility. a high surface:volume ratio. Some of the drug/cell delivery systems and their design strategies are given in the following sections. Hydrogel-Based Systems Hydrogel matrices are physically or chemically cross-linked. Growth factors are released from hydrogels through diffusion of the growth factor Critical Reviews™ in Therapeutic Drug Carrier Systems . low binding affinity would lead to dose dumping. a high degree of pore interconnection. Of these.A.6 Garg et al. 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.

27 Microspherebased technology has an application for tissue engineering as well as gene therapy. 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.32. 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. and to enhance cell proliferation and expansion simultaneously.27 For example. and cells. and/or targeted drug delivery29.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.35–37 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. facilitating the regeneration process. mechanical stimulation.31 Above critical concentrations. For example. Chitosan scaffolds loaded with basic fibroblast growth factor contained in gelatin microparticles were effective in accelerating wound closure Volume 29.38 Poly(lactic acid–glycolic acid) (PLGA) grafted with PEG and PEG grafted with PLGA hydrogels capable of sustained insulin delivery and cartilage repair were synthesized.A Novel Carrier for Cell and Drug Delivery 7 through the highly hydrophilic scaffold. peptides. the porous structure (30 μm) would allow sufficient cell seeding in and out of the matrix.27 Additional advantages of hydrogels are that they may protect drugs.30 Release behavior can be regulated by controlling the chemical and physical properties of the gels from a few days to several months. and they have significant potential in wound healing applications.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. they enable enhanced residence times. genes.39 Pluronic copolymers at a higher concentration (more than 20% [w/v]) have been used to encapsulate chondrocytes and produce engineered cartilage.41 Prior to injection. such as the inherent stability of plasmid DNA. these hydrogels show a sol state at room temperature. a more economical use . sustained delivery. 2012 . injectable poly(N-isopropylacrylamide) physical hydrogels encapsulating cells have been prepared for cartilage and nerve regeneration. After injection in vivo. Gene delivery has several potential advantages. Number 1. Microsphere. extended shelf-life.34 Photo crosslinked poly(ethylene glycol) (PEG)–based hydrogels have been utilized for delivery of chondrocytes and osteoblasts.15 Microparticles also can be used as injectable scaffolds to support cell growth and proliferation directly and as vehicles of growth factor. reduced fabrication costs.B. or hydrolytic degradation of the scaffold28 or upon swelling in response to an environmental stimulus. though pore size and degradation properties must be optimized. and especially proteins against the potentially harsh environment in the vicinity of the release site. and application in skin repair.33 Pluronic/heparin composite hydrogels delivering growth factor also have been studied to induce angiogenesis. but change into a gel state at body temperature15. the porous matrix would permit infiltration of cells and ingrowth of tissue from the host.40 III.

and applications are described in Table 1. silk. fibrins.27 III.8 Garg et al. They can be used as biomaterials for cell/drug/gene delivery purposes. dextran. with incorporation of growth factors into these matrices for improved healing. collagens. gellan. poly(propylene fuma- Critical Reviews™ in Therapeutic Drug Carrier Systems . starch. BIOMATERIALS FOR SCAFFOLD FABRICATION A number of different categories of biomaterials are commonly used as scaffold for cell and drug delivery. scleroglucan. 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. IV. advantages. which was shown to facilitate the dermal wound healing process. and conformability with the surrounding tissue with respect to thickness and pigmentation. chitosan (chitin). Natural Polymers Natural polymers include alginate. and they more closely mimic the natural ECM of tissues. pullulan. Membrane-based Systems Human skin is considered the gold standard for treatment of skin wounds.43 Biodegradable PLGA microspheres have been studied for delivery of chondrocytes for cartilage engineering. improving the healing of the wound area. gelatin hydrogel containing epidermal growth factor–loaded microspheres has an enhanced effect on re-epithelization. limitations are short supply. heparin. commercial availability. of pressure ulcers. gelatin. a bilayered membrane combines silver sulphadiazine and a laminin-modified collagen membrane. elastin. chondroitin 6-sulfate. For example. and polyhydroxyalkanoates. graft rejections. IV. polyanhydride. expense. Synthetic Polymers Synthetic polymers are largely divided into two categories: biodegradable and nonbiodegradeable. skin grafts are not always the perfect solution.B. proteins. curdlan. They are limited in terms of the conditions needed for tissue availability. easy processing.C. fibroin. galactan. cellulose. elsinan. emulsan. pectin (pectinic acid). disadvantages. Biodegradable polymers are polyglycolide.45 Current strategies for wound dressings have been aimed at the development of the bilayer-structured membrane. For example.46 IV. Advantages of natural polymers include their biocompatibility. however. and susceptibility to cross-contamination. levan.15 Nanofabricated particles could offer better delivery properties to direct cell fate and to regulate processes such an angiogenesis and cell migration.44. gluten.47 Different natural polymers and their properties. polyphosphazene. albumin.A. hyarulonic acid. polylactide and its copolymer poly(lactide-co-glycolide). batch-tobatch variation. However.

liver. A. orthopaedic.1. reconstruction of blood vessels. neurosurgery. and survival.1 Volume 29. osteochondral. Silkworm Bombyx mori produces silk to weave its cocoon. cardiovascular. differentiation. and exhibits mechanical properties comparable to the best synthetic fibers produced by modern technology. intervertebral disc.58. cartilage. Number 1. including sponges and injectable hydrogels Environmentally safe Biodegradable material Used as a textile fiber Biocompatibility Slow degradability Excellent mechanical properties Used for surgical sutures Gelatin57–62 Gelatin is a denatured protein obtained by acid and alkaline processing of collagen. tissue augmentation. wound dressing.Biodegradability and biocompatibility in physiological environments Low antigenicity Easy to process into a range of shapes. proliferation. hemostatic device.adipose. artificial skin. with watersoluble carbodiimides and glutaraldehyde. heart. A. adipose. 2012 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. and its major components are fibroin and sericin. Scaffold No. anterior cruciate ligament Bone.2 A. vasculature. thoracic surgery. wound closure.1. Advantages.1 A. genitourinary tract. extremely strong and elastic. Insoluble in water to prepare hydrogel through chemical cross-linking.1. angiogenesis. Silk fibroin57. skin regeneration. artificial skin. capsule coating for oral drug delivery Applications Table 1. renal glomerular tissue. nerve.63–65 Spider silk is an intriguing biomaterial that is light weight. ocular surgery. dental. ligament. migration. Properties. drug delivery Bone and cartilage. Disadvantages and Applications of Natural Biomaterials Used as Scaffolds for Cell and Drug Delivery A Novel Carrier for Cell and Drug Delivery 9 .3 Advantages Good biocompatibility Low antigenicity High mechanical strength Ability to be cross-linked Good cell recognition Polymers and Properties Protein-origin Collagen48–58 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.

Low mechanical stiffness Disadvantages Growth factor. Difficult to maintain structural integrity.6 A. regulations important for preventing fibrocellular pathology.5 Induce improved cellular interaction. Skin. in the food industry. Cardiovascular. Fibrin has haemostatic. mesenchymal progenitor cells. Instable. Elastin57. 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 Polymers and Properties Table 1. murine embryonic stem cells. specially cells. Elastin is a potent regulator of vascular smooth muscle cell activity. proliferation. carbohydrates (26–30%). providing an immune-compatible carrier for delivery of active biomolecules. Intervertebral disc. keratinocytes and urothelium cells Fibrin27. Peripheral nerve generation. and nonglycosylated. Soybean57. and has been investigated as a substrate for cell adhesion.1. chemotactic and mitogenic properties. Spinal cord injury. computer casings. cardiovascular. A. cell and drug delivery. electronic chip packaging Drug delivery. blood vessel replacements. Critical Reviews™ in Therapeutic Drug Carrier Systems . spreading. Used as a cell carrier to many cell types. hydrophobic.64. Osteochondral.A. such as tracheal epithelial cells. vascularization in bone regenerations Bone and Cartilage.57. septal chondrocytes Applications 10 Garg et al. migration. and lipids (20–30%). Tissue sealant.66–71 Fibrin is a protein matrix produced from fibrinogen.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.1. (continued) Scaffold No. Fibrin naturally contain sites for cell binding.58. Vascularisation.72–74 Elastin is synthesized by vascular smooth muscle cells and secreted as a tropoelastin monomer that is soluble.75 Rich in proteins (40–50%).

79–81 Starch is stored as insoluble granules composed of α amylase (20–30%) and amylopectin (70–80%).2. and the molecular weight between 10 and 1000 kDa. encapsulation of cells.3 A. Number 1.linking. Degradation products are oligo saccharides that can be readily metabolized to produce energy. (continued) Bone and cartilage. wound dressing. vascularization. sutures Applications A Novel Carrier for Cell and Drug Delivery 11 .57.2. drug delivery. Extremely difficult to process Brittle Semicrystalline native starch granules structure is either destroyed. drug delivery. encapsulation of cells.Volume 29. vascularization. A. Alginate13.58. It is an anionic polymer with carboxyl end groups is a good mucoadhesive agent with a high degree of swelling and shrinking during cationic cross. drug delivery including cancer therapy.2.2 Scaffold No. intervertebral disc. Disadvantages Inherent biodegradab-ility Overwhelming Abundance Renewability Advantages Polymers and Properties Table 1. osteochondral. Chitosan exhibits a pH-sensitive behavior as a weak poly-base because of the large quantities of amino groups on its chain. A. nasal administration of insulin Bone and cartilage.2. or both. nerve.76–78 A fully/partially deacetylated form of chitin. skin.58. wound dressings. gene expression Bone. Biologically renewable Biodegradable and biocompatible Nonantigenic and nontoxic Biofunctional Inexpensive Additional control over chitosan’s final property Polysaccharide polymers Chitosan57. periodontal bone. Physical properties of starch are greatly influenced by the amount of water present. vascularization. reorganized. 2012 A.82 Originates from seaweed and is structurally similar to natural GAGs. Starch57. Degree of deacetylation of commercial chitosan is usually between 70% and 95%. sutures.1 Poor mechanical properties 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). peripheral nerve regene ration. liver and pancreas.

drug delivery. (continued) Scaffold No. nonsulfated glycosamino-glycan and a major macromolecular component of the inter-cellular matrix of most connective tissues such as cartilage.83–88 This is a major macromolecular component of the ECM. vascularization. Hyaluronan is a naturally occurring. Polymers and Properties Table 1. vitreous of human eye.6 A.91–93 Dextran is a branched. such as chitosan. high molecular weight polymer of D-glucose.89. Dextran57. produced by different bacterial strains by dextransucrase enzyme from sucrose. Biocharacteristics of GAGs include the binding and modulation of growth factors and cytokines. osteochondral. the inhibition of proteases. implantable delivery devices for gene delivery.2. skin Adipose. guided cell and axonal regeneration. bone. blood substitutes.90 This is the most physiologically important GAGs. pulmonary. vascularization. cartilage. migration. A. plasma expanders.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. central nervous system. nasal. and synovial fluid. and the involvement in adhesion. chondrogenesis Applications 12 Garg et al. Critical Reviews™ in Therapeutic Drug Carrier Systems .5 Hyaluronic acid57. spinal cord. Chondroitin sulphate57. collagen. poly(vinyl alcohol).2. drug delivery. kidney. heart valve. liposome modified.2. skin. drug targeting. proliferation. Poor mechanical properties Biocompatible Expense of preservation and Easily functionalized storage in a cryo-freezer. hyaluronan. to produce more stable materials. dermal. and differentiation of cells. Good cell recognition Easily and controllably produced in a large scale through microbial fermentation Advantages Bone.A. cartilage tissue engineering Cartilage and bone.58. gelatin. umbilical cord. nerves. drug delivery.

102–104 Cellulose is the most abundant organic polymer in the world. soft.58.2.9 A. (continued) Scaffold No. can form a thermoreversible gel at room temperature.92 This is produced by Pseudomonas elodea. in its native or high acyl form. and flexible gels Thixotropic nature Highly flexible molecules Biocompatible Biodegradeable Advantages Cartilage and bone. Gellan gum57.10 A. A. as adjuvants and as vehicles for drug delivery Cartilage and bone. heart. drug delivery. 2012 A2. wounds Applications Food industry. is not present in the reaction bone tissue engineering mixture. Its able to form transparent gels.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.94. Its highly cohesive. adhesion barrier. When a gel-inducing reagent in the food industry.2. elastic. and two acyl substituents D-acetate and D-glycerate are present Cellulose57. intervertebral disc. nerve. Number 1. The viscoelastic properties of agarose gels decrease with a decrease in the degree of desulfation of its native polysaccharide agar. Carrageenans96–101 Extracted from red marine algae. dissolution of the gel will occur Difficult to process Difficult to obtain from resources Disadvantages A Novel Carrier for Cell and Drug Delivery 13 .2. nonelastic brittle Poor degradation in vivo Needs more time to regenerate High melting tempera-ture Drug delivery. cardiac.8 Agar57. Polymers and Properties Table 1. hemostat.Volume 29. cornea. hydrogen-bonded structure gives cellulose fibers exceptional strength and makes them water insoluble despite their hydrophilicity. carrageenans exhibit a high degree of protein reactivity. cell culture Low acyl form produces firm.95 Agar forms thermoreversible gels dissolved in water. pancreas. Due to the strong ionic nature. ophthalmology.

Polymers and Properties Table 1. cartilage Liver. A2. A2. 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. the require a longer duration for growth Less stable Disadvantages Sustained release of growth factors. Critical Reviews™ in Therapeutic Drug Carrier Systems .11 When cells are imbibed in this scaffold. glycosaminoglycans. bone. cartilage Applications 14 Garg et al. bone. extracellular matrix.Improved cell attach-ment. (continued) Scaffold No. GAG.12 Galactose105 Galactose is recognized by mammalian hepatocytes through an asialoglycoprotein receptor leading to regulation of a degradative pathway in glycoprotein homeostasis. viability.

solvent casting/particulate leaching. no immunogenicity. Number 1. processing with various techniques. cells and tissue are organized into 3D architecture.A Novel Carrier for Cell and Drug Delivery 15 rate). SCAFFOLD FABRICATION TECHNIQUES In the body. and (2) bioactive or surface active (semi-inert).D. (2) synthetic–natural and (3) natural–natural polymers have ability to tailor mechanical. a number of researchers have developed composite scaffolds comprising two or more phases to combine the advantageous properties of each phase. scaffolds have to be fabricated by different methodologies to facilitate the cell distribution and guide their growth into 3D space. and silicon nitride.C. for example glass ceramics such as dense hydroxyapatites [9CaO·Ca (OH)2·3P2O5]. To engineer these functional tissue and organs. IV. and poly(N-isopropylacrylamide). disadvantages. Advantages of this scaffold are easily controlled physicochemical properties and quality. aluminium calcium phosphates. IV. Combinations of (1) synthetic–synthetic. Nonbiodegradeable polymers include polyvinyl alcohol. 2012 . The conventional methods include fiber mesh. and biological properties but compromise the “best” qualities of individual polymers with properties of the overall scaffold.13 Bioceramics polymers and their properties. advantages. disadvantages. Electrospinning also has been utilized in producing a nanofibrous 3D matrix. Volume 29. advantages. coralline. 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). phase separation. gas foaming/particulate leaching. melt molding. V. and calcium aluminates. and biodegradable or resorbable (noninert) such as calcium phosphates. and high-pressure processing. zirconia.13 Composite polymers and their properties. tricalcium phosphates (3CaO·P2O5). and polyurethanes. and applications are described in Table 2. disadvantages. polydioxanone. polycaprolactone. and these porous final products are used mainly for scaffolds.13 Different synthetic polymers and their properties. Bioceramics Melting inorganic raw materials to create an amorphous or crystalline solid body is known as bioceramics. and rapid prototyping technologies have enabled solid free-form fabrication directly from a computer-aided design (CAD) model. zinc calcium phosphorus oxides.15 Many different techniques that are used to fabricate scaffolds for tissue engineering are summarized in the following sections. advantages. polycyanoacrylate. and applications are described in Table 3. and consistent supply of large quantities. polyhydroxyethymethacrylate. degradation. zinc sulphate calcium phosphates. fiber bonding. and applications are described in Table 4. Bioceramics classified as (1) nonresorbable (relatively inert). ferric calcium phosphorus oxides. for example alumina.

nerve.109 Used as an injectable gel.13. poly(glycolic acid). PLGA) and collagen blends57.13. nerve cartilage. and tissue engineering.107 The lactic and glycolic acid polymers are the most widely used synthetic polyesters for absorbable implants. guided tissue regeneration (in dental). stents. bone. Disadvantages. Synthetic polyesters (PLA. 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 Polymers and Properties Adipose. liver.57. heart Barrier membranes. and Applications of Synthetic Biomaterials Used as Scaffolds for Cell and Drug Delivery 16 Garg et al. Critical Reviews™ in Therapeutic Drug Carrier Systems . sutures. bone .1. cartilage. drug delivery.1.111 The sponges of synthetic polymer were immersed in a collagen sol under vacuum (to fill the pore with collaged solution).110. Advantages. Mechanical degradation properties can be tuned by varying polymer segments.1 Good biocompatibility Excellent wide range of biodegradetion rate Good bioresorption Biodegradable polymer Poly(lactic acid). staples.1. Poly(ethylene glycol)9. and copolymers9. Properties. drug delivery. mechanical degradation properties can be tuned by varying polymer segments. orthopedic applications. B. 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.B. muscles Adipose. tissue engineering Applications Table 2.106.58. then lyophilized and crosslinked by treatment with glutaraldehyde. B.2 Scaffold No.108.1.3 B.

drug delivery Applications A Novel Carrier for Cell and Drug Delivery 17 . drug delivery. cartilage. Supports the growth of a variety of cells.1. Number 1. hepatocytes.1. smooth muscle.3 B. the capacity of a material to suffer electric polarization due to mechanical stress.1.4 B.1. cardiac muscle.4 B.1 Aliphatic/aromatic degradable polyesters PPFs111.2 Scaffold No. (continued) Biocompatible and biodegrad.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.4.Volume 29. bone. Poly(glycerol sebacate)121–123 This polymer class can form elastomeric and tough biomaterials. i. and degradation products of PPF have been shown to be primarily fumaric acid and propylene glycol.116–120 Physical properties include nonlinear optical activity and piezoelectricity. Polymers and Properties Table 2. Hydrolysis of the ester bond allows PPF to degrade.4.1. and Schwann cells. cardiac tissue engineering Artificial skin. cardiac Tissue engineering.4. endothe-lial.4. PHAs57. including fibroblasts. 2012 B..113 Linear polyester with a repeating unit contains 2 ester bonds and one unsaturated carbon– carbon double bond. bone tissue engineering Orthopaedic. B.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. PET– PBT114.e.

6 B.1. Amine group containing polymers PAA124 Contains tertiary amino and amido groups that are regularly arranged along their polymer chain.5. orthopedic. Poly(depsipeptide-co-lactide) 127.B. N-succinimidyl tartarate mono-amine– poly(ethyleneglycol block poly(D.2 Scaffold No.3 B.1. orthopedic.128 Has positive or negative charges exhibiting higher cell attachment ability. 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. cell delivery.5. (continued) Good mechanical property Biocompatibility characteristics Control of fiber diameter. vascular epithelial. cartilage Drug delivery. including mechanical behavior compatible tothe native tissues they are intended to replace. bone. Critical Reviews™ in Therapeutic Drug Carrier Systems .5. endothelium. cell delivery.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. B. protein and peptide delivery Applications 18 Garg et al.1 Poly(urethane)s129–131 Tissue-engineered constructs must exhibit tissue-like functional properties.5.1. B. Polymers and Properties Table 2. orthopedic.L-lactic acid)125. bone Drug delivery. cell delivery.1. protein and peptide delivery Drug delivery.1.

By adding varying amounts of lactide segment. as scaffold for cell growth or as growth supporting filling material Applications A Novel Carrier for Cell and Drug Delivery 19 . Polyanhydrides139 Surface erosion properties B. characteristics such as crystallinity. drug delivery systems.ity. 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. the degradability of these polymers can be easily tuned from 15–100 days. stents Orthopedic scaffold applications Cartilage.10 B. Bone tissue engineering Drug delivery. Biocompatible. so autocatalytic degradation and toxic effects to the local environment problems are removed Rate of breakdown are easily controlled Advantages Polymers and Properties B. Number 1.1.8 Scaffold No. (continued) By altering the side groups. B.1. and hydrophobicity can be varied Degradation products of NH3.138 Due to the flexible P–N backbone of polyphosph-azenes. and amino acid cause little harm in vivo Mechanical strength much lower than that of bone Poor mechanical properties Degrades too slowly(in vitro) Loss in mechanical strength in vivo Difficult to maintain stability Disadvantages Drug delivery. 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. researchers have assessed the scope of this polymer with regards to both hard and soft tissue engineering.Volume 29.7 Table 2. bone regeneration.9 B.11 Polyorthoesters136 Degrades through the hydrolysis of the surface. Stimulated chondrocyte proliferation Improved cartilage matrix deposition in terms of histology and biochemistry Pluronic F-127 (PEO–PPO– PEO)132–134 Copolymer of PEO and PPO. phosphate. skeletal reconstruction. blood contacting devices Orthopedic.1. wound dressing.degradabil.1. Pluronic F-127 is biocompatible hydrogel with surfactant properties.1. 2012 Polyphosphazenes137.

Nonbiodegradeable polyibility Degradation rate not controlery.1. PLA. poly(butylene terephthalate). B. polyethylene oxide. Brittle endovascular surgery Mechanical stability and flex. poly(lactic acid). Mechanical stability and flex.12 Table 2. polyhydroxyethymethacrylate.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 diester–diamide segment through an ether bond. cartilage.1.2 PHEMA143 Biocompatible Induces hypersensitivity reacBone. tyrosine-derived polycarbonate. contact lens. polypropylene oxide.3 Poly(N-isopropylacrylibility longer durations environmental fields. TDP. PHEMA. PEO. PPO. PET.Difficult to maintain stability for Textile industry.2. PVA.141 so its wet ability and charge Difficult processing drug delivery. Polypyrrole140. B. polyhydroxyalkanoate. poly(ethyleneterephtalate). Scaffold No. PHA. gated as a conductive polymer density can be varied to best mimic neural structure doping Difficult to fabricate bone tissue engineering that could allow signal transduction to take place while the nerve cells are growing. PBD.1 mers lable Polyvinyl alcohol (PVA)142 Hydrophilic polymer produced by hydrolysis of polyvinyl acetate. PPF. forms a hydrogel in water. PLGA. poly(propylene fumarate).Polymers and Properties Advantages Disadvantages Applications Its ability to be easily doped High cost Nerve tissue engineering. medicine.2. poly(lactic acid–glycolic acid). Polypyrrole has been investiLack of mechanical stability after cell delivery. poly(amido amine).Limited durability Chondrocytes. The PVA with a high degree of hydrolysis is not soluble in water at room temperature but is soluble at elevated temperatures (usually above 70°C). B.2. PAA. B. drug delivB. (continued) 20 Garg et al. bone tissue engineering B. Critical Reviews™ in Therapeutic Drug Carrier Systems .2. 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. PHEMA is a polymer that High purity tions in humans drug delivery. poly vinyl alcohol.

ceramics (bioglass. intervertebral disc C.Adipose. artificial skin.1. renal glomerular tissue.106 ture).146 Excellent biocompatibility AdPoor mechanical properties Bone and cartilage. Advantages. ligament and nent of mineral Poor mechanical properties dental. Number 1. osteochondral. drug delivery. C. Biodegradable case of crystalline strucand dental. heart and nerve. intervertebral disc. osteogenic differentiation Slowly degradable (crystal. Calcium phosphate based equate mechanical strength Slowly degradable cartilage. renal glomerular Good osteoconductivity ture) tissue. bone and C. ligament mineral phase of bone.Table 3. cardiovascular. C. phase of bone. Excellent biocompatibility AdNonresorbable Bone regeneration. bone.2 Bioactive glasses and glass Good biocompatibility and osteoconductivity line structures) nerve. wound closure. Disadvantages.2 Tricalcium phosphate145. vascularization.144 Found naturally as a compo.Good osteoconductivity Brittle artificial skin. drug delivery Show the capability to bond to angiogenetic both bone and soft tissue and Adequate mechanical strength to stimulate bone growth.1 Hydroxyapatite58. A Novel Carrier for Cell and Drug Delivery Volume 29. and Applications of Bioceramics Biomaterials Used as Scaffolds for Cell and Drug Delivery Scaffold Polymers and Properties Advantages Disadvantages Applications No. vasculature. geniBrittle tourinary tract. phate glass)57. heart and Compositional similarity to the equate mechanical strength Slowly degradable (in the nerves. 2012 21 .1. phosTailorable resorption Good Brittle (amorphous strucspinal cord. Properties. cartilage.1. skin.

interverpossible. PEG. vascularization. PLLA. periodontal bone.147.Good osteoconductivity “best” qualities of indiand nerves. Advantages. Bone and cartilage. polycaprolactone.1 Ability to tailor mechanical Fabrication techniques degrada-tion and its biological can be complex properties Table 4. poly(lactic acid). PLGA. artificial skin.2 Polymer –Polymer58. poly(ethylene glycol). renal (3) natural–natural polymers are Improved mechanical proper. osteochondral.Polymer-Ceramic 13. poly-l-lactic acid. Critical Reviews™ in Therapeutic Drug Carrier Systems .148 Good biocompatibility Compromise between Bone and cartilage. Disadvantages. Properties. polyglycolic acid. poly(lactic acid–glycolic acid).overall scaffold properties glomerular tissue.148 Natural or synthetic polymers combined with ceramics are often used for bone tissue engineering applications. thetic. drug delivery D. PLA.58. ties tebral disc. and Applications of Composite Biomaterials Used as Scaffolds for Cell and Drug Delivery Scaffold No. nerve. wound dressing. wound closure. (2) synthetic –natural and Tailorable degrdation rate vidual components with ligament and dental. genitourinary tract. skin. D. vasculature.147. Polymers and Properties Advantages Disadvantages Applications 22 Garg et al. PGA. cardiovascular PCL. heart Combinations of (1) synthetic –syn.

19 The main advantage of this technique is that it requires neither high temperature nor a separate leaching step. 3).155 The pore size can be controlled by optimizing the freezing rate and pH. Yannas et al. Particulate Leaching Method Particulate leaching methods are split into two categories: (1) solvent casting–particulate leaching. however. Preparation of PLGA scaffolds of pore sizes of up to 200 μm with 95% porosity was reported by Whang et. Volume 29. This technique is applied to a number of different polymers including silk proteins. 2012 . are limited to small pore size154 (porosity is often irregular) and a long processing time.153 Emulsification/freeze-drying allows for faster preparation of highly porous structures with high pore interconnectivity’s. al. poly-l-lactic acid (PLLA).B.156 V. Its disadvantages.18. Scaffolds are generally prepared by dissolving/ suspending polymers/ceramics in water or in an organic solvent followed by emulsification with a water phase. and (2) melt molding–particulate leaching. PEG.13 In solvent casting–particulate Figure 3.150. solvents are removed by freeze-drying and porous structures are obtained (Fig. PLGA/poly(propylene fumarate) blends.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. Fabrication of scaffold using the emulsification/freeze-drying method. This technique is based upon the principle of sublimation. Number 1.149 prepared collagen scaffolds by freezing a dispersion or solution of collagen and then freeze drying. a fast freezing rate produces smaller pores.A Novel Carrier for Cell and Drug Delivery 23 V.A.152. After pouring this mixture into a mold. Emulsification/Freeze-Drying Method The freeze-drying technique is use for fabrication of porous scaffolds.

the polymer is cast into a mold with the embedded solid porogen. first developed by Mikos et al. and again the porogen is leached away by washing the resulting product with water to yield a porous polymer scaffold (Fig. 4).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 μm with ease of control of porosity and geometry can be prepared using this technique. the solvent is then evaporated to make a polymer monolith embedded with the salt particles. Advantages include large range of pore sizes. nose. and specific organ types can be fabricated as nanocomposite hybrid scaffolds. 4).165 Nevertheless. poly(lactic acid) (PLA). PLGA. Fabrication of scaffold using the particulate leaching method. Critical Reviews™ in Therapeutic Drug Carrier Systems .161 later the method found applications in the creation of porous scaffolds for the growth of endothelial cells.24 Garg et al. or small intestine submucosa–impregnated PLGA scaffolds have been fabricated successfully into a biodegradeable sponge structure with more than 93% porosity and a desired pore size of 1000 μm. collagen.163 The pore size can be controlled by controlling the amount of porogen added and the size and shape of the porogen. this method suffers from major drawbacks because of the long period of soaking in water required to leach all of the salt particles. and highly porous structures. ability to tailor crystallinity. resulting in the formation of a porous scaffold (Fig. poly(ortho ester). a polymer dissolved in a solvent is mixed with salt particles in a mold. independent control of porosity and pore size.164 Complex geometries such as tube.157 In melt molding–particulate leaching. leaching. The polymer is set by applying heat and pressure.158 The solvent casting and particulate leaching method.159 was used primarily to manufacture composite scaffolds160. which are then removed by washing the scaffold with water. This leaching period is particularly detrimental to the manu- Figure 4.

Gas Foaming Method A “gas foaming” method was developed by Nam et al166 using an effervescent salt as a gas foaming agent. The evolution of ammonia and carbon dioxide gas. Efforts have resulted in the production of thin scaffolds with open-cell morphology with high porosity. citric acid. resulting in a porous microstructure. Number 1.15 The other disadvantages include limited membrane thickness (3 mm). limited mechanical properties. resulted in the formation of pores with high interconnectivity (Fig. Fabrication of scaffold using the gas foaming method. into the aqueous solution. limited interconnectivity.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. 2012 . Volume 29.168 synthesised PLA scaffolds using ammonium bicarbonate. along with the leaching out of ammonium bicarbonate particulates from the solidifying polymer matrix.15 The gas foaming process is used to fabricate highly porous foams without the use of organic solvents. and as the carbon dioxide gas tries to escape it causes the nucleation and growth of bubbles.24 Nam et al.13 The gas foaming/salt leaching method was further improved for preparing porous PLGA scaffolds by adding another salt.167 The porosity and mechanical strength could be controlled by adjusting the extent of an acid–base gas evolving reaction between the two salts. 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. 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. it can damage the cells seeded on the scaffold. which acted as both a gas foaming agent and a solid salt porogen. 5).A Novel Carrier for Cell and Drug Delivery 25 facture of controlled release scaffolds because a high percentage of the drug payload can be lost.C. Organic solvents may leave residues behind that can have toxic Figure 5.9 The method also produces thin membranes with a dense surface skin layer that might contain residual salt particles used during the process.165 If an organic solvent is used and is not completely removed. and poor control over internal architecture.15 V. the presence of residual porogen and solvents. this causes a decrease in solubility of the carbon dioxide within the polymer.

The dry polymer is dissolved in supercritical carbon dioxide to form a single-phase polymer/gas solution. Critical Reviews™ in Therapeutic Drug Carrier Systems . given that there is no need for the leaching process and no residual organic solvent. exposed to high-pressure CO2. 6). The significant advantage is no loss of bioactive molecules in the scaffold matrix. and rates of parameter reductions can modulate pore sizes.26 Garg et al. Fabrication of scaffold using supercritical fluid technology.16 The disadvantage of this technique is the presence of skimming film layers on the scaffold surface. Gas foaming yields high porosities (up to 93%) and varying the temperature.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. 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. Harris et al. A PLGA/sodium chloride mixture was compression molded into solid disks. uses a gas such as carbon dioxide (CO2) in a supercritical state at high pressure. also known as high-pressure processing. pressure. 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. and poor interconnectivity of the porosity.34 Porosities as high as 90% with pore sizes from 200 to 500 μm are attained using this technique.170 utilized this technique to fabricate highly porous sponges of PLGA. To overcome this problem. Some disadvantages of this method are nonporous external surface and closed pore structure165 and insufficient interconnectivity of pores within the matrix. effects in vitro and may cause inflammation in vivo. Supercritical Fluid Technology Supercritical fluid technology.171 modified this technique by combining it with the particulate leaching method. V. resulting in the process to remove this skin layer. and immersed in water to leach out the Figure 6.D.

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.175–177 It can produce ultrafine fibers with special orientation. poly(ethylene oxide).F. polyvinyl alcohol. Various materials can be electrospun into nanofiber-like biodegradable polymers such as PLGA and polycaprolactone.15 V. leading to the formation of fine fibers that mat in to porous scaffold (Fig. The other advantage of this technique is its simplicity. The droplet of polymer solution obtained sprouts followed by solvent evaporation. cylindrical shapes can be fabricated with this technique but the electrospinning method Figure 7. Electrospinning Electrospinning is a process whereby electrical charge is used to form a mat of fine fibers. all of which are favorable for better cellular growth in vitro and in vivo. 2012 . 7). Number 1. collagen. In this technique the polymer solution is passed under mechanical pressure through a high voltage (10–20 kV).172 developed a novel PLGA nanofibrous mesh with fiber diameter ranging from 500 to 800 nm and pores that were well interconnected. silk protein.172–174 Li et al. high surface area. The apparatus using this method was patented by J.A Novel Carrier for Cell and Drug Delivery 27 salt. and high aspect ratio that have control over pore geometry. Volume 29.E. Electrospinning is the most widely used method for fabrication of nonwoven nanofiber matrices. and sheets. Fabrication of scaffold using the electrospinning method.Cooly as early as 1902. and other peptides. high efficiency. The process led to the formation of a highly interconnected porous network with no sign of a nonporous surface.

and carbon. which is not sufficient for cell seeding and infiltration. Fabrication of scaffold using the sol-gel method. which allows creation of a hole of a desired size in electrospun matrices. Melt Molding Technique Scaffolds are prepared by melting polymers/ceramics in the presence of porogens (such as sodium chloride and sugar crystals). residual fine pores. 9). hydroxyl. where a series of hydrolysis and polymerization reactions allow the formation of a colloidal suspension (sol). the porous scaffolds are usually lyophilized (Fig. and with further drying and heat treatment the gel is converted into dense ceramic or glass articles (Fig. The  advantages of sol-gel technology can be used for construction of biomedical sensors. or for delayed drug delivery.15 Cell seeding is the main problem of the electrospinning method.180 The disadvantages are the high cost of raw materials. and a health hazard from the long processing time of the organic solution.G. Finally. once the mixture has cooled.  laser materials. 8). after casting the sol into a mold a wet gel is formed. low processing temperatures. porosity is achieved by dissolving the porogens in water. Critical Reviews™ in Therapeutic Drug Carrier Systems . and the possibility of controlling  the size and morphology of particles. Sol-Gel Technique Scaffolds are prepared by dissolving inorganic metal salts or metal organic compounds in a solvent.178 V. This is overcome by sacrificial biopolymer or cryospinning.181 Figure 8. V. One of the most important features of doped sol-gel materials is their ability to preserve chemical and physical properties of the dopants.179 Sol-gel techniques have become popular recently because of their high chemical homogeneity.F. The sol-gel–derived materials provide excellent matrices for a variety of organic and inorganic compounds. primarily results in a two-dimensional mesh structure with a nanoscale pore size. large shrinkage during processing.28 Garg et al.

In particular. the gelatin component is leached out by immersion in water.H. and pore interconnectivity and geometry.I. 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. and the scaffold is then dried. Fabrication of scaffold using the melt molding method. the velocity of compaction of the projectile or punch and dies is adjusted to achieve powder consolidation with the desired porosity. 2012 . the mold was heated above the glass-transition temperature of PLGA while pressure was applied to the mixture.182 V. macroshape control. The advantage of this technique is independent control of porosity and pore size. Thermally Induced Phase Separation Thermally induced phase separation (TIPS) was first applied to PLA scaffolds by Schugens et al. It consists of inducing a solid–liquid or liquid–liquid phase separation. Number 1. In 1995. Thompson et al. The quenching induces a phase separation into a polymer-rich phase and a polymer-poor phase.183 and later several other researchers applied this technique to prepare composite scaffolds. 11A. This treatment causes the PLGA particles to bond together.A Novel Carrier for Cell and Drug Delivery 29 Figure 9. TIPS uses thermal energy as the latent solvent to induce phase separation. This is done by dissolving the polymer in a solvent and quenching the solution at a certain temperature.165 V. which is important for the exchange of nutrients/waste from pore to pore. B).181 used the compression molding principle: a Teflon mold was used with PLGA and gelatin microspheres of a specific diameter. The process can include sintering as an alternative to use uniaxial or isostatic pressing (Fig. The disadvantage is the high temperature required for nonamorphous polymers and residual porogens. Powder Compaction Scaffolds are prepared by compressing the polymers/ceramics using projectiles or punch and dies. Volume 29. 10). Once the mold is removed.

Critical Reviews™ in Therapeutic Drug Carrier Systems . 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. however. (B) Fabrication of scaffold using liquid–solid phase separations. poor control over internal architecture. and packaging. filtration membranes.63 However. Fabrication of scaffold using the powder compaction method. mechanically damping materials.186 Nam and Park187 used the TIPS technique to obtain scaffolds with a macroporous structure with an open cellular morphology.184 Its disadvantages include the use of potentially toxic solvents.165 It can combine easily with other fabrication technology (particulate leaching) to design 3D structures with controlled pore morphology. actually may be beneficial for certain biomedical and industrial applications such as nerve regeneration. (A) Fabrication of scaffold using liquid–liquid phase separations. It can be combined with rapid prototyping to create nanofibrous scaffolds for tissue engineering applications. thus en- A B Figure 11.30 Garg et al. and limited range of pore sizes.185. Figure 10. The coarsening process was used to increase the size of phase-separated droplets. tThe latter disadvantage. and it is a highly porous structure and permits incorporations of bioactive agents (hydrophilic or hydrophobic).

188 Injectable. residual organic solvents. 3. Loading capacity to various types of bioactive molecules and cells by simple mixing. cooling. They can fill any shape of defect because of their good flow property 2. and subsequent removal of PLLA.A Novel Carrier for Cell and Drug Delivery 31 larging the pores (~100 μm). which provides more surface area for cell attachment and sufficient space for the regeneration of ECM. which makes them ideal for tissue engineering applications and high porosity.189 The scaffolds were fabricated by bonding a collagen matrix to PGA polymers with threaded collagen fiber stitches. In addition. resulting in a porous structure as a portion of the solvent. Number 1. PGA fibers have been bonded by embedding in PLLA solution. They do not contain residual solvents that may be present in a performed scaffold 4. and then freeze dried. The solvent used is then removed by freeze drying. Formation of sponge-structured injectable gel scaffolds also have been reported. freeze immersion precipitation. quickly frozen in liquid nitrogen at –198°C. The emulsion freeze drying method is also useful for the fabrication of porous structures. freeze thawing. In this case. 2012 . For example. 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. Volume 29. This leads to the formation of macroporous hydrogel. 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.to 250-μm sizes. scaffold structures of synthetic polymers such as PLA and PLGA have been made successfully using this method.J.15 The phase separation method is divided into freeze drying. Collagen scaffolds with varying pore sizes were developed using a collagen–glycosaminoglycan blend (90–120 μm) and chitosan scaffolds (1–250 μm) by varying the freezing condition. followed by the polymerization of the hydrophilic monomer by means of ultraviolet irradiation and removal of the solvent by thawing. They do not require surgical procedure for placement16 V.190 who produced scaffolds made of polyglycolic acid (PGA) polymer. Phase separation by freeze drying can be induced by a polymer solution with an appropriate concentration by rapid freezing.165. with more than 90% porosity and 15.192 The main advantage of the fiber-bonding technique is the high surface area:volume ratio. and emulsion freeze drying. The freeze thawing technique induces phase separation between a solvent and a hydrophilic monomer upon freezing. Fiber Bonding The fiber bonding method was first developed by Cima et al. The resultant scaffolds also had pores with a uniform size distribution and porosity of more than 90%. They took advantage of the fact that PGA was available as sutures and thus in the shape of long fibers. gelforming scaffolds provide several advantages such as the following: 1.193 Disadvantages are poor mechanical integrity. a mixture of polymer solution and nonsolvent are thoroughly sonicated.

improved ability to visualize the part geometry due to its physical existence. all the materials cannot be used for all the processes. earlier detection and reduction of design errors.203 use of toxic binders. 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. Each layer is created as defined by a computer-generated file. including stereolithography (SLA). V. which are subtractive.194 It is prepared by the deposition of a polymer solution over a nonwoven mesh of another polymer followed by subsequent evaporation. 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. This problem can be overcome by hot drying of PLLA fibers to improve crystallinity and structure orientation. depending on the technique).195 PGA is the first biocompatible and biodegradable polymer to be spun into fiber and used as a synthetic suture thread. V. lack of structural stability. RP or SFF fabrication technologies currently are being used by investigators to manufacture scaffolds for use in tissue engineering. and 3D printing (3DP).L. that they can be used only to make small membranes. The main limitations of these techniques are their resolution limit (50–300 μm. and poor feature symmetry. There are a few techniques that come under this group. 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. and morphology. It is thus an additive process unlike traditional methods of manufacturing.202 The main advantages of these techniques are reduced lead times to produce prototype components. SFF methods are based on the premise that a material in either powdered or liquid form is solidified one layer at a time.32 Garg et al. and increased capability to compute manufacturing properties of components and assemblies.196 One of the main drawbacks of this technique is a lack of structural stability. Once the layer is complete.K.All the techniques share the same principle: powders or liquids are solidified one layer at a time to gradually build a 3D scaffold. fused depositional modeling (FDM). selective laser sintering (SLS).197–200 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. Rapid Prototyping Rapid prototyping (RP) also is known as solid free form (SFF) fabrication. membrane porosity is difficult to control. the build platform is indexed down by one layer of thickness and the process is repeated. The systems that fall under rapid Critical Reviews™ in Therapeutic Drug Carrier Systems . which makes it difficult to design scaffolds with fine microstructures.

Stereolithography In this technique. Number 1. and free from solvents. macro shape control. and part of the cross-section is computed at the current height. the powders are loose and can be poured out of the completed part. Fused Deposition Modeling FDM uses a moving nozzle to extrude a fiber of polymeric material (x. a wide range of materials.165 High processing temperatures. (5) organ printing. 1.204 In this technique. support structures required for irregular shapes are a few disadvantages.A Novel Carrier for Cell and Drug Delivery 33 prototyping technique are (1) SLA.165 3. raw material is converted in a photo-curable monomer by a laser beam and partially constructed in layers of thickness. After each layer is completed. 2012 .and y-axis control) from which the physical model is built layer by layer. Polymerization occurs by the exposure of liquid resin to a laser. achievable pore sizes of 45 to 200 μm. 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. The disadvantage. is mainly that the technique is limited by the development of photopolymerisable liquid monomer material. In areas that are not sintered. which are then cured in an oven. and no materials are trapped in small features. The completed part is removed and breaks off supporting structures. independent control of porosity and pore size. however. an ink-jet printer head deposits drops of binder (starch. (2) SLS. 2. good compressive strengths. good compressive strengths. y and z directions. However. complete pore interconnectivity. (4) 3DP. 4. a new layer of loose powders is spread across the surface. Advantages of this technique are that it is relatively easy to remove support materials and easy to achieve small features. (3) FDM. inconsistent pore opening in x. complete pore interconnectivity. limited range of materials. An ultraviolet laser solidifies part of the cross-section and platform is lowered. high processing temperatures and difficulty removing materials trapped in small inner features are some disadvantages. Advantages of the technique include high porosity. The powders are gradually bonded by the laser beam into a solid mass that forms the 3D part of the geometry. achievable pore sizes of 250 to 1000 μm. and (6) membrane lamination. Advantages of the technique include high porosity. plaster- Volume 29. solvent free. The fiber must also produce external structures to support overhanging or unconnected features that need to be manually removed. Three-Dimensional Printing This technology was invented at the Massachusetts Institute of Technology by Bredt et al. The model is lowered (z-axis control) and the procedure is repeated. high surface area:volume ratio.

Organ Printing (Mironov) Organ printing can be defined as layer-by-layer additive robotic biofabrication of 3D functional. The resulting porous Critical Reviews™ in Therapeutic Drug Carrier Systems . achievable pore sizes of 45 to 500 μm. ceramic powder) on the layer of powder spread on the platform. 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). 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. Thus. and (3) postprocessing or organ conditioning and accelerated organ maturation. particularly when the technique is applied to drug/cell delivery. organ printing is a new emerging. V. A new layer of powder is deposited above the previous layer. The binder dissolves and joins adjacent powder particles. lack of mechanical strength. high porosity. enabling technology paradigm that represents a developmental biology-inspired alternative to classic biodegradable solid scaffold-based approaches in tissue engineering. 5. and a wide range of materials. high surface area:volume ratio. The membranes with an appropriate shape are soaked with solvent and then stacked in 3D assemblies with continuous pore structure and morphology.208 and it is a time consuming process because only a thin membrane can be used in this process.34 Garg et al.205 6. and materials trapped in small inner features that are difficult to remove are some disadvantages. the internal phase is removed to give a template of porous material. Organ printing involves three sequential steps: (1) preprocessing or development of blueprints for organs. easy processing. and limitation in the selection of materials. Emulsion Templating Porous structures can be obtained by using emulsion template techniques. The disadvantages of this technique are that layering of porous sheets results in less pore interconnectivity207. A disadvantage of the method includes cell aggregation within a droplet. cell damage. Use of toxic organic solvents. After polymerization. independent control of porosity and pore size.63 The technique has advantages such as a low heat effect on raw materials. 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.M. and the powder is shaken to get a 3DP. 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. living macrotissues and organ constructs using tissue spheroids as building blocks.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. (2) processing or actual organ printing.

A Novel Carrier for Cell and Drug Delivery 35 microstructures are replicas of the internal phase droplets around which polymerizations were performed.212 Textiles lack the structural stability and mechanical properties to withstand biomechanical loading. such fibrous structures have been found to be useful in growing different types of cells. a water-in-oil type of emulsion containing styrene and divinylbenzene was used as the external phase. For example. nonwoven polyglycolide structures have been tested for tissue engineering applications. These categories are detailed in Table 5.209 The first reported use of emulsions as templates was for the production of highly porous hydrophobic polymer called poly high internal phase emulsion (HIPE). PGA/PDLA. Textile Technologies A number of textile technologies have the potential to be applied to the design and fabrication of highly porous scaffolds. In particular. including fibers of PGA. These techniques include all the approaches that have been successfully employed for the preparation of nonwoven meshes of different polymers.N. Combination of Techniques The techniques discussed earlier can be combined with each other.O.213 V. A phase separation technique can easily combine with other fabrication technology (particulate leaching) to design 3D structures with controlled pore morphology. producing polymer foams with approximately the same size and size distributions as that of the emulsion at the point of polymerisation.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. and the Volume 29. Number 1. To improve mechanical properties. The size of the cell in polyHIPE polymers was 5 to 100 µm with the interconnecting pore size constituting approximately 20% to 50% of the cell diameter. The size of the emulsion droplets is preserved. a fiber-bonding technique was developed to prepare interconnecting fiber networks with different shapes. Fibers provide a large surface area:volume ratio and are therefore desirable as scaffold matrix material. 2012 . For example. Whang et al. and application of scaffold is mainly categorized into those three categories: (1) cell delivery. cartilage. In this work. APPLICATION OF SCAFFOLD Scaffold is used mainly to deliver the cell/drug/gene into the body. (2) DNA/ gene delivery. and liver have been achieved using nonwoven mesh composed of polymer. and (3) drug delivery.211 V.184 VI. and PGA/PLLA. promising results in tissue engineering of bone. depending on the exact requirements of the scaffold. heart valves. which was then freeze dried to produce porous PLGA polymeric monoliths. It can be combined with rapid prototyping to create nanofibrous scaffolds for tissue engineering applications.214 created an emulsion that was quenched using liquid nitrogen. The principal drawbacks are related to the difficulties of obtaining high porosity and regular pore size. bladder.

Critical Reviews™ in Therapeutic Drug Carrier Systems .230 Silk fibroin fiber scaffolds231. Ascorbate2-phosphate -----Platelet-derived growth factor -----Bone morphogenetic protein-2 gene -----Bone morphogenetic protein-2 gene Recombinant human bone morphogenetic protein-2 Nerve growth factor ----------Basic fibroblast growth factor Gentamicin sulphate -----Bone morphogenetic protein-2 -----Nonglycosylated form of bone morphogenetic protein-2 Platelet-derived growth factor Platelet-derived growth factorBB Corticosteroids Active Biomolecule In vitro and in vivo (rat.232 Silk fibroin hydrogel232 Fibrin gel233 Chitosan hydrogel234 Chitosan freeze-dried scaffolds235 Starch-based microparticles236 Starch-based microparticles237 Starch-based microparticles238 Starch-based fiber mesh scaffolds239 Alginate hydrogel240 Alginate–chitosan microcapsules241 Hyaluronate gel240 Chondroitin sulfate collagen coated discs242 Chondroitin sulfate–chitosan sponges243 Dextran beads244 Dextran/gelatine hydrogel microspheres245 Agarose gel240 PLGA Scaffold246 Scaffold No. mouse) in vitro In vitro and in vivo (mice) In vitro In vitro In vitro In vitro and in vivo (rabbit) In vitro and in vivo (rat. -----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 Bone marrow stromal cells -----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. dog) In vitro and in vivo (rat) In vitro In vitro In vitro In vitro In vitro In vitro and in vivo (mouse) In vitro and in vivo (mice) In vitro and in vivo (mouse) In vitro and in vivo (rat) In vitro In vitro and in vivo (dog) In vitro In vitro and in vivo (mouse) In vitro and in vivo (mice) In vitro and in vivo (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.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. A.

Table 5.Volume 29.keratinocytes ----------- ------ Human venous myofibro-blasts Bone marrow-derived mesenchymal stem cells Human foreskin fibroblasts cell line Encapsulated/Seeded Cell Type Basic fibroblast growth factor Bone morphogenetic protein-2 gene -----Transforming growth factor -β1. D. C. Number 1. (continued) 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 Human articular chondrocytes Bovine articular chondrocytes Chondrocytes Bone marrow stromal cells Chondrocytes ------ Melanocytes. 2012 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 Fibrin–collagen gel263 Fibrin gel264–266 B.insulin and plasmin ------ Active Biomolecule In vitro and in vivo (mice) In vitro and in vivo (mouse) In vitro and in vivo (rabbit) In vitro In vitro In vitro In vitro In vitro and in vivo (mice) In vitro and in vivo (rabbit) In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro and in vivo (rabbit) In vitro and in vivo (rat) In vitro and in vivo (mice) In vitro In vitro and in vivo (rat) In vitro In vitro Experimental Trial A Novel Carrier for Cell and Drug Delivery 37 . insulin growth factor1 Transforming growth factor-β1 Transforming growth factor-β1 Vitronectin/fibronectin -----------------------------------Transforming growth factor-β1 plasmid Transforming growth factor-β1 ------ Platelet-derived growth factor-A and B gene Human epidermal growth factor Fibroblast growth factor-2----- -----Transforming growth factor -beta 1. Fibrin gel in a PGA nonwoven mesh267 Porous fibrin gel268 Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Scaffold No.

Critical Reviews™ in Therapeutic Drug Carrier Systems . (continued) Bone morphogenetic protein2 gene Recombinant human osteogenic protein-1 Human platelet superna-tant Porcine platelet-rich plasma -----Glucose (medium) -------------------------Transforming growth factor-β1 ---------------Fibroblast growth factor-2 ------ Active Biomolecule In vitro In vitro In vitro In vitro In vitro In vitro and in vivo (mice) In vitro In vitro and in vivo (rat) In vitro and in vivo (mice) In vitro and in vivo (rabbit) In vitro and in vivo (mice) In vitro and in vivo (mice) In vitro In vitro and in vivo (rabbit) In vitro In vitro In vitro and in vivo (rabbit) In vitro Experimental Trial 38 Garg et al. Table 5.Rabbit mesenchymal stem cells Porcine articular chondro-cytes Bovine articular chondro-cytes Periostal explants Bovine and human Chondrocytes Alginate beads and disks258 Alginate hydrogel276 Alginate freeze-dried sponge combined with hyaluronic acid277 Alginate hydrogel in Ethisorb210278 Chondroitin sulfate–collagen –chitosan freeze-dried scaffolds with chitosan microspheres281 Chondroitin/gelatin hyaluronate–PLGA porous scaffolds282 Chondroitin sulfate–gelatin–hyaluronan freeze-dried scaffolds283 Chondroitin sulfate–collagen scaffolds284 Agarose film285 Cellulose porous scaffold286 Alginate gel alone and in PGA-PLA pads279 Alginate–chitosan microcapsules241 Hyaluronic acid hydrogel280 Alginate beads272 Alginate beads273 Alginate beads274 Alginate beads275 Human articular chondrocytes Porcine articular chondrocytes Human adipose-derived adult stem cells Cattle articular chondrocytes Rat chondrocytes Bovine articular 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. Encapsulated/Seeded Cell Type Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Scaffold No.

Number 1.306 Fibrin gel306 Alginate hydrogel305–307 Agarose gel305–307 Scaffold No.Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Vascularization Collagen gel287 Collagen/heparin sulfate matrix 288 Fibrin gel containing heparin-conjugated nanospheres289. insulin growth factor-1. G. F.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 Encapsulated/Seeded Cell Type Fibroblast growth factor-2 -----Fibroblast growth factor-2 Basic fibroblast growth factor. (continued) Volume 29.290 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. 2012 -----Human preadipocytes Preadypocytes Human intervertebral disc cells Human intervertebral disc cells Human intervertebral disc cells 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. insulin Basic fibroblast growth factor --------------Transforming growth factor -β1 Transforming growth factor -β1 Vascular endothelial growth factor Basic fibroblast growth factor Basic fibroblast growth factor Vascular endothelial growth factor ----------Fibroblast growth factor-2 Fibroblast growth factor-2 -----Vascular endothelial growth factor DNA ----Vascular endothelial growth factor Basic fibroblast growth factor Active Biomolecule In vitro and in vivo (mouse) In vitro and in vivo (mice) In vitro and in vivo (mouse) In vitro and in vivo (mice) In vitro and in vivo (mice) In vitro and in vivo (mice) In vitro In vitro In vitro In vitro In vitro In vitro and in vivo (rat) In vitro and in vivo (mouse) In vitro In vitro In vitro In vitro and in vivo (mice) In vitro and in vivo (rabbit) In vitro In vitro In vitro and in vivo (rat) In vitro In vitro In vitro and in vivo (mice) Experimental Trial A Novel Carrier for Cell and Drug Delivery 39 . Table 5. E.

Osteochondral Gelatin and chemically modified hyaluronic acid hydrogel316 Fibrin glue (Tisseel) combined with plotted medical-grade PCL317 Chitosan–glycerol phosphate hydrogel318 Hyaluronic acid (Hyaff11) nonwoven mesh scaffold319 Silk fabroin microsphere impregnated alginate scaffold320 Angiogenesis Silk fibroin nonwoven net321. L. Table 5.insulin-like growth factor 1 ------ ------ -----Transforming growth factor -β1 plasmid Platelet-derived growth factor plasmid Platelet-derived growth factorBB Dentin matrix protein 1 Bone morphogenetic proteins Active Biomolecule In vitro In vitro and in vivo (rabbit) In vitro and in vivo (rabbit) In vitro and in vivo (rabbit) In vitro and in vivo (rabbit) In vitro In vitro In vitro and in vivo (mice) In vitro and in vivo (rat) In vitro and in vivo (mice) In vitro and in vivo (mice) In vitro and in vivo (rat) In vitro and in vivo (mice) In vitro and in vivo (mice) Experimental Trial 40 Garg et al. (continued) Endothelial cells Rabbit bone marrow–derived mesenchymal stem cells Rabbit bone marrow–derived mesenchymal cells -----Bone marrow mesenchymal cells Human bone marrow–derived 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 Encapsulated/Seeded Cell Type ------ ----------Autologous blood -----Growth factor: bone morphogenetic protein 2.322 K. Critical Reviews™ in Therapeutic Drug Carrier Systems . Genito-urinary tract Collagen scaffold (fleece)314 I. J. Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Scaffold No. 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.

beta-nerve growth factor Neurotrophin-3 Epidermal growth factor brain derived neutrophic factor Neurotrophin-3 ------ ------ ----------- -----Vancomycin Dexamethasone Doxycycline Active Biomolecule In vitro In vitro and in vivo In vitro In vitro In vitro and in vivo (rat) In vitro In vitro and in vivo (rat) In vitro and in vivo (rat) In vitro In vitro In vitro In vitro In vitro In vitro and in vivo (rat) In vitro Experimental Trial A Novel Carrier for Cell and Drug Delivery 41 . Q. 2012 Porcine mitral valve interstitial cells and endothelial cells Myofibroblast cell.Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure 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. M. N. S. R. vascular endothelial growth factor. P. (continued) Volume 29.330 Fibrin scaffold331 Peripheral nerve regeneration Fibrin gel332–334 Chitosan/chitin tubular device with PLGA microspheres335 Alginate beads336 Pancreas Alginate beads337 Agarose sponge338 Heart valve Chondroitin sulfate–collagen hydrogels339 Acellular aortic valve scaffold340 Scaffold No. endothelial cell Murine insulinoma βTC3 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 ------------ Encapsulated/Seeded Cell Type ----------- -----Insulin Fibroblast growth factor. Table 5. O. Number 1.

Y.Cornea Agarose–fibrin gel343 Diabetics PLGA scaffold344 PLG scaffolds345 Chondrogenic differentia-tion PEG and PCL ccaffold V. Guided cell and axonal regeneration Dextran hydrogel porous scaffolds342 U. W. laminin-332 growth factor ------ extracellular matrix –derived peptides Active Biomolecule In vitro In vitro In vitro and in vivo (rabbit) In vitro and in vivo (mice) In vitro and in vivo (mice) In vitro and in vivo (rabbit) In vitro Experimental Trial 42 Garg et al. X. Critical Reviews™ in Therapeutic Drug Carrier Systems . Tumor PLGA microsphere in gelatin scaffold347 Hydroxyapatite–chitosan nanocomposite348 346 Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Scaffold No. Table 5. (continued) ----------- Rabbit chondrocytes Islet-like cell from human embryonic stem cell Islet-like cell from mouse Epithelial. fibronectin. stromal and endothelial cells Primary embryonic chick dorsal root ganglia cells Encapsulated/Seeded Cell Type Doxorubicin Celecoxib ------ -----Collagen IV.

poly-l-lactic acid. polyglycolic acid. PLLA. Number 1. PLGA. Tissue Engineering Application With Polymer(s)/Carrier/Scaffold Structure Scaffold No. PGA.Volume 29. Table 5. poly(lactic acid–glycolic acid). (continued) A Novel Carrier for Cell and Drug Delivery 43 . PEG. --------------------------------------------------------------------------------- Encapsulated/Seeded Cell Type 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 and in vivo In vitro and in vivo In vitro In vitro In vitro In vitro In vitro In vitro Experimental Trial PCL. poly(ethylene glycol). 2012 Antibacterial effect PLGA nanosphere incorporated into PLLA scaffold349 β-tricalcium phosphate /calcium phosphate invert glasses/ chitosan porous matrix350 Bioactive glass pieces351 Mesoporous bioactive glass352 Mesoporous silica-hydroxyapatite/ PLGA microspheres porous matrix353 Bioactive glass/ β-cyclo-dextrin354 β -tricalcium phosphate /Agarose porous matrix355 Calcium phosphate ceramic pieces356 β -tricalcium phosphate/ poly-εcaprolactone(PCL) porous matrix357 Hydroxyapatite/ β -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. poly(lactic acid). PLA. polycaprolactone.

and addition of microspheres encapsulating them. Local and sustained delivery of paracrine factors. cycle of reimplantation of cell/drug/gene scaffold constructs in the human body is shown in Fig. may greatly enhance tissue remodelling or organogenesis.215 Growth factors can be incorporated into the scaffold matrix by bulk encapsulation. either by inducing or inhibiting cell proliferation.A. specific or nonspecific surface adsorption.44 Garg et al. migration. the cells with growth factor are encapsulated or seeded into the scaffold and administered into the body.15 Figure 12. 12. survival. Critical Reviews™ in Therapeutic Drug Carrier Systems . Cycle of reimplantation of cell/drug/gene scaffold constructs in the human body. MATRICES/SCAFFOLD FOR CELL DELIVERY In these. and/or differentiation. VI.

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. intracellular uptake. thereby transfecting to seeded cells and expressing the growth factor to stimulate morphogenesis of specific cells to form the desired tissue.218 When implanted in vivo. dexamethasone. was loaded into the bulk phase of PLGA scaffolds for sustained release. British Columbia. Number 1. inFUSE. and transfection efficiency. also commercialized by Organogenesis. Polycationic agents such as polyethylenimine condense the plasmid DNA into positively charged nanoparticles and enhance DNA stability. commercialized by Angiotech Pharmaceuticals. MA). a steroidal anti-inflammatory drug. 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. bioengineered skin) or Forta-Derm antimicrobial (an antimicrobial wound dressing) are collagen-based products. marketed by Medtronic Sofamor Danek (Memphis. Inc. 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. For example. (Vancouver. TN) in the United States.221 VII.A Novel Carrier for Cell and Drug Delivery 45 VI. used as the “dermal” matrix of an artificial skin product. tricalcium phosphate.C.B. Inc. Polymer scaffolds have been designed to release the genetic material continuously as naked DNA or in the form of polyplexes.217 Nanoparticulate polyplexes composed of DNA and polycationic-condensing agents have been incorporated within the scaffold to increase the efficiency of gene transfection. Collagen sponges also have been used for the treatment of long bone fractures. has been used clinically for the treatment of long bone fractures for more than a decade. Volume 29. Revitix (a topical cosmetic product). Collagraft is a mixture of porous hydroxylapatite. is a collagen sponge that has been used as an osteoconductive carrier of bone morphogenetic protein for spinal fusion. Canton. the seeded cells in the scaffold with the polyplexes exhibited a much higher level of gene expression than those with naked DNA. and animal derived collagen I. 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. VCTO1 (bilayered. Canada). Organogenesis. 2012 .220 It was observed that sustained release of dexamethasone effectively induced differentiation of bone marrow stem cells to osteoblasts or chondrocytes. Inc. Healos bone graft replacement.

CA). CultiSpher. Gelfoam is an absorbable gelatin surgical sponge used as a hemostatic device. absorbable gelatine disk is Surgifoam. (Plainsboro. Opelead is commercialized by Shiseido (Japan). Bionect. (Englewood. commercialized by CSC Pharmaceutical. Opegan R is commercialized by Seikagaku. these have been used widely for implantation of artificial intraocular lens. The HemCon bandage. thoracic. 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. and Orthovisc is commercialized by Anika Therapeutics (Bedford. distributed in the United States by Ethicon Inc. Inc. EmbryoGlue is commercialized by Vitrolife. NJ). Sweden). IL). or AlgiSite by Smith & Nephew (Continental). which enables the production of autologous fibrin sealant components from a single unit of a patient’s blood plasma in approximately 60 min.46 Garg et al. which is a bilayered membrane system for skin replacement that provides a scaffold for Critical Reviews™ in Therapeutic Drug Carrier Systems . Inc. commercialized by Hexal (Holzkirchen. Hyalgan and Hyalubrix. (Portland. commercialized by Fidia (Turin. (Cornelia. The Vivostat system. has been commercialized by Vivolution (Denmark). an absorbable gelatine film designed for use as an absorbable gelatin implant in neuro. commercialized now by Pfizer (New York. in several minutes attracts blood cells (negatively charged surface) that merge with chitosan to form a blood clot. IN). and Artz. have been marketed widely as wound dressings. marketed by DePuy Orthopaedics. CultiSpher-G is a gelatin-based product in which macroporous gelatine microcarrier beads are used as microcarrier cell cultures. NY). which is an automated system for the onsite preparation and application of patient-derived fibrin sealant or platelet-rich fibrin. (Warsaw. MA). have been used widely as lubrication and mechanical support for the joints in osteoarthritis. The Integra dermal regeneration template. Italy). GA). Curasorb by Kendall (Mansfield. and ocular surgery. Germany) have been used widely as viscoelastic gels for surgery and wound healing. CO) and has been used widely for in vitro fertilization. Germany). Alginate-based products Nu-Derm.S is the same product with a different cross-linking procedure conferring a higher thermal and mechanical stability. and Jossalind. Pfizer also has a commercially available Gelfilm. commercialized by Johnson & Johnson (New Brunswick. commercialized in the United States by Baxter (Deerfield. GeniaBeads CN are hydrogel beads made from chitosan and have been commercialized by geniaLab (Braunschweig. MA). Biomend is a collagen membrane conventionally used in the regeneration of periodontal tissue and is a registered trademark of Integra Lifesciences Corp. Tisseel VH consists of a two-component fibrin biomatrix with highly concentrated human fibrinogen to produce fibrin gel from a blood sample. commercialized by Seikagaku Corporation (Tokyo. (Rancho Cordova. marketed by Percell Biolytica AB (Åstorp. Healon is commercialized by Advanced Medical Optics (Santa Ana. A commercially available porous. it has been commercialized by HemCon Medical Technologies Inc. which is a chitosan bandage applied with pressure to a severe external wound. 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. CA). is manufactured in the United States by Thermogenesis Corp. OR). NJ). The CryoSeal fibrin sealant system. it has been used widely as a biomaterial for biomedical applications. Japan).

a novel ophthalmic vehicle. Most of the scaffolds studied are still in the investigation stage and are yet to be approved for clinical use. cancer. few scaffolds are available commercially. through the use of adhesion peptides and growth factors) to the cells. one of the key challenges will be to try to mimic more accurately Volume 29.hydroxybutyrate-co-β-hydroxyvalerate) containing 24% hydroxyvalerate. At present. The field of biomaterials has played a crucial role in the development of tissue-engineered products. and as a material for cardiac tissue engineering. New biodegradable polymers need to be developed to meet all requirements for surgically implantable scaffolds.A Novel Carrier for Cell and Drug Delivery 47 dermal regeneration. Inc.. mainly for scaffold materials in combination with ceramic materials. and involve the use of safe adjuvants. it is marketed by Integra in the United States.and high-viscosity grades are used in sustained-release matrix formulations. Commercially available poly-β-hydroxybutyrate homopolymer BIOPOLGO4 is commercialized by ICI Biological Products (Angiotech Pharmaceuticals. In spite of this. many of them are already listed in the Generally Recognized as Safe list or even have been approved by the Food and Drug Administration. As the field progresses. Scaffolds provide adequate signals (e. Gelrite. England). properties. particularly for cell/drug delivery. Natrosol 250HX. marketed by geniaLab.or divalent cations present in the lacrimal fluid. it is commercialized by Alcon Laboratories (Hemel Hempstead. in Canada) in the form of compression-molded sheets 0. Thus.5 mm thick. 2012 . used as polyhydroxybutyrates.119 Commercialized scaffold products and their major research applications are described in Table 6. there is a vast amount of research being performed worldwide on all aspects of tissue engineering/regenerative medicine. and medium. New approaches targeting cell/drug delivery are the need of the hour. Similarly. Looking into convenience and practicability. particularly for tissue regeneration. as a vehicle for drug delivery. which have been studied to some extent for tissue engineering applications. 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. versatile. the copolymer poly(β. distributed by Hercules (Wilmington). Viscoat is a solution of 4% chondroitin sulfate and 3% sodium hyaluronate that is used as a surgical aid in anterior segment procedures. and congenital malformations. Number 1. are used in pharmaceutical formulations for various purposes: low-viscosity grades are used as tablet binders in immediate-release dosage forms. CONCLUSIONS AND FUTURE STUDIES Scaffolds have been well investigated with respect to the material requirement. ICI commercialized BIOPOLP05.g. gels in the presence of mono. there is immense scope in developing injectable gel-sol scaffolds because they are easy to use. postsurgical management. 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. including cataract extraction and intraocular lens implantation. and technology for the production of scaffolds. and geniaBeads MC. VIII. and are necessary for their survival and growth. induce and maintain them in their desired differentiation stage.

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 patient’s
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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