TISSUE ENGINEERING: Part B

Volume 17, Number 4, 2011
ª Mary Ann Liebert, Inc.
DOI: 10.1089/ten.teb.2011.0077

Hydrogels for the Repair of Articular Cartilage Defects
Kara L. Spiller, Ph.D.,1,* Suzanne A. Maher, Ph.D.,2 and Anthony M. Lowman, Ph.D.1,3

The repair of articular cartilage defects remains a significant challenge in orthopedic medicine. Hydrogels, threedimensional polymer networks swollen in water, offer a unique opportunity to generate a functional cartilage
substitute. Hydrogels can exhibit similar mechanical, swelling, and lubricating behavior to articular cartilage,
and promote the chondrogenic phenotype by encapsulated cells. Hydrogels have been prepared from naturally
derived and synthetic polymers, as cell-free implants and as tissue engineering scaffolds, and with controlled
degradation profiles and release of stimulatory growth factors. Using hydrogels, cartilage tissue has been engineered in vitro that has similar mechanical properties to native cartilage. This review summarizes the advancements that have been made in determining the potential of hydrogels to replace damaged cartilage or
support new tissue formation as a function of specific design parameters, such as the type of polymer, degradation profile, mechanical properties and loading regimen, source of cells, cell-seeding density, controlled release of growth factors, and strategies to cause integration with surrounding tissue. Some key challenges for
clinical translation remain, including limited information on the mechanical properties of hydrogel implants or
engineered tissue that are necessary to restore joint function, and the lack of emphasis on the ability of an
implant to integrate in a stable way with the surrounding tissue. Future studies should address the factors that
affect these issues, while using clinically relevant cell sources and rigorous models of repair.

Introduction

C

artilage damage and cartilage-related diseases are the
most common cause of disability in the United States
today, occurring in approximately 6% of people of 30 years
of age and older, at a cost to the economy of $128 billion.1–3
The prevalence of arthritis is projected to reach 25% of the
population, or 67 million people, by the year 2030, as a result
of the aging population and the obesity epidemic.4
The three types of cartilage include hyaline cartilage,
found in articulating joints, nose, trachea, intervertebral
disks, and vertebral endplates; elastic cartilage, found in
tendon and ligament insertion sites and the meniscus; and
fibrocartilage of the ear. Fibrocartilage has a higher collagen
content and lower proteoglycan content than hyaline cartilage, and elastic cartilage contains elastic fibers in addition to
collagen and proteoglycans.5,6 Although the focus of this
review is the repair of hyaline cartilage, and more specifically
the cartilage in articulating joints, much of the information
can be extended to apply to the repair of other types of
cartilage.
Articular cartilage is a multiphasic tissue consisting of
< 5% chondrocytes, 60%–85% interstitial fluid, and a solid

extracellular matrix (ECM), composed of about 15%–22%
type II collagen, 4%–7% proteoglycans, and other protein
macromolecules.7–9 Cartilage can be modeled as a material
having three layers that are consistent with depth-dependent
variations in the mechanical environment. The superficial
layer is in contact with the articulating surfaces; collagen
fibrils are arranged parallel to the surface; fluid flow is high
and compressive strains can reach up to 50%.8,10 Chondrocytes in this layer, subjected to fluid flow and matrix
consolidation, are flattened parallel to the surface.10 Chondrocytes in the middle zone experience little strain or fluid
flow and are loaded primarily under hydrostatic pressure.
They are rounded and produce high amounts of glycosaminoglycans and type II collagen in random orientation.10
In the deep zone the fibers form thicker bundles that are
perpendicular to the joint surface, which anchor the cartilage
to bone at the tidemark, the transition to calcified cartilage and
subchondral bone.8 The cell density in mature cartilage
decreases from about 60 cells/cm3 in the superficial layer to
about 10 cells/cm3 in the deep zone, a result of high rates of
synthesis of ECM.11,12
Cartilage damage typically begins as a focal defect, the
result of trauma, mechanical injury, or wear and tear. The

1

Biomaterials and Drug Delivery Laboratory, Drexel University, Philadelphia, Pensylvania.
Laboratory of Functional Tissue Engineering, Hospital for Special Surgery, New York, New York.
3
Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pensylvania.
*Current affiliation: Laboratory for Stem Cells and Tissue Engineering, Department of Biomedical Engineering, Columbia University,
New York, New York.
2

281

282
treatment of damaged articular cartilage in the knee has been
a challenging endeavor because of its limited capacity for
self-repair and its complex structure that imparts unique
functional properties to the tissue. It is aneural, alymphatic,
and avascular, severely limiting spontaneous repair that requires access to reparative stem cells. Cartilage also withstands some of the highest loads in the body; articular
cartilage in the hip joint can endure stresses of up to 18 MPa
during daily activities such as rising from a chair.9,13
If a cartilage defect is in contact with the underlying bone
marrow, known as a full-thickness defect, spontaneous repair is possible but the resultant tissue is fibrotic and mechanically and structurally inferior to the native tissue, and
eventually degenerates under the high loads found in the
knee.14 Surgical procedures directed at trying to induce repair include subchondral microfracture, the transplantation
of cartilage plugs, and autologous chondrocyte implantation.15–18 Biomaterials intended to function as a synthetic
cartilage replacement or to encourage new tissue regeneration have been developed to address the shortfalls of
currently used techniques.19–22 Cartilage is composed of
long-chain polymers of glycosaminoglycans and collagen
swollen in a large amount of water, giving it properties akin
to hydrogels, three-dimensional hydrophilic polymer networks that are highly swollen in water.23,24 Since the development of methacrylate-based hydrogels for biological
applications in the early 1960s,25 hydrogels have been utilized in drug delivery, surface modification of biomedical
implants, diagnostic devices, and tissue engineering of
multiple tissue types.26 Hydrogels are considered biocompatible, although the immune response depends on numerous properties, such as the type of polymer, crosslinking
methods, degradation rate, and byproducts, whether cells
are included, and the release of bioactive factors.27 The
material properties of hydrogels can be tailored by varying
parameters such as polymer composition, crosslinking density, network morphology, and degradability.24,26
Hydrogels have been used in two forms for the purpose of
replacing articular cartilage—as permanent implants to replace damaged cartilage, or as cell carrier materials to encourage tissue regeneration. As cell-free implants, hydrogels
can be structurally and mechanically similar to cartilage and
allow efficient load transfer.28,29 As cell-seeded tissue engi-

FIG. 1. Schematic representation of how design variables
can affect hydrogel properties
and response of encapsulated
cells. Color images available
online at www.liebertonline
.com/teb

SPILLER ET AL.
neering scaffolds, hydrogels are also extremely useful: they
promote chondrocyte attachment in a manner that is similar
to the cartilage ECM,30 they maintain the chondrocyte phenotype in a way that is impossible in monolayer culture,31–33
and their viscoelastic nature permits effective transfer of
loads to the chondrocytes, which depend on mechanical
signals for survival.34,35
There are several design variables that can be modified
with resulting effects on the potential of a hydrogel to
function as a cartilage substitute or tissue engineering scaffold (Fig. 1). The main parameters are type of polymer,
crosslinking density, degradation profile, mechanical properties and loading regimen, source of cells, cell-seeding
density, controlled release of growth factors, and strategies
to cause integration with surrounding tissue.
Design Variables
Type of polymer
Hydrogels can be composed of naturally derived materials, such as agarose and collagen, or of synthetic polymers
like poly(ethylene glycol) (PEG) and poly(vinyl alcohol)
(PVA), and can be physically, ionically, or covalently crosslinked.
Naturally derived polymers. Hydrogels formed from
naturally derived polymers, such as agarose, alginate, chitosan, hyaluronan, collagen, fibrin, and polysaccharides, are
attractive biomaterials because they are biochemically similar to cartilage and can be degraded by cell-secreted enzymes. Scaffolds prepared from naturally derived polymers
have been used in matrix-assisted autologous chondrocyte
implantation, including collagen type I/III, hyaluronan
(Hyalograft-C, HYAFF11; Fidia Advanced Biopolymers,
Abano Terme, Italy), and fibrin (Tissucol, Baxter, Austria).36,37 Although naturally derived hydrogels lack the
mechanical properties to withstand physiological loads, they
have the potential to support the formation of healthy cartilage, and some commercially available products are based
on these polymers (Table 1).
Agarose and alginate: Agarose and alginate, both derived
from marine algae, were among the first hydrogels studied

cysts formed in the subchondral bone.40. good adhesion to surrounding tissue Promotes cartilage formation by encapsulated cells. 45–62 32. and are crosslinked physically by spontaneous gelation or chemically through aldehyde or carbodiimide chemistry.7 preoperatively. collagen gels have been prepared from atelopeptides. and promote cartilage formation by encapsulated cells. Tissue Bank of France. Collagen hydrogels are chemically biomimetic. UT) 63–67 Improvement in IKDC and Lysholm scores at 12 months in phase II (ref. achieving a mean score at 2 years of 77.63) In preclinical trials 32.110 but less success in osteoarthritic knees.109 Hydrogels based on alginate and agarose are available commercially (CARTIPATCH. and Lysholm scores at 24 and 25 months in phase II (ref. PureCol/VitroCol/ Nutragen (Glycosan Biosystems. reported that MSCs embedded in type I collagen gels differentiated into chondrocytes and repaired cartilage defects in rabbits with hyaline-like cartilage. Quebec. agarose Collagen Commercially available products Strengths Prepared from Polymer Table 1.32 Because biomaterials prepared from animal byproducts may induce immune responses. the MSCs differentiated into chondrocytes and repaired the defects with zonally organized cartilage. Salt Lake City. Austria). and can remodel collagen through the secretion of collagenase. can be prepared without the risk of animal pathogens Structurally analogous to cartilage glycosaminoglycans Blood Fibrin Animal cartilaginous tissue HyStem/Extracel/Glycosil (Glycosan Biosystems. Types of Naturally Derived Hydrogels Clinical results (all in combination with autologous chondrocytes) References HYDROGELS FOR REPAIR OF ARTICULAR CARTILAGE DEFECTS Collagen: Hydrogels can be formed from collagen of type I or type II.43–45) CARTIPATCH (Tissue Bank of France.46 In addition.34 They have been used extensively as model systems to study the effects of dynamic loading and other conditions on cell behavior.38 Alginate has also been used as the substrate in the in situ biofabrication of a geometrically matched hydrogel ex vivo into a cartilage defect using additive printing methods. the landmark study by Wakitani et al. Can be designed for specific cell–matrix interactions Oligopeptides Self-assembling peptide Chitosan 283 for tissue engineering due to ease of gelation and cell encapsulation.. International Knee Documentation Committee. MA) 68–83 Animal tissue or microbial fermentation Arthropod exoskeletons Hyaluronan Can be prepared autologously. Deerfield. which promotes proliferation and production of ECM components. 34. maintains chondrocytic phenotype Biochemically similar to cartilage Marine algae Alginate. Cambridge. using the International Knee Documentation Committee scoring system.50. but with areas of incomplete integration with the surrounding cartilage. the latter being the dominant component of articular cartilage. France) CaReS (Arthro Kinetics Biotechnology. 43.7 out of 100 at 25 months from 70. Krems.34.46 Type I collagen gels have been used as cell delivery vehicles for the transplantation of bone marrow stem cells into cartilage defects in humans. IL) Ease of preparation.32 Type II collagen hydrogels have been shown to promote more efficient chondrogenic differentiation of embedded mesenchymal stem cells (MSCs) than type I collagen gels because they invoke a more round cell shape.49 Autologous chondrocytes embedded in type I collagen gels repaired chondral defects in 26 patients. Brittberg.107 and have supported the formation of cartilage tissue with similar mechanical properties to native cartilage. chondrocytes suspended in alginateagarose hydrogels repaired chondral defects. France). although there were areas of incomplete integration as well as high variability within groups.38) Improvement in IKDC.54 Chondrocytes interact with collagen gels via integrins. 38–42 Improvement in IKDC score at 2 years in phase II (ref. Salt Lake City.43 Collagen hydrogels have also been useful in studying the behavior of chondrocytes and stem cells in vitro under various conditions. Canada) (chitosan. have high swelling ratios. UT) Tissucol (Baxter.8 out of 100 from a mean score of 37 preoperatively.48 When type I collagen gels containing autologous MSCs were implanted into cartilage defects in a sheep model for 6 months.84–96 97–106 In phase II trials In preclinical trials IKDC.41 Alginate gels in the presence of divalent ions and agarose undergo spontaneous gelation under mild conditions due to hydrogen bonding.56–60 Type I collagen gels are available commercially as CaReS (Arthro Kinetics .62 In 1994. such as compression and the presence of growth factors. Lyon. Lyon. which the authors attributed to a lack of mechanical support from the collagen gels.38 BST-CarGel (Biosyntech. achieving mean Lysholm scores of 96.61. in which potentially immunogenic residues are removed.51 with some instances of impressive repair in otherwise healthy knees47. glycerol phosphate) PuramatrixTM (3DM Inc.108 In a clinical trial involving 17 patients.

86 In situ-gelling hydrogels based on chitosan and glycerol phosphate (BST-CarGel.89. Cambridge. bypassing the risk of animal-derived pathogens.72 For example. and is SPILLER ET AL. Bray and Merrill suggested the use of synthetic hydrogels as cartilage replacements. which has been shown to support cartilage formation by encapsulated chondrocytes and MSCs.72 Interestingly.95 Chondrocytes encapsulated in injectable chitosan hydrogels repaired non-weightbearing defects in sheep. Krems.66 MSCs differentiated into chondrocytes and produced more cartilage tissue when encapsulated in fibrin hydrogels when compared to alginate hydrogels. reducing the risk of a foreign body reaction.112 and to prepare injectable scaffolds. Quebec.71 Hydrogels based on hyaluronan are available commercially (HyStem/Extracel/Glycosil. In addition. with good integration with the surrounding cartilage after 12 weeks. isolated from a patient’s own blood.. MA). nanofibrous hydrogels when exposed to electrolytes. Peptides: Hydrogels can also be prepared from selfassembling peptide sequences.82 but decreased such markers by chondrocytes encapsulated in collagen hydrogels. ECM organization. with good integration with the surrounding tissue.111 Hyaluronan hydrogels supported cartilage formation by human embryonic stem cells in non-weight-bearing defects in a rat model. by chondrocytes encapsulated in alginate hydrogels.74 Hyaluronan can be prepared from a variety of animal tissues or from microbial fermentation. however. describing the structural and mechanical similarities between cartilage and PVA hydrogels.88. Biosyntech. Glycosan Biosystems).64.113 This strategy is currently being investigated in phase II clinical trials. Synthetic polymers.97 They also have much smaller fibers than polymer hydrogels.98. this trend was reversed in the presence of exogenous insulin-like growth factor1 (IGF-1). Poly(vinyl alcohol): In 1973. Canada) mixed with blood repaired 1 cm3 weightbearing cartilage defects in sheep with more hyaline cartilage than microfracture controls. structurally similar to the glycosaminoglycans found in cartilage. Austria)45 and as PureCol/VitroCol/ Nutragen (Glycosan Biosystems.65 but they have been investigated as carriers in autologous chondrocyte transplantation in clinical trials in Europe (Tissucol). Most commonly. allowing its controlled release based on hydrogel chemistry.104–106 A commercially available hydrogel formed from self-assembling peptides is PuraMatrixTM (3DM Inc. Fibrin: Fibrin hydrogels can be prepared from fibrinogen in the presence of thrombin.77 Hyaluronan is degraded by cell-secreted hyaluronidase.103 The peptide sequences theoretically can be designed for specific properties or cellular interactions.98 Unlike other naturally derived hydrogels.96 The gelation of chitosan can be induced by ionic or chemical crosslinking. the addition of hyaluronan to collagen I hydrogels increased markers of cartilage formation by encapsulated chondrocytes in a subcutaneous implantation model.92 Chitosan has been modified to increase biochemical similarity to cartilage85. For example.72 Chitosan: Chitosan is prepared by partial N-deacetylation of chitin.81 although conflicting results regarding the combination of hyaluronan with other types of hydrogels indicate a more complex system. photocrosslinkable hyaluronan hydrogels are prepared through the addition of a methacrylate group to the hyaluronan backbone and subsequent crosslinking by optical trigger.93 The kinetics of degradation of chitosan by cell-secreted lysozyme can be controlled through hydrogel properties such as crystallinity and through chitosan’s degree of acetylation. a marker of fibrous scar-like cartilage formation. Salt Lake City. cell motility.100 Peptide gels were also designed with binding sites for the growth factor transforming growth factor b-1 (TGFb1).84–86. peptide hydrogels can be synthesized without the risk of animal-derived pathogens.94.99 The peptides self-assemble into b-sheets when dissolved in water and form injectable.25 mm gap in a cartilagegap model in vitro.75 Aqueous solutions of hyaluronan can be crosslinked to form hydrogels through a variety of methods. markers of the cartilage phenotype. and exhibit excellent adhesion to surrounding tissue.69 Cartilage formation by chondrocytes and by MSCs was enhanced in hyaluronan hydrogels in comparison to fibrin and to PEG hydrogels.90. the potential for disease transmission through materials derived from animals has led to investigations into synthetic hydrogels. UT).98.114 Aqueous solutions of PVA can be chemically .63 Hyaluronan: Hyaluronan is a natural glycosaminoglycan found in articular cartilage and synovial fluid and is also involved in the regulation of wound healing. peptide gels with reminiscent chemistry of hyaluronan were designed to increase lubrication between articulating cartilage surfaces.98 Hydrogels composed of repeating units of the peptide sequence lysine-leucine-aspartic acid and of arginine-alanineaspartic acid supported formation of cartilage by encapsulated chondrocytes that was comparable to that formed in agarose gels.76.102 In general. emphasizing the role of biochemical cues in cartilage formation. which are composed of amino acids containing alternating hydrophobic and hydrophilic side groups.284 Biotechnology.70 Chondrocytes cultured in PuraMatrixTM also generated sufficient cartilage tissue to close a 0. and the rate of degradation can be tuned by adding hydrolytically degradable moieties such as lactic acid for faster degradation78 and poly(caprolactone) for slower degradation.101 These hydrogels have been useful for evaluation of cartilage formation by a number of different cell types and in the presence of growth factors or dynamic loading.102 Controlled release of TGFb1 using this system caused encapsulated MSCs to differentiate into chondrocytes over 4 weeks in vitro.91.67 Fibrin hydrogels have poor mechanical properties. the lack of mechanical integrity of hydrogels prepared from naturally derived materials presents difficulties as weight-bearing implants.83 Other studies have shown that the addition of hyaluronan to alginate hydrogels caused an increase in the expression of type I collagen. and cell differentiation. suggesting a role for hyaluronan in the modulation of IGF-1 signaling by entrapped chondrocytes.73 The addition of hyaluronan to cell culture medium increased deposition of type II collagen and glycosaminoglycans.87.80 MSCs encapsulated in these hydrogels repaired non-weight-bearing defects in rabbits after 8 weeks with a continuous joint surface but some areas of incomplete integration.64.80 Hyaluronan may stimulate chondrogenesis through interactions with cell surface receptors.68.69. derived from the exoskeleton of arthropods. potentially allowing investigations into the length scales of cell–matrix interactions.

The addition of collagen-mimetic peptide. Germany) hydrogels are composed of poloxamers or triblock copolymers of PEG and poly(propylene oxide).058 0.79. GA) were press-fit into 49 stage IV chondral lesions in 18 patients.29. The authors attributed the failures to dislocation due to inadequate fixation to surrounding tissue. and degradation by cell-secreted chondroitinase.153–155 Pluronic (BASF.136 These hydrogels were also modified with chondroitin sulfate. Comparisons Between Poly(Vinyl Alcohol) Hydrogels (All Prepared by Freeze–Thaw) and Articular Cartilage Property Compressive modulus Aggregate modulus Shear modulus Permeability Coefficient of friction Coefficient of friction Test Unconfined compression Confined compression Torsion Confined compression Continuous sliding versus cartilage Cyclic load versus cartilage Polymer concentration Value for hydrogel Value for mature cartilage 20%. but the harsh manufacturing techniques of traditional PVA hydrogel fabrication prevent the addition of cells before crosslinking. and frictional properties (Table 2).25 MPa 10%.23.11 MPa 25%. the lack of integration between the hydrogels and the surrounding cartilage tissue has so far prevented their use as cartilage replacements.132 PVA hydrogels have also been used as tissue engineering substrates.151 In a rabbit osteochondral defect. resulted in enhanced retention of cell-secreted collagen and increased production of both collagen and proteoglycans by chondrocytes and by MSCs. and embryonic stem cells have been encapsulated in these hydrogels and induced to form cartilage tissue in the presence of growth factors. shear modulus.171 0.17–0. greater biochemical similarity to cartilage. 129 120 125 125 over the swelling properties.13–0.2 · l0 . Cartilix.138 Chondrocytes. Foster City.152–0.046–0. modified with methacrylate groups to allow photo-crosslinking.136 The abundance of pendant hydroxy groups on PVA simplifies chemical modification to vary hydrogel properties.24.141–145 PEG macromers have also been modified with moieties that made the hydrogels more biomimetic.131 PVA hydrogels (SaluCartilage. also known as poly(ethylene oxide). providing control References 126–128 120 29. w/w 10%.151.14 m4/ Ns (bovine) 0. and the main results of these studies are described later.28.118–120 PVA hydrogels have also been used as model systems to study the lubricating and swelling properties of articular cartilage. with similar coefficients of friction. the average McDermott knee scores decreased after 12 months.150 Other synthetic hydrogels: The PEG macromer has also been modified with fumaric acid to form hydrogels made of oligo(poly(ethylene glycol) fumarate) (OPF).14 m4/Ns 15%. PEG hydrogels can be easily modified and have been useful in studying the effects of hydrogel properties on cartilage formation.138–140 Like PVA. allowing mechanical similarity to cartilage.137 Poly(ethylene glycol): Hydrogels prepared from PEG.33 MPa (bovine) 0. Smyrna.136 Cell–matrix interactions have also been varied by conjugating the adhesive peptide arginine-glycine aspartic acid (RGD) to the PVA chains. the compressive moduli ranged from 5 to 2600 kPa.HYDROGELS FOR REPAIR OF ARTICULAR CARTILAGE DEFECTS 285 Table 2.136 Depending on the concentration of PVA. tensile modulus. or by electron beam or gamma irradiaton.121 They have similar frictional and lubricating behavior to articular cartilage. cell-free OPF hydrogels allowed migration and fibrocartilage formation by host MSCs.152 These hydrogels have also been used to evaluate the effects of the controlled release of various growth factors on cartilage formation in vitro and in vivo. the quality of the repair tissue was improved.3–0. –(Pro-Hyp-Gly)x–. Encapsulated chondrocytes maintained their spherical morphology over 3 days in vitro. Salumedica. were first introduced by Elisseeff et al. MSCs.132 Although initial results were positive. as an injectable and transdermally photopolymerizable hydrogel for cartilage tissue engineering.115–117 PVA hydrogels have been extensively characterized and compared to articular cartilage in terms of their mechanical.8 MPa (bovine) 0. CA). freeze–thaw cycling.121–125 Although the mechanical properties of PVA hydrogels are closer to those of cartilage than other hydrogels.147 The incorporation of chondroitin sulfate to PEG hydrogels resulted in enhanced ECM deposition by encapsulated chondrocytes when compared to pure chondroitin sulfate hydrogels and increased expression of chondrogenic markers by encapsulated MSCs. Ludwigshafen.152 When MSCs were encapsulated in the hydrogels.148. w/w 0. directing fluid to contact surfaces according to the squeeze-film lubrication model under low loads and the boundary lubrication model under high loads.43 3. and permeability were similar to articular cartilage.029 (human) crosslinked into hydrogels through the formation of acetal linkages using difunctional crosslinking agents like formaldehyde and glutaraldehyde.135 or must be crosslinkable under gentle conditions to encapsulate cells. which are photocrosslinkable.146.26 PVA hydrogels can also be physically crosslinked through the formation of crystallites during annealing and dehydration.149 PEG hydrogels are currently being investigated in clinical trials as a system in conjunction with a bioadhesive based on chondroitin sulfate (ChonDux. or by phase separation from theta-solutions. fluid flow. w/w 0. Values of compressive modulus. and can be prepared with compressive moduli as high as cartilage. w/v 0.130. w/w 0. PVA hydrogels have been modified with methacrylate groups to allow photoencapsulation of cells.133 PVA hydrogels must therefore be rendered porous to seed cells after preparation134. w/w 0. injectable.22 (canine) 0. Hydrogels prepared from Pluronics . and the hydrogel implants were surrounded by fluid.029 (human) 15%.546 · l0 .

2.156 The conjugation of TGF-b1 was necessary to maintain the hydrogel in the defect site. matrix metalloproteinases. which allows faster diffusion of nutrients and waste to and from encapsulated cells. or the distance between crosslinks. the ratio of its swollen weight to its dry weight. such as diffusion coefficients. Color images available online at www . tained by the hydrogel.182 Compared to nondegradable hydrogels.178 The swelling ratio of a hydrogel. respectively. such as the presence of growth factors or in coculture systems.168. with corresponding increases in compressive modulus. Schematic representation of ways to control the degradation of synthetic hydrogels. which affect cell–matrix interactions. PEG-based hydrogels have been modified with groups that are sensitive to matrix metalloproteinases (MMP).160 These hydrogels are nondegradable and have been investigated in vitro for cartilage formation by chondrocytes and MSCs under several conditions.166. modified with hydrolytically labile poly(lactic acid). Higher swelling ratios are beneficial for cartilage matrix production but decrease the mechanical properties of the hydrogels. decreasing the molecular weight of the PEG macromers.24.143 Control over hydrogel degradation (Fig. Chondrocytes encapsulated in PEG hydrogels with lower crosslinking densities and higher swelling ratios produced more ECM components that were more homogenously dispersed than hydrogels with lower swelling ratios. most studies on the effects of hydrogel properties have been performed using PEG hydrogels.143.170 Bryant and Anseth also noted that the mesh size of the hydrogels should be larger than the size of a proteoglycan aggregate to ensure sufficient diffusion. is related to the crosslinking density and is a measure of how much water is re- FIG.142.165 Implantation into weight-bearing defects or analysis of integration with surrounding tissue has not yet been performed.167 To tie the kinetics of hydrogel degradation to cartilage formation.N¢-dimethyl acrylamide).liebertonline. mechanical behavior. these properties of Pluronic F127 hydrogels were improved with the addition of crosslinked hyaluronic acid and evaluated in osteochondral defects in rabbits. Aqueous solutions undergo gelation at a lower critical solution temperature that can be increased or decreased through the modification of the PNIPAAm polymer with more hydrophobic or hydrophilic polymers. with significant effects on the behavior of entrapped cells. theoretically mimicking the collagen and glycosaminoglycan phases of cartilage.143.166 Degradation.170.175 These results were confirmed using MSCs encapsulated in PEG-based hydrogels. MMP. probably because of the effects on encapsulated adipose-derived stem cells.156 Pluronic hydrogels have also been combined with chitosan and with the adhesive peptide RGD.180 The more diffuse distribution of ECM components then led to higher levels of ECM production.167 Less crosslinked hydrogels may allow the formation of a thicker pericellular matrix.167. which was attributed to enhanced diffusion as the hydrogels degraded.160.179 Because of the facility of modulating the properties of PEG hydrogels.141 The crosslinking density of PEG hydrogels can be increased by increasing the concentration of the PEG solutions.94 Other thermoreversible and injectable hydrogels are based on poly(N-isoproylacrylamide) (PNIPAAm). which experience increases in swelling ratio with degradation. allow initial mechanical support that is transferred to the evolving cartilage matrix over time.164 The two hydrogel networks combine to form one material.141. Degradable hydrogels. the . The network crosslinking density of a hydrogel controls many of its properties.com/teb SPILLER ET AL. 2) also allows control over nutrient and waste diffusion in a growing cartilage construct. with higher percentages of degradable moieties supported greater production of ECM components by encapsulated chondrocytes.143 Less crosslinked hydrogels have a larger mesh size. with positive effects on cartilage formation by encapsulated chondrocytes. the ECM components immediately surrounding the cells.162.164.147. which underwent chondrogenic differentiation and produced some cartilaginous tissue.286 are thermoreversible and injectable. Physical properties of hydrogels Crosslinking density.161 PNIPAAm hydrogels have also been modified with chitosan and with gelatin.156–159 For example.143 Collagen fibrils are significantly larger than proteoglycans.181 PEG hydrogels. providing another parameter that would affect the distribution of ECM components.165 These degradation-resistant hydrogels exhibit similar compressive moduli to articular cartilage and lower coefficients of friction against normal cartilage than cartilage articulating against cartilage.163 Composite hydrogels have also been prepared with entangled hydrogel networks of poly(2-acrylamido-2-methylpropane sulfonic acid) and poly(N. but generally require chemical modifications to improve mechanical stability and cell viability. or by using branched PEG structures instead of linear structures. allowing control over cell–matrix interactions. and rate of degradation.

184 and by combining with dextran-based hydrogels.69. a critical step in chondrogenesis.144 Mechanical considerations. which has potential applications in directing cell behavior. first identified as an enzyme with a temporal profile that corresponded with cartilage development.201 and around the periphery of the hydrogel where flow during unconfined compression is higher. Cells proliferate more and produce more ECM in less crosslinked hydrogels. The magnitude of increased ECM synthesis depends on the type of hydrogel.200 a critical balance exists between synthesis and degradation in response to mechanical loading to achieve maximal ECM synthesis.107. precisely controlled hydrogel degradation by incorporating a photodegradable nitro-benzyl-derived moiety into PEG-based hydrogels.192. and the structures of the hydrogels were controlled by focusing light on specific areas of the hydrogels through photomasks. forming a protective layer around the cells and reducing cellular strain.69.186 Cells deform to different extents in hydrogels with different mechanical properties. resulting in a decrease in ECM production.185 In addition to the amount of degradation.174.40 Such synergistic effects were also observed with TGFb3. so that their degradation could be controlled by the application of light.176.190.108.104 Mechanotransduction. PEG hydrogels with an intermediate rate of degradation supported more cartilage formation by encapsulated chondrocytes than hydrogels with slower or faster degradation. which may indicate that the retained matrix components were more functionally similar to native cartilage.199 In some cases in which the net increase in ECM retention was higher than free-swelling controls.175–177. The degradation of PEG hydrogels has also been varied by crosslinking with biodegradable genipin. the engineered cartilage tissue achieved a higher dynamic modulus after 12 weeks in vitro than that of corresponding nondegradable hydrogels.168 When human MSCs were encapsulated in PEG hydrogels that were sensitive to MMP7.196.174. which was more pronounced in peptide hydrogels than agarose hydrogels.106 Furthermore. applied for a few hours per day for several weeks.107.108 The . is an important regulator of chondrocyte metabolism and cartilage homeostasis.106. proteoglycan synthesis.170 The application of 15% static strain to PEG hydrogels containing chondrocytes caused an inhibition of proteoglycan production in weaker gels but stimulation in stiffer gels.78 The degradation properties of hydrogels are also important because they determine the changing structural and physical properties of the hydrogels.177 The results of these studies show that the response of chondrocytes to their mechanical environment is a complicated system of factors contributed from the structure and stiffness of the hydrogels. magnitude and frequency of dynamic loading.171.183 phosphate-releasing groups. in which cells deformed more due to network heterogeneities.169.173.175.106. generally result in net increases in ECM synthesis by encapsulated chondrocytes or chondrogenically induced MSCs. resulting in differences in cell proliferation. Hydrogels have also been useful as model systems to study the response of cells to applied loads in a number of specific conditions.107.HYDROGELS FOR REPAIR OF ARTICULAR CARTILAGE DEFECTS increased diffusion of ECM components secreted by encapsulated chondrocytes led to a more dispersed matrix.189 Cyclic loading regimens.40. The mechanical properties of hydrogels are controlled by their polymer concentration and crosslinking density. cell-seeding density.144 The degradation of these hydrogels was manipulated externally by varying the duration and intensity of the light.194 In addition.196 which may be related to increased aggrecanase activity and the fact that proteoglycans are primarily responsible for resisting compression.198 The distribution of proteoglycan accumulation may also vary depending on the structure of the hydrogel and the distribution of fluid flows.187 Further studies are still required to elucidate the effects of mechanical properties of the hydrogel on chondrocyte response in the presence of loading.170. and the biosynthetic and catabolic behavior of the chondrocytes. a thick pericellular matrix formed around chondrocytes in less crosslinked PEG gels because of enhanced diffusion. and timing of the initiation of loading.178. was also higher. static loading inhibits cartilage synthesis in cartilage explants and chondrocytes encapsulated in several types of hydrogels.173.190–197 These increases in ECM synthesis often corresponded to upregulation of catabolic matrixmetalloproteinases. and 287 gene expression. given that static compression has been shown to decrease biosynthetic activities and increase catabolic activities of chondrocytes. hydrogel stiffness did affect the aggregation of MSCs. was manipulated through the addition of hydrolytically degradable units. In general. Kloxin et al. the amount of ECM components lost to the surrounding medium. which in turn led to more ECM production.175. the application of intermittent dynamic loading to chondrocytes cultured in agarose gels increased the biosynthetic response to insulinlike growth factor-1 (IGF1) and to TGFb1. creating difficulties for analyzing the effects of stiffness using hydrogels of increasing crosslinking densities. because it regulates the diffusion of the ECM components. the process in which external mechanical signals lead to intracellular signaling cascades. a result of enzymatic degradation. resulting in greater deposition in a cell’s pericellular vicinity170. probably because the peptide gels were considerably weaker and easier to displace than agarose. the dominant parameter that determines cartilage formation within tissue engineering scaffolds appears to be crosslinking density. In the absence of load. without the confounding effects of mass transport limitations.34.169.182 This increase in mechanical properties occurred in spite of less proteoglycan retention in the hydrogels. several studies showed opposite effects of dynamic loading on proteoglycan and collagen synthesis for a given cell– hydrogel system.169 In another study.78 A balance exists between a degradation rate that is fast enough to allow room for newly synthesized ECM components and a rate that is slow enough to sufficiently retain the proteins. so that they responded to dynamic loading to roughly the same extent as stiffer gels. and diminish as the polymer degrades. the rate is also important.177 These results suggest that matrix remodeling by metalloproteinases is beneficial for cartilage production.141 Similar results were obtained when the degradation rate of hyaluronan hydrogels.198.188.202 For example. which are degraded by cell-secreted hyaluronidase. However. so that the increases in ECM production and compressive modulus were greater than those due to either growth factor alone. the loading regimen.174.

209 However. response to external forces. nasoseptal. and potential to produce new cartilage tissue. immature chondrocytes tend to proliferate more. Cell source and seeding density Many preliminary analyses of tissue engineering strategies employ immature chondrocytes due to the ease of cell isolation and expansion.288 SPILLER ET AL. 170 34. with cells from each source differing slightly in behavior. then the loading regimen can be manipulated to optimize cartilage production by a variety of cell types. 166. 106. 143. If cell–hydrogel constructs are to be immediately implanted into cartilage defects without prior cultivation. More studies are required to determine the effects of hydrogel stiffness on cartilage tissue engineering in the presence of load.208 In another study. agarose. 169–177 . extracellular matrix. although there were no differences in the absence of TGFb1. For example. articular chondrocytes upregulated expression of type II collagen and aggrecan to greater extents in response to stimulation by dynamic loading. utilizing a variety of hydrogels. 142.207 Auricular chondrocytes encapsulated in hyaluronic acid or fibrin hydrogels experienced increased ECM production and mechanical properties compared to articular chondrocytes after 12 weeks of subcutaneous implantation. poly(vinyl alcohol).204 Adult chondrocytes were used successfully to generate cartilage in agarose hydrogels that repaired non-weight-bearing defects in a canine model with good integration with the surrounding tissue.60 Adult bone marrow-derived MSCs accumulated proteoglycans at a higher rate than adipose-derived MSCs in agarose hydrogels in response to TGFb1. and peptide hydrogels. especially of the catabolic enzymes. ECM. if the hydrogels are to be cultured in bioreactors before implantation.203 The MSCs also proliferated in response to TGFb1.205 Chondrocytes can also be isolated from a patient’s auricular. 78.195.143 On the other hand. it may be beneficial for hydrogels to begin with appropriately high compressive moduli and degrade into less crosslinked networks that are also weaker.104 When encapsulated in peptide hy- Table 3.70 MSCs derived from skeletally mature horses produced superior cartilage tissue compared to age-matched chondrocytes in peptide hydrogels. they must be stiff enough to support physiological loads or they will collapse. 167 PEG. 143. whereas the mature chondrocytes did not. poly(ethylene glycol). collagen. stiffer gels had higher ECM production under static strain Static strain: generally inhibits ECM synthesis Dynamic strain: increases ECM synthesis and catabolic gene expression 141. In any case. In contrast. application of TGFb1 or TGFb3 also enhanced chondrogenesis of MSCs under the application of dynamic loading. 168 69. PVA. The source of MSCs also affects cartilage tissue engineering. the isolation of chondrocytes from any of the cartilages causes considerable damage to the donor site. produce more ECM components.196 Although the ideal mechanical properties for a cartilage replacement are not known. and respond more to the application of growth factors. the potential of chondrocytes suspended in fibrin gels to integrate with native articular cartilage did not depend on the source of the chondrocytes. 169. so that stiffer gels have lower ECM production. compared to mature chondrocytes. Mature MSCs isolated from bone marrow and synovium and encapsulated in type I collagen gels produced superior cartilage tissue when implanted in articular cartilage defects in rabbits than MSCs from adipose or muscle tissues. and costal cartilages. PEG Agarose.206.208. More studies are required to determine the effectiveness of the chondrocyte sources in repairing articular cartilage defects. 141 131. Whereas immature chondrocytes produced greater levels of cartilage tissue than immature bone marrow-derived MSCs encapsulated in hyaluronic acid. which more closely resembles the auricular environment than the articular environment. nasal and auricular chondrocytes proliferate much faster than articular chondrocytes. stem cells isolated from mesenchymal tissues can produce cartilage tissue under the right conditions. Observations on the effects of various hydrogel properties on the response of encapsulated cells are summarized in Table 3. PEG Loading regime PVA.203. PEG Observation References Less crosslinked resulted in greater production of ECM components that are more dispersed Level of degradation that allowed increasing space and load transfer to evolving cartilage matrix resulted in better cartilage formation Rate that matched ECM formation led to more ECM production Has not yet been studied without the effects of crosslinking density. In this case. fibrin. peptide. are necessary to definitively delineate the differences in the effects of different loading regimens on cartilage tissue engineering.131 Because the mechanical properties must be balanced with crosslinking density. Effects of Hydrogel Properties on Cartilage Tissue Engineering Property Type of hydrogel tested Crosslinking density Amount of degradation PEG-poly(lactic acid).203 It is important that future studies utilize cells from clinically relevant sources to determine the effectiveness of tissue engineering strategies.210 However. understanding the effects of mechanical properties and loading regimens is important for predicting cartilage-hydrogel behavior in vivo and also for designing bioreactors to maximize cartilage production. PEG-biodendrimer PEG-based Degradation rate Compressive modulus Hyaluronan. 143. more investigations that examine the temporal profile of gene expression and protein synthesis. many of these studies utilized a subcutaneous implantation model. However. whereas the new cartilage tissue takes over more of the load.

234 When chondrocytes were co-encapsulated with IGF1 in the gels. poly(Nisoproylacrylamide). which allows delayed or tempered release profiles. 227 Chondrocytes. many have turned to drug delivery systems to provide controlled. because release profiles can be modulated by changing the hydrogel crosslinking density.228.233 and greater stability and bioactivity of the encapsulated protein. in the presence of mechanical loading. Delivery of IG1 from cell-free fibrin hydrogels over a few weeks enhanced repair of cartilage defects in adult rabbits and in horses.79 These studies suggest that stimulation by mechanical loading or growth factors can result in greater ECM production from fewer cells. such as charge interactions. although the expression of the cartilage markers collagen type II and aggrecan was much lower than with the addition of exogenous growth factors. in addition to rapid diffusion or clearance from the defect site. peptide. IGF1 alone 153.HYDROGELS FOR REPAIR OF ARTICULAR CARTILAGE DEFECTS 289 Table 4.221 Fibrin hydrogels loaded with TGFb1 recruited MSCs and induced chondrogenic differentiation when implanted subcutaneously in rabbits.195. PNIPAAm-PEG PEG. TGFb.190.214.229 Another useful tool for controlling the release of growth factors is the encapsulation of growth factor-loaded microparticles. oligo(poly(ethylene glycol) fumarate). insulin-like growth factor-1.22 Therefore.215 However. the chemoattractive effects of these growth factors may enhance integration with surrounding tissue by further stimulating chondrocytes to migrate toward the scaffolds.190 Chondrogenic gene expression of MSCs co-encapsulated with TGFb1 was greater for a seeding density of 10 million cells/ mL than 20 million cells/mL in OPF hydrogels. In freeswelling culture.108. MSCs Increased ECM synthesis by chondrocytes in vitro. Collagen PNIPAAm-PEG PNIPPAm-AAc. their short half-lives. Growth Factors Investigated for Controlled Release from Hydrogels for Cartilage Tissue Engineering Growth factor IGF1 IGF1 and TGFb1 TGFb1 TGFb2 TGFb3 Hydrogels OPF. which changes the free space available for diffusion. whereas adipose-derived MSCs produced more collagen. MSCs. The presence of TGFb1 was also necessary for chondrogenesis of MSCs derived from human embryoid bodies in response to mechanical stimulation. These growth factors have also been shown to improve the quality of engineered cartilage when added to the culture media of chondrocytes encapsulated in hydrogels in vitro. increases in the density of chondrocytes seeded in agarose. because of their roles in stimulating chondrocyte differentiation.216. possibly because of a higher dose of TGFb1 per cell. enhanced 153. however.195 In contrast. TGFb1. 160. alginate.228 The mechanisms of release can also be varied by manipulating interactions between encapsulated proteins and the hydrogel polymer. indicating that cell–matrix interactions affect chondrogenesis. sustained release of growth factors. OPF Cell type Main effects References Chondrocytes Increased ECM synthesis. Controlled release of growth factors The use of controlled release of growth factors in combination with carefully designed biomaterials may result in improved cartilage tissue engineering. and basic fibroblast-derived growth factor.230–232 spatial control over delivery. 222 repair of chondral defects in horses Chondrocytes Synergistic results in vitro.231 The controlled release of growth factors from hydrogels has been used to stimulate repair of cartilage defects by cells from the surrounding tissue. Furthermore. Some commonly investigated growth factors include IGF1. 156. MSCs Induced MSC chondrogenesis and enhanced repair of rabbit osteochondral defects Chondrocytes Increased collagen synthesis in vitro 160 139. 223 more effective in repair of rabbit osteochondral defects 79. prevent their therapeutic potential as injections. OPF. to enhance cartilage production by encapsulated chondrocytes.104 Bone marrow-derived MSCs produced more aggrecan. the repair of chondral defects in horses was greater than those treated with gels containing chondrocytes alone. and to induce chondrogenesis of MSCs. transforming growth factor b. PNIPAAm. eliminating the need for repeated administration. which down-regulated chondrogenesis in the absence of TGFb1. 221. and peptide gels over a range from 4 to 64 million cells/ml resulted in increases in ECM production and mechanical properties.213 These studies suggest that MSCs derived from a variety of sources are suitable for cartilage tissue engineering when cultured under specific conditions. 160. Pluronic. OPF.107. -2. 102. there were no differences in ECM accumulation and mechanical properties between hydrogels seeded with 20 or 60 million cells/mL.40. which occurs through upregulation of TGFb production.224 When OPF hydrogels .217 However. drogels. and -3. adipose-derived MSCs did accumulate ECM components in response to TGFb1. 152.211. growth factors are not required for the stimulation of chondrogenesis of bone marrow-derived MSCs by mechanical loading. or by changing the degradation profiles of the hydrogels.218–220 Hydrogels have long been popular as controlled delivery systems for proteins. Induced chondrogenesis of MSCs and stimulated proteoglycan synthesis in subcutaneous space in vivo IGF1. fibrin.212 The combination of mechanical loading and adenoviral transduction of the cartilage transcription factor Sox9 resulted in increased chondrogenesis of bone marrow-derived MSCs in a fibrin-polyurethane hydrogel–scaffold composite. mesenchymal stem cells. and matrix synthesis (Table 4).103. OPF Agarose. 224–226 Chondrocytes. The seeding density of chondrocytes or MSCs in hydrogels also affects the quality of engineered cartilage tissue. proliferation.

103.225.227 Although the TGFb1.131 Oka and coworkers combined PVA hydrogels with titanium fiber mesh to anchor into the subchondral bone. suggesting SPILLER ET AL. peptide. to Pluronic F127 hydrogels allowed the controlled release of TGFb1 over the course of three weeks. TGFb1. The complexity of the joint surface and the limited regenerative potential of chondrocytes result in discontinuities between implants and surrounding cartilage.139 The release of TGFb1 or TGFb3 from OPF hydrogels was also used to stimulate chondrogenic differentiation of MSCs in vitro.239 Even cartilage explants that are implanted back into the defect from which they were removed do not integrate well with the surrounding tissue. Hydrogels have also been modified to control the release bioactive molecules and growth factors that are bound directly to hydrogel polymer.240.245 Other studies in which the encapsulation of cells significantly enhanced integration between hydrogels and surrounding cartilage confirm that tissue engineering approaches can be useful mechanisms of integration.79. but more in vivo investigations are required to determine their efficacy.135 However.235 The rate of release of dexamethasone was controlled from hydrogels composed of Pluronic and hyaluronic acid through the use of porous and nonporous microparticles of poly(lactic-co-glycolic acid).135. IGF1-releasing hydrogels were the most effective in improving cartilage repair. and a PEG macromer solution is injected into the defect and photopolymerized via tyrosyl radical initiation.210 Adhesion strength was also shown to increase when the surrounding tissue was treated with enzymes to remove glycosaminoglycans.236 Heparin was bound to TGFb3 to retard its release profile. loads cannot be transferred effectively.236 The faster release profile. which was 100% release in 4 weeks. were implanted into osteochondral defects in rabbits.156 Peptide gels were formed using a sequence that had a binding affinity for TGFb1. or a combination of the two.241 Synthetic hydrogels are generally too hydrophilic to allow protein adsorption or cell attachment. TGFb3 was required for proteoglycan production and hyaluronic acid reduced the production of type I collagen.80. resulting in enhanced cartilage production by chondrocytes in PNIPAAm-based hydrogels compared to the faster release of TGFb3.102 When these hydrogels were used to fill non-weight-bearing cartilage defects in rabbits in combination with microfracture.144 By controlling the release using the application of light to match the temporal presentation experienced by MSCs natively.223 These results suggest that caution should be exercised when translating in vitro results to in vivo repair.226 which was further enhanced by including dexamethasone.238 Integration with surrounding tissue Even if the properties of a hydrogel are optimized to regenerate healthy hyaline cartilage. when chondrocytes suspended in fibrin hydrogel were injected into the pores of the hydrogels.237 their effects have not been directly compared in a cartilage tissue engineering application.48. that prolonged presence of cell-secreted growth factor also contributed to healing. animal models. A similar approach was used in the design of an adhesive bridge between PEG hydrogels and .240. and new defects will form around the periphery. the proteoglycans in the tissue surrounding a cartilage defect are digested.226 The delivery of TGFb3 and hyaluronic acid alone or in combination enhanced chondrogenesis of MSCs in PEG hydrogels. The inclusion of TGFb1 to agarose. resulting in chondrogenesis by encapsulated adiposederived MSCs and enhanced repair of chondral defects in rabbits compared to hydrogels without TGFb1. neocartilage tissue formed in the pores and integrated firmly with the cartilage discs. which has a growth factorbinding domain.130. which ultimately lead to cartilage fibrillation and implant failure. allowing its controlled release over the course of a few days.241 Strategies that aim to maximize synthetic activity of chondrocytes at the interface may result in maximal integration. which stimulated chondrocytes to proliferate. When PVA hydrogels were implanted into cartilage defects in several animal models and in humans.246 In this method. and -3 isoforms have different functions in embryonic chondrogenesis.160. Elisseeff and coworkers have investigated the chemical attachment of PEG hydrogels to surrounding tissue through tissue-initiated photopolymerization. the encapsulated cells secreted a four-fold higher amount of ECM components than hydrogels that persistently expressed RGD. and repair in humans. Another complicating factor will be the diminished response of arthritic chondrocytes and aged MSCs to growth factors. with little to no improvements in hydrogels releasing TGFb1 only or a combination of TGFb1 and IGF1.153 These results were in contrast to previous studies in vitro. which will complicate dosage calculations and further increase the disparity between in vitro results. resulted in greater chondrogenesis by encapsulated MSCs after 4 weeks of subcutaneous implantation. but gaps were still visible around the PVA hydrogels after 24 weeks in canine osteochondral defects.242–244 so hydrogel implants are unlikely to integrate with surrounding tissue. MSCs from the subchondral bone filled the defects and differentiated into zonally organized hyaline cartilage with excellent integration with the surrounding tissue.290 loaded with gelatin microparticles containing IGF1.102 Considerable progress has been made using growth factors to augment tissue engineering.154. resulting in tight integration of the hydrogel to the cartilage. which was enhanced by co-culture with osteogenic cells in a subchondral layer of the hydrogel. there was no integration between the hydrogels and the surrounding tissue. no integration was observed between the hydrogels and cartilage.124. -2. The release of the adhesive peptide RGD from PEG hydrogels was controlled through conjugation to a photolabile group.144 The conjugation of heparin.46. if an implant does not integrate well with the surrounding tissue.130 When discs of PVA hydrogels were sutured to cartilage discs and implanted subcutaneously into nude mice for 12 weeks. More studies investigating the effects of release rates of these and other growth factors on chondrogenesis and cartilage formation are still required.246 Photopolymerizable PEG gels can thus be formed in situ and crosslinked to collagen fibrils in the surrounding tissue. which indicated that TGFb1 alone or a synergistic combination of TGFb1 and IGF1 improved cartilage tissue generation in hydrogels. tyrosyl radicals are generated in the collagen by photooxidation of tyrosine residues.102 These results were also positive without the addition of exogenous growth factor. and collagen hydrogels was sufficient to induce chondrogenesis of encapsulated MSCs.

R. cells remained viable and the hydrogels remained firmly attached to the cartilage. and Poole. Projections of US prevalence of arthritis and associated activity limitations.HYDROGELS FOR REPAIR OF ARTICULAR CARTILAGE DEFECTS surrounding tissue using a bioadhesive based on chondroitin sulphate. and control over cell–matrix interactions. Hydrogels prepared from naturally derived polymers have the benefits of biodegradability. 635.L.C. 226. and Lai. Felson. J.. Controlled release of growth factors can augment tissue engineering strategies. Hunziker.P. and Zhang. References 1. Dynamic loading protocols have been developed that aim to maximize cartilage production by encapsulated chondrocytes or MSCs. P. D. Part 1: the disease and its risk factors.150. Helmick. but a significant challenge remains in securing integration between tissue-engineered implants and the surrounding tissue. M. An ideal hydrogel for cartilage tissue engineering should initially support the loads found in the joint and gradually degrade.T. Future studies must focus on strategies that address integration. transferring the loads to the evolving cartilage 291 matrix. Biomaterials 13.. V. such as by encouraging encapsulated cells to migrate out or cells from the surrounding space to migrate in. Hirsch. R. C. Quantitation of structural features characterizing weight. Acknowledgments Work in our laboratories was supported by grant UL1 RR024996 from the Clinical and Translation Science Center at Weill Cornell Medical College.. Morphology and mechanical function of long-term in vitro engineered cartilage.218 the disc-ring model. Fluid transport and mechanical properties of articular cartilage: a review. Mow. G. Disclosure Statement No competing financial interests exist.and less-weight- . W. 6. Summary and Future Directions A multitude of hydrogels have been investigated for the repair of articular cartilage defects. Hydrogels encapsulating chondrocytes were attached to cartilage explants and implanted subcutaneously in athymic mice for 5 weeks. D. 5. 1998. biocompatibility. National and state medical expenditures and lost earnings attributable to arthritis and other rheumatic conditions— United States..103 the sandwich model. which is important if the implants are expected to take over loads found in the knee joint. 3. 377.T.247 and mechanical evaluation indicated that the hydrogel failed before the interface did. The hydrogel should encourage chondrogenesis by encapsulated stem cells. Future studies should address methods to generate zonal organization in cartilage tissue engineering strategies and to determine if it is even necessary. 1984. 2007. 2003.150 These hydrogels are currently being investigated in phase II trials (ChonDux. the hydrogel system should have a strategy for integrating the engineered tissue with the surrounding tissue. Bone 33. M. 67. 9.247 The polysaccharide was modified with methacrylate groups to bind to photopolymerizable PEG hydrogels and with aldehyde groups to react with amines in surrounding tissue via a Schiff-base reaction. 2001.. 11.. More studies are required that investigate the optimal timing and conditions surrounding implantation of developing neocartilage.M.S. 1343. Osteoarthritis: new insights. and Helmick.. Cartilix). Arthritis Rheum 54. J.248 although analysis of the integration in vivo is also necessary. 1999. although some have begun to investigate the engineering of zonally organized cartilage using layered hydrogels and chondrocytes isolated from the different zones of cartilage. 4. 2003. Studies on the effects of hydrogel properties on cartilage tissue engineering have shown that less crosslinked gels that degrade at moderate rates allow maximal production of ECM components because of increased nutrient transport. Most importantly.G. synthetic hydrogels allow precise control over their material properties....M. E. Ann Intern Med 133. 2. Fundamentals of Histology. D. and Langer.. 2006. so it is unclear if these results will extend to hydrogels with diverse properties and degrees of cell–matrix interactions. Finally.. 2000. and by the Widgeon Point Foundation. 1. 7. New Dehli: New Age International Limited. such as through the controlled release of growth factors like TGFb1. Holmes. More studies investigating the anabolic and catabolic response of cells to loading will provide further insight into the optimal loading regimen.249 there is still little understanding of how to generate cartilage with appropriately organized ECM. Wong. P. Ma. V. Ratcliffe.G. Biology of Cartilage Cells. We are grateful to the National Science Foundation Graduate Research Fellowship Program and the Institute of International Education Fulbright Program for grants to K.S. Articular cartilage functional histomorphology and mechanobiology: a research perspective. Hootman. considering that cartilage explants do not even integrate with the surrounding tissue when implanted into the defect from which they were removed. and Carter.. A.A. Future studies of any tissue engineering strategy should address the strengths of interfaces between tissue engineered cartilage or hydrogel implants with surrounding tissue.B.241 and the defect repair model. Cartilage and Bone. Jordan. 8. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. 217. Verma.. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. 10.210. A. R. which would reduce the time needed for in vitro cultivation before implantation. It is possible that perfect hyaline cartilage can be engineered but will not integrate upon implantation.. Mow. R. Lawrence. These studies show that integration between tissueengineered constructs and the surrounding tissue can be accomplished through chemical crosslinking or through biological interactions between the tissues. R. Most studies were conducted using PEG hydrogels due to ease of manipulation. Journal of Biomedical Materials Research 44. P.150 Adhesion to articular cartilage was 10 times stronger than that of fibrin glue. Felson. However. Arthritis Rheum 41. Y. C. Dieppe. 4. J Biomech 17..K. Cambridge: Cambridge University Press. 1979. Eggli. 1992. and Schenk. 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