Scaffolds for Articular Cartilage Repair | SpringerLink

P1: GXB Annals of Biomedical Engineering [AMBE]

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Style file version 14 Oct, 2003

Annals of Biomedical Engineering, Vol. 32, No. 1, January 2004 (© 2004) pp. 26–34

Scaffolds for Articular Cartilage Repair SALLY R. FRENKEL and PAUL E. DI CESARE NYU—Hospital for Joint Diseases, Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York, NY (Received 1 July 2003; accepted 9 September 2003)

healing.13 In animal studies, untreated partial-thickness defects show little evidence of lasting repair even in immature animals.30,85 Osteochondral fractures cross the tidemark, penetrating the underlying subchondral plate. Cells, growth factors, and cytokines, including transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), bone morphogenic proteins (BMPs), and insulin-like growth factors, migrate into the wound site and initiate a repair that is typically fibrocartilaginous in nature.65,85 While this repair may afford the patient relief from pain and restoration of function for a limited time, the altered biochemical and mechanical properties of the neocartilage do not allow it to withstand the repetitive loads to the articular surface,16 leading to a gradual failure of the tissue.48 Over time, untreated articular cartilage damage, whether chondral or osteochondral, frequently results in arthritic lesions of the joint surface and concomitant loss of function. Researchers in the fast-growing field of tissue engineering seek ways to stimulate regeneration of tissues that are normally incapable of intrinsic repair.35,96 The tissue engineering approach to cartilage repair employs two basic methods, alone or in combination: delivery of cells to wound sites in the joint surface and mobilization of native cells by delivery of factors, cytokines, genes, and/or gene products. Common to all attempts at tissue engineering is the need for a means of delivering the repair material to the injury site and ensuring that it stay in place long enough to effect the desired repair. This review addresses this issue by examining the various scaffolds currently being evaluated in vivo for engineering of articular cartilage, including adhesives tested for maintenance of scaffolds within surgical sites.

Abstract—Tissue engineering of articular cartilage seeks to restore the damaged joint surface, inducing repair of host tissues by delivering repair cells, genes, or polypeptide stimulatory factors to the site of injury. A plethora of devices and materials are being examined for their potential to deliver these agents to wound sites, and to act as scaffolds for ingrowth of new tissue. This review will discuss various promising scaffolds for cartilage tissue engineering applications.

Keywords—Tissue engineering, Implantable matrix, Animal and human studies.

INTRODUCTION Despite the availability of surgical and nonsurgical techniques, the repair of articular cartilage lesions remains an intractable problem. Once injured, the tissue’s capacity to regenerate is severely limited by its avascular nature and consequent lack of access to a pool of potential reparative cells and humoral factors. Cartilage has a low cell-to-matrix ratio65 ; the likelihood that local chondrocytes, entrapped in this matrix, could contribute to repair is small.28,60 Injuries that penetrate the subchondral bony plate allow migration of cells and growth factors from the marrow compartment; the tissue then mounts an inflammatory response and an attempt at regeneration of the injured surface. Unfortunately, the result is typically a suboptimal repair; the biochemical and mechanical properties of the regenerate do not equal those of the native cartilage, resulting in a gradual failure of the regenerated tissue’s load-bearing capability and its subsequent erosion.8,59 Microdamage to chondrocytes and cartilage matrix, as well as chondral fractures, may be caused by a single impact or by repetitive blunt trauma. Accumulated microdamage eventually becomes irreversible.8,59 Following trauma, there may be a transient increase in mitotic and metabolic activity of the surviving chondrocytes at the defect margin. After approximately 2 weeks, this anabolic activity is reduced to preinjury levels, with little if any resultant

SCAFFOLD DESIGN CRITERIA What criteria should be employed in the design of a cartilage repair scaffold? Any implantable device must of course be biocompatible; both the intact scaffold and its degradation products must be “friendly” to the host tissues. Fabrication of the scaffold must therefore take into account local effects on the surrounding tissue, as the scaffold is

Address correspondence to Sally R. Frenkel, PhD, Musculoskeletal Research Center, Hospital for Joint Diseases, 301 E 17th Street, New York, New York 10003. Electronic mail: [email protected]

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Scaffolds for Cartilage Repair

degraded and replaced by host cells.57 Examples of factors to be considered include the release of chemical cross-linking agents and the levels of acidic by-products of degradation. A tissue-repair scaffold must moreover have sufficient porosity to allow ingrowth of host tissue (and/or preloading with appropriate cell types), yet also have adequate mechanical integrity to withstand both the implantation procedure and the mechanical forces typically experienced at the joint surface. A final consideration is the ability of the scaffold to be retained at the implantation site76 ; delivery of cells or factors is of little use if the delivery device is easily dislodged. Ensuring cartilage scaffold survival while it is being replaced by neocartilage is complicated by the fact that osteochondral devices must conform to the requirements of two different tissue types, bone and cartilage. Bone may tolerate a device over a longer period of time, but if subchondral bone is not regenerated in a timely fashion, the repair of the overlying cartilage will be adversely affected.47 As Coutts et al. stated in their review of matrices for cartilage repair, scaffolds should be optimized for cell attachment both to encourage retention of implanted cells and to favor colonization by native cells.17 It should also promote integration of regenerated tissue with the native tissue; in a recent review of the state of the art in cartilage repair, Hunziker noted that islands of repair that do not fully bond with adjacent cartilage and subchondral bone are destined to fail.44 If it is to serve as a delivery device for a protein factor or drug, it must allow an appropriate release profile. Different factors will have different kinetics, depending on the nature of both the scaffold and the factor itself; furthermore, the ideal release profiles for many factors remain to be established. Of course, scaffolds must be surgeon-friendly. Handling properties and implantation techniques should be as uncomplicated as possible. Materials that allow arthroscopic or even percutaneous delivery and “off-the-shelf” usage are extremely attractive. AUTOLOGOUS “SCAFFOLDS” Progenitor cells for bone and cartilage are found in the cambium layer of perichondrium and periosteum. These lining tissues have been tested as potential autogenous cell sources/scaffolds for repair of cartilage defects, with mixed results.2,23,43,68,73,87,89 When placed within an injury site, typically an osteochondral defect, a filler tissue is generated with some cartilaginous characteristics, but the regenerate does not often form a complete filler.52 Seradge used perichondrihaal grafts in the metacarpophalangeal and interphalangeal joints in humans; among his findings were that their effectiveness appears to vary according to patient age: no patient over the age of 40 years had good results.84 Furthermore, the procedure is often complicated by detachment of the graft, and the grafts may ossify. Hunziker44 noted that the osteochondral nature of the treatment sites


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means that repair cells are available from the bone marrow as well as from the graft; even with this additional source of cells, these native types of grafts do not perform consistently well. To improve their performance, periosteum and perichondrium have been used in combination with other scaffold materials, such as demineralized bone matrix91 and polylactic acid.92 Results were similarly variable. Most recently, periosteum has been utilized not primarily as a cell source or scaffolding, but as a flap sutured over chondral defects into which autologous chondrocytes have been injected.5,6 This model was first tested by Grande et al. in rabbits.38 Chondrocytes were isolated from cartilage collected from a non-weight-bearing area in the injured joint, expanded in vitro for 3 weeks, and transplanted into 3-mm patellar defects. A sutured periosteal flap held the graft in place; the periosteum was not acting as a scaffold, but rather to protect the scaffold-free deposit of cells at the site. Histologic examination at 6 weeks confirmed the presence of viable chondrocytes within a regenerated cartilage matrix. Brittberg et al. pioneered the clinical use of this technique.5 At 8 weeks, the mean amount of filling of the defects was 71%, and the repair tissue appeared to be predominantly hyaline-like cartilage. The cells matured into a columnar arrangement by 12 weeks, and at 52 weeks the repair tissue appeared mature, with a high degree of columnarization and extracellular matrix formation. Minas66 reported that patient satisfaction at 24 months for simple and complex cases was 60 and 70%, respectively. Studies are in progress to improve this technique via delivery of cells within a scaffold. Mosaicplasty, the use of osteochondral autografts, has been reported to result in pain relief and recovery of function.40,54 In this treatment a scaffold is created by removing osteochondral plugs from low-weight-bearing areas on the femoral condyles, which are then implanted in damaged areas that have been cored out to create defects congruent with the plugs. Thus, fresh cartilage and bone grafts, populated with native cells, are used to repair arthritic degeneration. Animal studies (e.g., Hurtig et al.46 ) suggest that the cartilage surface does not survive over the long term; indeed, it may be damaged by the insertion method, which involves hammering the graft into the defect site. Moreover, a loss of chondrocytes from cartilage at the donor site was recently demonstrated.45 Use of cadaveric allografts avoids the creation of additional pathological sites, but fresh or frozen allograft is not intended to restore viable cartilage. Rather, it serves as a filler that may allow some restoration of pain-free function for extended periods of time.18 Immunological reactions and the possibility of disease transmission, while sharply reduced in recent years, remain a consideration with this treatment. Similarly, the use of demineralized bone matrix chips, powders, or pastes have not resulted in a sustained cartilaginous repair.27,62,67


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NATURAL SCAFFOLD MATERIALS Fibrin A logical candidate for a cartilage repair matrix is fibrin, the major component of the clot that forms at wound sites. Fibrin has been tested as both a stand-alone scaffold and a delivery device for chondrocytes42 and growth factors.24,25,71 In an equine study, the incorporation of insulin-like growth factor or chondrocytes within polymerized fibrin improved the histologic appearance and amount of type II collagen in full-thickness lesions, although neither the biochemical nor morphologic features were consistent with those of normal articular cartilage. Fibrin does not have intrinsic mechanical strength; in addition, exogenous fibrin may trigger an immune response.49 To improve retention of the scaffold, fibrin glues have been used. Animal studies have failed to demonstrate an effective repair with a fibrin glue matrix, probably because it fails to permit host cell ingrowth.7,93 These glues nevertheless continue to be used to demonstrate the effectiveness of implanted materials. Peretti et al.74 created a scaffold of lyophilized articular cartilage chips mixed with fibrin glue and chondrocytes. The addition of lyophilized cartilage chips to their construct resulted in preservation of the biomechanical properties and the original mass of the implant. Gelse et al.33 implanted perichondrial mesenchymal stem cells (MSCs) transfected ex vivo with adenoviral vectors carrying bone morphogenetic protein—2 (BMP-2) or insulin-like growth factor 1 (IGF-1) cDNA, suspended in fibrin glue, into partial-thickness lesions in rat articular cartilage. They obtained good results in these small defects with both growth factor cDNAs and found that cells delivered in fibrin glue were able to attach to the wounded articular cartilage and were not displaced from the lesions by joint movement. Fibrin glue has also been used clinically to secure perichondrial scaffold grafts.4 Agarose and Alginate Agarose and alginate, polysaccharides derived from seaweed, form hydrogels that have the advantage of allowing a uniform distribution of seeded cells throughout implantable scaffolds.19,95 They may also be prepared as injectible scaffolds. Agarose has been used extensively in in vitro studies of chondrocyte behavior. Agarose does not resorb well, however, and may elicit a foreign body giant cell response in vivo.75 Diduch et al.20 reported that alginate beads containing bone marrow stem cells remained within rabbit osteochondral defects and progressively filled the defects with regenerate tissue. Histologic analysis showed phenotypically chondrogenic cells; the matrix stained positively for proteoglycan synthesis, and bonding between the regenerate and host tissue was excellent. Marijnissen et al.63 found that alginate used to deliver chondrocytes within a collagen scaffold allowed the device to retain its shape better than

collagen and cells alone. A more recent study by Dausse et al.,19 however, showed that despite good histological results with cell-seeded alginate, biochemical parameters were significantly inferior to those evaluated in native cartilage. The authors stated that “only biochemical parameters allow to discriminate between various biomaterials in tissue engineering and are essential informations which should be taken into account in addition to macroscopic and histological observations.” Collagen Because collagen is a naturally occurring component of skeletal tissues, collagen-based scaffolds favor the attachment of cells normally found in joint tissues, as well as exogenous cells embedded within a collagen delivery device.29,37 Collagen scaffolds have been used extensively for decades for the in vitro characterization of chondrocyte and stem cell behavior,31,69,77,90 as well as in a variety of rabbit,29,83 sheep,78 horse,80 and canine studies.55 Collagen gels have been tested as scaffolds for chondrocytes and bone-marrow-derived mesenchymal stem cells (MSCs).72,94 Wakitani et al.94 reported that MSCs in collagen gels brought about repair in rabbit full-thickness defects. At 12 weeks, the subchondral bone had healed and the defects were filled with hyaline-like cartilage, although in some samples there was a slight gap between the edges of the repair tissue and the surrounding articular cartilage. By 24 weeks, there was thinning of the repair tissue. There were areas of incomplete integration of the repair and host cartilage, and the repair was found to be less stiff and more compliant than normal cartilage. As with fibrin gels, collagen fiber scaffolds have been used to deliver chondrocytes treated with gene therapy to injury sites.3 Collagen matrices containing glycosaminoglycans are also under investigation for gene therapy applications.81 Encouraging results have been obtained using collagen fiber scaffolds to deliver chondrocytes29 and bone morphogenetic protein83 in rabbits. Chondrocytes in collagen fibers induced a hyaline-like repair that was, biochemically, and mechanically, similar to native tissue at 6 months.29 At 1 year, cell-free BMP-collagen implants resulted histologically in excellent repair; trials in defects of clinically relevant size, with appropriate means of implant retention, are being undertaken to confirm the effectiveness of this treatment.83 Chitosan Chitosan, a polysaccharide, forms a hydrogel when cross-linked with chondroitin sulfate.52 These hydrogels can be prepared as thermally sensitive carrier materials. They are injectable as fluids and form gels at body temperature.12 Chitosan hydrogels have been successfully used to deliver growth factors to chondrocytes12 and are


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being studied as potential vehicles for cell-based therapies as well.82 Hyaluronan Hyaluronan (hyaluronic acid) is a major component of cartilage matrix. Cross-linked forms of hyaluronan have been studied as cartilage repair scaffolds. Butnariu-Ephrat et al.9 implanted marrow MSCs in a hyaluronan-based glue in goat cartilage defects. They found that the repair tissue within the defects appeared different than neighboring normal articular cartilage shortly after surgery. More recently, Knudson et al.50 determined that hyaluronan oligosaccharides induced chondrocytic chondrolysis, including neartotal loss of stainable proteoglycan-rich matrix and activation of gelatinolytic activity. Despite these findings, Grigolo et al.,39 Gao et al.,32 and Solchaga et al.88 have used hyaluronan alone and in combination with calcium phosphate as a scaffold for MSCs in rabbits, with good results. The cartilage formed using these implants, however, appeared thinner than the host cartilage.88 Marcacci et al.61 reported the use of an arthroscopic surgical technique for tissue-engineered cartilage grafting. In this study, a three-dimensional hyaluronic acid support was used for autologous chondrocyte culturing and subsequent implantation, without the use of a periosteal flap; transplant site morbidity was reduced. In their comprehensive review of tissue engineering scaffolds, Woodfield et al.96 point out that concerns remain regarding batch variations and the potential for pathogen transfer with the use of natural scaffold materials. Recently, collagens derived from bovine sources have come under fire because of prion-induced bovine spongiform encephalopathy.10,58 SYNTHETIC SCAFFOLD MATERIALS Polymeric scaffolds have been extensively employed for tissue engineering of cartilage. The most widely used are the poly(α-hydroxy esters), polylactic acid (PLA), polyglycolic acid (PGA), and their copolymers.64 Polylactic Acid Chu et al.14 performed a 1-year study of cartilage repair in rabbits implanted with allogenic perichondrial cell/PLA composites. Dounchis et al.21 performed the same study, using autogenous perichondrial cells. A high percentage of grossly successful repairs that showed inconsistent subchondral bone reformation was observed in both studies. In addition, repair tissue that appeared cartilaginous at gross inspection was found to have biochemical properties inferior to those of normal articular cartilage. More recently, Giurea et al.34 found that the retention of perichondrial cells within these matrices could be significantly improved by preincubation of the cells in the scaffolds prior to im-

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plantation. Previously, the number of cells remaining in a cartilage defect implanted with a PLA composite in vivo declined markedly within 2 days. Preincubation resulted in only 7% of seeded cells detaching at 1 week, an encouraging improvement over previous results. Caterson et al.11 have shown that marrow MSCs displayed chondrocytic differentiation when cultured within PLA or PLA/alginate scaffolds in the presence of exogenous transforming growth factor beta-1 (TGF beta-1). Goomer et al.36 used a PLA scaffold to implant perichondrial cells transfected with parathyroid hormone receptor gene and the gene for TGF beta-1 in rabbits. The transformed cells overexpressed their cognate gene products for the entire test period of 7 days. Frenkel et al.26 conducted a rabbit study, using a composite D,D,L,L-polylactic acid and collagen device that has separate tissue-specific microenvironments for regeneration of bone and cartilage. As with other PLA scaffolds, its mechanical properties allow the device to remain at the site of implantation, requiring no additional fixation. The BMP-2-treated composite induced a high-quality, hyaline-appearing repair tissue that was maintained at 24 weeks. Integration with host tissues was excellent. Similar studies in a large animal model are in progress. Polyglycolic Acid and Copolymers Polyglycolic acid (PGA) in the form of foam and woven and nonwoven fiber mesh have been evaluated in vitro and in vivo for repair of cartilage defects. Ruuskanen et al.79 wrapped perichondrial grafts from rabbit auricular and rib cartilage around self-reinforced PGA rods. The grafts were placed inside pectoralis major muscles. Grafts were biopsied 6 weeks postoperatively. Neocartilage formed a tube-like structure around the implant in seven of eight cases. Liu et al.56 implanted autologous chondrocytes in PGA into porcine defects. At 24 weeks, histological, mechanical, and biochemical results were good, with excellent healing at tissue interfaces. More widely studied are the copolymers of PGA, with PLA, polyethylene glycol, and other viscous materials. The use of copolymers is so broad that only a few of the more recent studies are mentioned here; these materials have been scrutinized for over 20 years.53 Utilization of PLA/PLG copolymers allows one to control the degradation rate of the scaffold. This is significant, as the catastrophic degradation of the acid homopolymers could result in release of unacceptable amounts of acid byproducts into the local environment. Of course, the residence time of the polymer in the defect must be sufficient to serve its scaffolding purpose—without being so long as to impede tissue regeneration. Cohen et al. (2003) used alginate to deliver chondrocytes homogeneously dispersed throughout PLA/PGA pads implanted in rabbits; at 12 weeks they demonstrated good histological and


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S. R. FRENKEL and P. E. DI CESARE TABLE 1. Scaffold performance: Summary of in vivo findings (animal and clinical studies). Scaffold

I. Autologous scaffolds Perichondrium, periosteum

Autologous chondrocyte transplants

Positive findings

Negative findings

Refs.

• Contain progenitor cells • Best results in young patients • Uncomplicated surgical handling

• Incomplete filling of defects • Unsatisfactory results, age >40 years • Graft detachment

4,12,43,52,68,73,84

• Repair appears hyaline-like • Graft matures over time • High percentage of patient satisfaction, with pain relief and recovery of function

• Creates defects in non-weight-bearing areas • Requires two surgical procedures (harvest, implantation) • Autologous cells must be expanded in vitro • Technically difficult surgical technique

5,6,38,66

• Creates defects in non-weight-bearing areas

40,46,54

• Pain relief, recovery of function • Implantation procedure may damage implant surface II. Natural scaffolds, carrying cells, and/or growth factors Fibrin • Improved histological appearance, but not to normal levels • As carrier of growth factor cDNAs, produced good result in rat defect Mosaicplasty

• Poor mechanical properties • May evoke immune response • Does not permit host cell ingrowth

7,42,71,92

Agarose, alginate

• Cells uniformly distributed within implant • Injectible • Good histological result in rabbit

• Foreign body giant cell reaction (agarose) • Does not resorb well • Biochemical properties significantly inferior to native tissue

19,20,63,75,95

Collagen

• Native to joints • Excellent histological result when carrying cells or BMP-2

• Good early repair may thin over time • Incomplete integration with host tissues • Possible transmission of prion-induced disease?

3,29,37,55,69,72,80,81,83,94

Hyaluronan

• Native to joints • Good integration with host tissues

• May induce chondrolysis • Repair cartilage is thinner than native tissue

9,32,39,50,61,88

• Biochemical properties inferior to native tissue • Inconsistent bone regeneration

14,21,26,34

III. Synthetic scaffolds, carrying cells, and/or growth factors Polylactic acid (PLA) • Excellent retention at implantation site • With BMP-2, good integration with host tissues Polyglycolic acid (PGA) PLA-PGA Copolymer, Polylactie-coglycolide

• Good short-term result in pigs • Allows controlled polymer degradation • Good early histological result in rabbit and goat

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15,70


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biochemical response. Sherwood et al.86 designed a biphasic scaffold designed to maximize bone ingrowth while maintaining mechanical properties: an upper, cartilage region composed of D,L-PLGA/L-PLA with macroscopic staggered channels to facilitate homogenous cell seeding and a lower, bone portion consisting of an LPLGA/tricalcium phosphate composite. Chondrocytes preferentially attached to the cartilage portion of the device, and biochemical and histological analyses showed that cartilage formed during a 6-week in vitro culture period. Ameer et al.1 developed a biodegradable composite designed to rapidly entrap cells within a support of predefined shape. The construct consisted of freshly isolated pig chondrocytes entrapped in a fibrin gel phase and dispersed throughout the void volume of a PGA nonwoven mesh. Composites were cultured for up to 4 weeks. Glycosaminoglycan content per cell in the composite scaffolds was 88% that of native pig cartilage. Total collagen content was not significantly different from the PGA-only cell construct group. Photopolymerizing hydrogel systems provide a method to encapsulate cells and implant materials in a minimally invasive manner.22 Controlled release of growth factors in the hydrogels may enhance the ability to engineer tissues. In a study by Eliseef et al.,22 polylactide coglycolide (PLGA) microspheres were loaded with IGFI and TGF-beta. The growth factor, containing microspheres, was photoencapsulated with bovine articular chondrocytes in polyethylene oxide- (PEO) based hydrogels and incubated in vitro for 2 weeks. Statistically significant changes in glycosaminoglycan (GAG) production were observed after a 14-day incubation period with IGF-I and IGF-I/TGF-microspheres combined. Cell content increased 10-fold. Niederauer et al.70 prepared multiphase implants from poly(D,L)lactide-coglycolide. PGA fibers, 45S5 Bioglass (BG), and medical grade calcium sulfate (MGCS) were used as additives to vary stiffness and chemical properties. Half the implants were loaded with autologous chondrocytes and placed in osteochondral defects. At 16 weeks, all groups had a high percentage of hyaline cartilage and good bony restoration, with new tissue integrating well with the native cartilage. Several other materials are in the early stages of investigation for appropriateness for cartilage repair, including poly(ethylene glycol)-terephthalate and poly(butylene terephthalate) copolymer blocks,96 oligo(poly(ethylene glycol) fumarate),89 poly(N -isopropylacrilamide),41 and carbon fiber scaffolds.51 The versatility of many of the scaffolds discussed here is often counterbalanced by a lack of one or more of the cited parameters of successful implant design. The vast effort being mounted to formulate scaffolds that are multipurpose delivery and tissue-regenerative devices will undoubtedly result in the eventual appearance of

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highly efficient clinical devices for articular cartilage repair (see Table 1). REFERENCES 1

Ameer, G. A., T. Mahmood, and R. Langer. A biodegradable composite scaffold for cell transplantation. J. Orthop. Res. 20:16–19, 2002. 2 Amiel, D., R. Coutts, F. Harwood, K. Ishizue, and J. Kleiner. The chondrogenesis of rib perichondrial grafts for repair of full thickness articular cartilage defects in a rabbit model: A one year postoperative assessment. Connect. Tissue Res. 18:27–39, 1988. 3 Baragi, V. M., R. Renkiewicz, L. Qiu, D. Brammer, J. Riley, R. Sigler, S. Frenkel, A. Amin, S. Abramson, and B. Roessler. Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. Osteoarthritis Cartilage 4:275–282, 1997. 4 Bouwmeester, S. J., J. Beckers, R. Kuijer, A. van der Linden, and S. Bulstra. Long-term results of rib perichondrial grafts for repair of cartilage defects in the human knee. Int. Orthop. 21:313–317, 1997. 5 Brittberg, M., A. Lindahl, A. Nilsson, C. Ohlsson, O. Isaksson, and L. Peterson. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Eng. J. Med. 331:890–904, 1994. 6 Brittberg, M., A. Nilsson, A. Lindahl, C. Ohlsson, L. Peterson. Rabbit articular cartilage defects treated with autologous cultured chondrocytes. Clin. Orthop. 326:270–283, 1996. 7 Brittberg, M., E. Sjogren-Jansson, A. Lindahl, and L. Peterson. Influence of fibrin sealant (Tisseel) on osteochondral defect repair in the rabbit knee. Biomaterials 18:235–242, 1997. 8 Buckwalter, J., V. Mow, and A. Ratcliffe. Restoration of injured or degenerated articular cartilage. J. Am. Acad. Orthop. Surg. 2:192–201, 1994. 9 Butnariu-Ephrat, M., D. Robinson, D. Mendes, N. Halperin, and Z. Nevo. Resurfacing of goat articular cartilage by chondrocytes derived from bone marrow. Clin. Orthop. 330:234–243, 1996. 10 Carruthers, J., and A. Carruthers. Mad cows, prions, and wrinkles. Arch. Dermatol. 138:667–670, 2002. 11 Caterson, E. J., W. Li, L. Nesti, T. Albert, K. Danielson, and R. Tuan. Polymer/alginate amalgam for cartilage-tissue engineering. Ann. N. Y. Acad. Sci. 961:134–138, 2002. 12 Chenite, A., C. Chaput, D. Wang, C. Combes, M. Buschmann, C. Hoemann, C. Leroux, B. Atkinson, F. Binette, and A. Selmani. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21:2155–2161, 2000. 13 Cheung, H. S., W. H. Cottrell, K. Stephenson, and M. E. Nimni. In-vitro collagen biosynthesis in healing and normal rabbit articular cartilage. J. Bone Joint Surg. 60A:1076–1081, 1978. 14 Chu, C. R., J. Dounchis, M. Yoshioka, R. Sah, R. D. Coutts, and D. Amiel Osteochondral repair using perichondrial cells. A 1-year study in rabbits. Clin. Orthop. 340:220–229, 1997. 15 Cohen, S. B., C. Meirisch, H. Wilson, and D. Diduch. The use of absorbable co-polymer pads with alginate and cells for articular cartilage repair in rabbits. Biomaterials 24:2653–2660, 2003. 16 Colletti, J., W. Akeson, and S. Woo. A comparison of the physical behavior of normal articular and the arthroplasty surface. J. Bone Joint Surg. 54A:147–160, 1972. 17 Coutts, R. D., R. Healey, R. Ostrander, R. Sah, R. Goomer, and D. Amiel. Matrices for cartilage repair. Clin. Orthop. 391(Suppl.):271–279, 2001.


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Czitrom, A. A., F. Langer, N. McKee, and A. Gross. Bone and cartilage allotransplantation. A review of 14 years of research and clinical studies. Clin. Orthop. 208:141–145, 1986. 19 Dausse, Y., L. Grossin, G. Miralles, S. Pelletier, D. Mainard, P. Hubert, D. Baptiste, P. Gillet, E. Dellacherie, P. Netter, E. Payan. Cartilage repair using new polysaccharidic biomaterials: Macroscopic, histological and biochemical approaches in a rat model of cartilage defect. Osteoarthritis Cartilage 11:16–28, 2003. 20 Diduch, D. R., L. Jordan, C. Mierisch, and G. Balian. Marrow stromal cells embedded in alginate for repair of osteochondral defects. Arthroscopy 16:571–577, 2000. 21 Dounchis, J. S., W. Bae, A. Chen, R. Sah, R. D. Coutts, and D. Amiel. Cartilage repair with autogenic perichondrium cell and polylactic acid grafts. Clin. Orthop. 377:248–264, 2000. 22 Elisseeff, J., W. McIntosh, K. Fu, B. Blunk, and R. Langer. Controlled-release of IGF-I and TGF-beta1 in a photopolymerizing hydrogel for cartilage tissue engineering. J. Orthop. Res. 19:1098–1104, 2001. 23 Engkvist, O., and S. Johansson. Perichondrial arthroplasty. A clinical study in twenty-six patients. Scand. J. Plast. Reconstr. Surg. 14:71–87, 1980. 24 Fortier, L. A., H. Mohammed, G. Lust, and A. J. Nixon. Insulinlike growth factor-I enhances cell-based repair of articular cartilage. J. Bone Joint Surg. Br. 84:276–288, 2002. 25 Fortier, L. A., A. Nixon, and G. Lust. Phenotypic expression of equine25. articular chondrocytes grown in three-dimensional cultures supplemented with supraphysiologic concentrations of insulin-like growth factor-1. Am. J. Vet. Res. 63:301–305, 2002. 26 Frenkel, S. R., G. Bradica, S. Goldman, R. Kronengold, R. D. Coutts, and J. H. Brekke. Multiphasic device engineered to regenerate articular cartilage. Trans. Orthop. Res. Soc. 28:249, 2003. 27 Frenkel, S. R., J. Chang, S. Maurer, A. Baitner, and K. Wright. Bone protein in a grafton flex carrier for articular cartilage repair. Trans. Am. Acad. Orthop. Surg. 26:356, 2001. 28 Frenkel, S., R. M. Clancy, J. Ricci, P. DiCesare, and S. B. Abramson. Effects of nitric oxide on chondrocyte migration, adhesion, and cytoskeletal assembly. Arthritis. Rheum. 39:1905– 1912, 1996. 29 Frenkel, S. R., B. C. Toolan, D. Menche, M. Pitman, M., and J. M. Pachence. Chondrocyte transplantation using a collagen bilayer matrix for cartilage repair. J. Bone Joint Surg. 79B:831– 836, 1997. 30 Fuller, J. A., and F. N. Ghadially. Ultrastructural observations on surgically produced partial-thickness defects in articular cartilage. Clin. Orthop. 86:193–205, 1972. 31 Fuss, M., E. Ehlers, M. Russlies, J. Rohwedel, and P. Behrens. Characteristics of human chondrocytes, osteoblasts and fibroblasts seeded onto a type I/III collagen sponge under different culture conditions. A light, scanning and transmission electron microscopy study. Anat. Anz. 182:303–310, 2000. 32 Gao, J., J. Dennis, L. Solchaga, V. Goldberg, A. Caplan. Repair of osteochondral defect with tissue-engineered two-phase composite material of injectable calcium phosphate and hyaluronan sponge. Tissue Eng. 8:827–837, 2002. 33 Gelse, K., K. von der Mark, T. Aigner, J. Park, and H. Schneider. Articular cartilage repair by gene therapy using growth factorproducing mesenchymal cells. Arthritis Rheum. 48:430–441, 2003. 34 Giurea, A., T. Klein, A. Chen, R. Goomer, R. D. Coutts, W. Akeson, D. Amiel, and R. Sah. Adhesion of perichondrial cells to a polylactic acid scaffold. J. Orthop. Res. 21:584–589, 2003.

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Glowacki, J. In vitro engineering of cartilage. J. Rehabil. Res. Dev. 37:171–177, 2000. 36 Goomer, R. S., L. Deftos, R. Terkeltaub, T. Maris, M. Lee, F. Harwood, and D. Amiel. High-efficiency non-viral transfection of primary chondrocytes and perichondrial cells for ex-vivo gene therapy to repair articular cartilage defects. Osteoarthritis Cartilase 9:248–256, 2001. 37 Grande, D. A., C. Halberstadt, G. Naughton, R. Schwartz, and R. Manji. Evaluation of matrix scaffolds for tissue engineering of articular cartilage grafts. J. Biomed. Mater. Res. 34:211–220, 1997. 38 Grande, D., M. Pitman, L. Peterson, D. Menche, and M. Klein. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J. Orthop. Res. 7:208–219, 1989. 39 Grigolo, B., L. Roseti, M. Fiorini, M. Fini, G. Giavaresi, N. Aldini, R. Giardino, and A. Facchini. Transplantation of chondrocytes seeded on a hyaluronan derivative (hyaff-11) into cartilage defects in rabbits. Biomaterials 22:2417–2424, 2001. 40 Hangody, L., G. Kish, I. Karpati, I. Udvarhelyi, I. Szigeti, and M. Bely. Mosaicplasty for the treatment of articular cartilage defects: Application in clinical practice. Orthopedics 21:751– 756, 1998. 41 Healy, K. E., A. Rezania, and R. Stile. Designing biomaterials to direct biological responses. Ann. N. Y. Acad. Sci. 875:24–35, 1999. 42 Hendrickson, D. A., A. J. Nixon, D. A. Grande, R. J. Todhunter, R. M. Minor, H. Erb, and G. Lust. Chondrocyte-fibrin matrix transplants for resurfacing extensive articular cartilage defects. J. Orthop. Res. 12:485–496, 1994. 43 Homminga, G. N., S. Bulstra, P. Bouwmeester, and A. van der Linden. Perichondral grafting for cartilage lesions of the knee. J. Bone Joint Surg. Br. 72:1003–1007, 1990. 44 Hunziker, E. B. Articular cartilage repair: Basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage 10:432–463, 2001. 45 Hunziker, E. B., and T. M. Quinn. Surgical removal of articular cartilage leads to loss of chondrocytes from cartilage bordering the wound edge. J. Bone Joint Surg. Am. 85A(Suppl. 2):85–92, 2003. 46 Hurtig, M., S. Pearce, S. Warren, M. Kalra, and A. Miniaci. Arthroscopic mosaic arthroplasty in the equine third carpal bone. Vet. Surg. 30:228–239, 2001. 47 Hutmacher, D. W. Scaffold design and fabrication technologies for engineering tissues—State of the art and future perspectives. J. Biomater. Sci. Polym. Ed. 12:107–124, 2001. 48 Jackson, D. W., P. A. Lalor, H. M. Aberman, and T. M. Simon. Spontaneous repair of full-thickness defects of articular cartilage in a goat model. A preliminary study. J. Bone Joint Surg. Am. 83A:53–64, 2001. 49 Kawabe, N., and M. Yoshinao. The repair of full-thickness articular cartilage defects. Immune responses to reparative tissue formed by allogeneic growth plate chondrocyte implants. Clin. Orthop. 268:279–293, 1991. 50 Knudson, W., B. Casey, Y. Nishida, W. Eger, K. Kuettner, and C. Knudson. Hyaluronan oligosaccharides perturb cartilage matrix homeostasis and induce chondrocytic chondrolysis. Arthritis Rheumatism 43:1165–1174, 2000. 51 Kus, W. M., A. Gorecki, P. Strzelczyk, and P. Swiader. Carbon fiber scaffolds in the surgical treatment of cartilage lesions. Ann. Transplant. 4:101–102, 1999. 52 Lahiji, A., A. Sohrabi, D. Hungerford, and C. Frondoza. Chitosan supports the expression of extracellular matrix proteins in human


PP1058-ambe-477007

December 8, 2003

19:40

Scaffolds for Cartilage Repair osteoblasts and chondrocytes. J. Biomed. Mater. Res. 4:586–595, 2000. 53 Langer, R., and J. P. Vacanti. Tissue engineering. Science 260:920–926. 1993. 54 Laprell, H., and W. Petersen. Autologous osteochondral transplantation using the diamond bone-cutting system (DBCS): 6–12 years’ follow-up of 35 patients with osteochondral defects at the knee joint. Arch. Orthop. Trauma Surg. 121:248–253, 2001. 55 Lee, C. R., A. Grodzinsky, H. Hsu, and M. Spector. Effects of a cultured autologous chondrocyte-seeded type II collagen scaffold on the healing of a chondral defect in a canine model. J. Orthop. Res. 21:272–281, 2003. 56 Liu, Y., F. Chen, W. Liu, L.Cui, O. Shang, W. Xia, J. Wang, Y. Cui, G. Yang, D. Liu, J. Wu, R. Xu, S. Buonocore, and Y. Cao. Repairing large porcine full-thickness defects of articular cartilage using autologous chondrocyte-engineered cartilage. Tissue Eng. 8:709–721, 2002. 57 Lu, L., X. Zhu, R. G. Valenzuela, B. L. Currier, and M. J. Yaszemski. Biodegradable polymer scaffolds for cartilage tissue engineering. Clin. Orthop. 391:S251–S270, 2001. 58 Lupi, O. Prions in dermatology. J. Am. Acad. Dermatol. 46:790– 793, 2002. 59 Mankin, H. Current concepts review: The response of articular cartilage to mechanical injury. J. Bone Joint Surg. 64A:460–466, 1982. 60 Mankin, H., V. Mow, J. Buckwalter, J. Iannotti, and A. Ratcliffe. Form and function of articular cartilage. In: Orthopaedic Basic Science, edited by S. Simon. Rosemont, IL: American Academy of Orthopaedic Surgeon, 1994, pp. 443–470. 61 Marcacci, M., S. Zaffagnini, E. Kon, A. Visani, F. Iacono, and I. Loreti. Arthroscopic autologous chondrocyte transplantation: Technical note. Knee Surg Sports Traumatol. Arthrosc. 10:154– 159, 2002. 62 Marijnissen, W. J., G. van Osch, J. Aigner, S. van der Veen, A. Hollander, H. Verwoerd-Verhoef, and J. Verhaar. Alginate as a chondrocyte-delivery substance in combination with a nonwoven scaffold for cartilage tissue engineering. Biomaterials 23:1511–1517, 2002. 63 Marijnissen, W. J., G. van Osch, J. Aigner, H. Verwoerd-Verhoef, and J. Verhaar. Tissue-engineered cartilage using serially passaged articular chondrocytes. Chondrocytes in alginate, combined in vivo with a synthetic (E210) or biologic biodegradable carrier (DBM). Biomaterials 21:571–580, 2000. 64 Martin, I., V. Shastri, R. Padera, J. Yang, A. Mackay, R. Langer, G. Vunjak-Novakovic, and L. Freed. Selective differentiation of mammalian bone marrow stromal cells cultured on threedimensional polymer foams. J. Biomed. Mater. Res. 55:229–235, 2001. 65 Mitchell, N., and N. Shepard. The resurfacing of adult rabbit articular cartilage by multiple perforations through the subchondral bone. J. Bone Joint Surg. 58A:230–233, 1976. 66 Minas, T. Autologous chondrocyte implantation for focal chondral defects of the knee. Clin. Orthop. 391:S349–S361, 2001. 67 Mizuno, S., and J. Glowacki. Three-dimensional composite of demineralized bone powder and collagen for in vitro analysis of chondroinduction of human dermal fibroblasts. Biomaterials 17:1819–1825, 1996. 68 Moran, M., H. Kim, and R. Salter. Biological resurfacing of full-thickness defects in patellar articular cartilage of the rabbit. Investigation of autogenous periosteal grafts subjected to continuous passive motion. J. Bone Joint Surg. Br. 74:659–667, 1992.

69


33

Nehrer, S., H. Breinan, A. Ramappa, S. Shortkroff, G. Young, T. Minas, C. Sledge, I. Yannas, and M. Spector. Canine chondrocytes seeded in type I and type II collagen implants investigated in vitro. J. Biomed Mater. Res. 38:95–104, 1997. 70 Niederauer, G. G., M. Slivka, N. Leatherbury, D. Korvick, H. Harroff, W. Ehler, C. Dunn, and K. Kieswetter. Evaluation of multiphase implants for repair of focal osteochondral defects in goats. Biomaterials 21:2561–2574, 2000. 71 Nixon, A. J., R. Saxer, and B. Brower-Toland. Exogenous insulin-like growth factor-I stimulates an autoinductive IGF-I autocrine/paracrine response in chondrocytes. J. Orthop. Res. 19:26–32, 2001. 72 Noguchi, T., M. Oak, M. Fujino, M. Neo, and T. Yamamuro. Repair of osteochondral defects with grafts of cultured chondrocytes: Comparison of allografts and isografts. Clin. Orthop. Rel. Res. 302:251–258, 1994. 73 O’Driscoll, S. W., A. Recklies, and A. Poole. Chondrogenesis in periosteal explants. An organ culture model for in vitro study. J. Bone Joint Surg. Am. 76:1042–1051, 1994. 74 Peretti, G. M., M. Randolph, V. Zaporojan, L.Bonassar, J. Xu, J. Fellers, and M. Yaremchuk. A biomechanical analysis of an engineered cell-scaffold implant for cartilage repair. Ann. Plast. Surg. 46:533–537, 2001. 75 Rahfoth, B., J. Weisser, F. Sternkopf, T. Aigner, K. von der Mark, and R. Brauer. Transplantation of allograft chondrocytes embedded in agarose gel into cartilage defects of rabbits. Osteoarthritis Cartilage 6:50–65, 1998. 76 Risbud, M. V., and M. Sittinger. Tissue engineering: Advances in in vitro cartilage generation. Trends Biotechnol 20:351–356, 2002 77 Ronziere, M. C., S. Roche, J. Gouttenoire, O. Demarteau, D. Herbage, and A. Freyria. Ascorbate modulation of bovine chondrocyte growth, matrix protein gene expression and synthesis in three-dimensional collagen sponges. Biomaterials 24:851–856, 2003. 78 Russlies, M., P. Behrens, L. Wunsch, J. Gille, and E. Ehlers. A cell-seeded biocomposite for cartilage repair. Ann. Anat. 184:317–323, 2002. 79 Ruuskanen, M. M., M. Virtanen, H. Tuominen, P. Tormala, and T. Waris. Generation of cartilage from auricular and rib free perichondrial grafts around a self-reinforced polyglycolic acid mould in rabbits. Scand. J. Plast. Reconstr. Surg. Hand. Surg. 28:81–86, 1994. 80 Sams, A. E., R. Minor, J. Wootton, H. Mohammed, and A. Nixon. Local and remote matrix responses to chondrocyte-laden collagen scaffold implantation in extensive articular cartilage defects. Osteoarthritis Cartilage 3:61–70, 1995. 81 Samuel, R. E., C. Lee, S. Ghivizzani, C. Evans, I. Yannas, B. Olsen, and M. Spector. Delivery of plasmid DNA to articular chondrocytes via novel collagen-glycosaminoglycan matrices. Hum. Gene Ther. 13:791–802, 2002. 82 Sechriest, V. F., Y. Miao, C. Niyibizi, A. Westerhausen-Larson, H. Matthew, C. Evans, F. Fu, and J. Suh. GAG-augmented polysaccharide hydrogel: A novel biocompatible and biodegradable material to support chondrogenesis. J. Biomed. Mater. Res. 49:534–541, 2000. 83 Sellers, R. S., R. Zhang, S. Glasson, H. Kim, D. Peluso, D. D’Augusta, K. Beckwith, and E. Morris. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). J. Bone Joint Surg. Am. 82:151–160, 2000. 84 Seradge, H., J. Kutz, H. Kleinert, G. Lister, T. Wolff, and E. Atasoy. Perichondrial resurfacing arthroplasty in the hand. J. Hand Surg. 9A:880–886, 1984.


34 85

PP1058-ambe-477007

December 8, 2003

19:40



Shapiro, F., S. Koide, and M. Glimcher. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J. Bone Joint Surg. 75A:532–553, 1993. 86 Sherwood, J. K., S. Riley, R. Palazzolo, S. Brown, D. Monkhouse, M. Coates, L. Griffith, L. Landeen, and A. Ratcliffe. A three-dimensional osteochondral composite scaffold for articular cartilage repair. Biomaterials 23:4739–4751, 2002. 87 Skoog, T., L. Ohlsen, and S. Sohn. Perichondrial potential for cartilagenous regeneration. Scand. J. Plast. Reconstr. Surg. 6:123– 125, 1972. 88 Solchaga, L. A., J. Gao, J. Dennis, A. Awadallah, M. Lundberg M, A. Caplan, and V. Goldberg. Treatment of osteochondral defects with autologous bone marrow in a hyaluronan-based delivery vehicle. Tissue Eng. 8:333–347, 2002. 89 Temenoff, J. S., K. A. Athanasiou, R. LeBaron, and A. Mikos. Effect of poly(ethylene glycol) molecular weight on tensile and swelling properties of oligo(poly(ethylene glycol) fumarate) hydrogels for cartilage tissue engineering. J. Biomed. Mater. Res. 59:429–437, 2002. 90 Toolan, B. C., S. Frenkel, J. Pachence, L. Yalowitz, and H. Alexander. Effects of growth-factor-enhanced culture on a chondrocyte-collagen implant for cartilage repair. J. Biomed. Mater. Res. 31:273–280, 1996.

91

van Osch, G. J., P. ten Koppel, S. van der Veen, P. Poppe, E. H. Burger, and H. Verwoerd-Verhoef. The role of trabecular demineralized bone in combination with perichondrium in the generation of cartilage grafts. Biomaterials 20:233–240, 1999. 92 van Susante, J. L., P. Buma, L. Schuman, G. Homminga, W. van den Berg, and R. Veth. Resurfacing potential of heterologous chondrocytes suspended in fibrin glue in large full-thickness defects of femoral articular cartilage: An experimental study in the goat. Biomaterials 20:1167–1175, 1999. 93 von Schroeder, H. P., M. Kwan, D. Amiel, and R. D. Coutts. The use of polylactic acid matrix and periosteal grafts for the reconstruction of rabbit knee articular defects. J. Biomed. Mater. Res. 25:329–339, 1999. 94 Wakitani, S., T. Goto, S. Pineda, R. Young, J. Mansour, A. Caplan, and V. Goldberg. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J. Bone Joint Surg. 76A:579–592, 1994. 95 Weisser, J., B. Rahfoth, A. Timmermann, T. Aigner, R. Brauer, and K. von der Mark. Role of growth factors in rabbit articular cartilage repair by chondrocytes in agarose. Osteoarthritis Cartilage 9A:S48–S54, 2001. 96 Woodfield, T. B., J. Bezemer, J. Pieper, C. van Blitterswijk, and J. Riesle. Scaffolds for tissue engineering of cartilage. Crit. Rev. Eukaryot. Gene. Expr. 12:209–236, 2002.