Craniofacial Tissue Engineering

Critical Reviews http://cro.sagepub.com/ in Oral Biology & Medicine

Craniofacial Tissue Engineering
E. Alsberg, E.E. Hill and D.J. Mooney CROBM 2001 12: 64 DOI: 10.1177/10454411010120010501 The online version of this article can be found at: http://cro.sagepub.com/content/12/1/64

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CRANIOFACIAL TISSUE ENGINEERING
E. Alsberg' E.E. Hil12 D.J. Mooneyl,3*,4 Departments of IBiomedical Engineering, 20ral Health Sciences, 3khemical Engineering, and 4Biologic and Materials Sciences, University of Michigan, 2300 Hayward, 3074 HH Dow Bldg., Ann Arbor,

Ml 48109-2136; *corresponding author, [email protected]

ABSTRACT: There is substantial need for the replacement of tissues in the craniofacial complex due to congenital defects, disease, and injury. The field of tissue engineering, through the application of engineering and biological principles, has the potential to create functional replacements for damaged or pathologic tissues. Three main approaches to tissue engineering have been pursued conduction, induction by bioactive factors, and cell transplantation. These approaches will be reviewed as they have been applied to key tissues in the craniofacial region. While many obstacles must still be overcome prior to the successful clinical restoration of tissues such as skeletal muscle and the salivary glands, significant progress has been achieved in the development of several tissue equivalents, including skin, bone, and cartilage. The combined technologies of gene therapy and drug delivery with cell transplantation will continue to increase treatment options for craniofacial cosmetic and functional restoration.
Key words. Inductive, transplantation, skin, bone, cartilage.

Introduction
Craniofacial tissue loss due to congenital defects, disease, and injury is a major clinical problem (Table 1). The craniofacial region is comprised of several tissues for which the most prevalent method of replacement is through autologous grafting. Often, there is insufficient host tissue for adequate repair of the defect site, and extensive donor site morbidity may result from the secondary surgical procedure. The field of tissue engineering aims to restore function to or replace damaged or diseased tissues through the application of engineering and biological principles. Clinicians' ability to create fully functional tissue equivalents will have an immense impact on the future of craniofacial medicine. There are three main approaches taken in the field of tissue engineering: conduction, induction by bioactive factors, and cell transplantation (Langer and Vacanti, 1993; Putnam and Mooney, 1996) (Fig. 1). The approach taken to engineer a tissue depends on several factors, including the size of the defect, the supply of cells from adjacent areas, cell migration speed, and the availability of surrounding vasculature. When a relatively small amount of tissue is needed, conductive and inductive techniques are often utilized to promote cell migration from host tissue into a scaffold. The replacement of large defects frequently requires the direct transplantation of cells. This approach is also attractive if there are not enough available cells in the surrounding tissue to populate the defect, or if relying solely on cell migration would require an unacceptably long healing time. In conductive approaches (e.g., guided tissue regeneration, GTR), the naturally derived or synthetic matrix simply acts as a passive three-dimensional mechanical scaffold on which cells can attach, proliferate, migrate, and differentiate. The host cells form their own matrix, which is integrated with the host tissue as the implanted matrix degrades over time. The scaffold can also
function as a barrier and control which cells have access to the defect site. Desired host cells are allowed into the defect site,

while undesirable cells are blocked by a physical boundary. The GTR approach is now widely used to treat periodontal disease (see "Bone Tissue Engineering", below). It is often desirable, however, to control cell migration into the scaffold, differentiation of these cells, and subsequent tissue formation. To this end, a promising tissue engineering technique is an inductive approach in which bioactive scaffold signals are utilized to induce cell migration and control cellular behavior. A common inductive method is the delivery of soluble signals such as growth factors to the surrounding tissues (Cochran and Wozney, 1999). Gene therapy may be similarly used to transfer specific genetic information to host cells; once transfected, the host cells can then produce specific growth factors to influence tissue development (Shea et al., 1999). Controlled delivery of growth factors and plasmid DNA is an attractive method to deliver these factors at a particular rate over a specific time span (Langer, 1990). The scaffold degradation rate can be controlled (Peppas and Langer, 1994) to provide space for new tissue formation and to optimize growth factor, drug, or plasmid DNA delivery. Alternatively, it has been shown that adherent cells receive, directly from the matrix, crucial insoluble signals which regulate cell gene expression (Ingber, 1991). Attaching specific peptides or proteins to a scaffold (Peppas and Langer, 1994; Tamura et al., 1997), controlling the mechanical properties of the scaffold (Opas, 1989), controlling the scaffold's mechanical environment (Kim et al., 1999), and manipulating cell-cell interactions (Putnam and Mooney, 1996) may provide inductive signals to influence cell behavior. When a large defect is present or the local supply of appropriate cells in the environment surrounding the defect is scarce, cell transplantation may be more appropriate. This cell technique typically involves taking a biopsy from a donor source, isolating and expanding the donor cells in vitro, and seeding the cells directly onto polymers typically fabricated into the physical forms of a fiberbased mesh, a sponge, or a hydrogel (Mooney and Mikos, 1999) (Fig. 2). The cells attach to the scaffold, proliferate, and ultimately
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form a new tissue This new tissue may then be CELL implanted into the recipient in the area of CONDUCI TRANSPLANTATION INDUCTION need It is important in this approach to consider the type of cell to be used. Autologous cells, or cells obtained from the patient, offer the advantage of minimal immune response, but it usually takes an extended time (e.g., weeks) for the cells to expand to the quantities needed Allogeneic cells, or genetically different cells from the same species as the patient, can he more readily acquired in larger quanti-A ties and pose some immunological challenges, Xenogeneic cells are available in large supply, but they usually invoke a strong immune response, since the cells are from a .a3, ? @ different species than the patient. Additional . options include the use of fetal cells, adult '> cells, stem cells, or cell lines (Mooney and Rowley, 1997, Pedersen, 1999). Following culture of a cell/scaffold construct and implanta6)0 tion into a defect, the intended outcome is a new tissue that is structurally and functionally integrated into the surrounding host tissue It is likely that cell transplantation will be used in the future in conjunction with the *gre 1 111 ion depicting the three approaches to the engineering of a tissue. (a) In inductive approaches (e.g., growth factor delivconductive appro aches, a scaffold can serve as a barrier controlling which cells can infilery) to control tissue formation and promote trate the defect sil ie and initiate repair. The barrier may be resorbed over time or removed vascularization of engineered tissues surgically. (b) Indijctive approaches can involve the release of bioactive molecules that bind (Sheridan et al., 2000). only to specific hcost cells with receptors for the molecules. The desired cells migrate into the In this review paper, efforts to engineer defect and begin t deposit new extracellular matrix. (c) Cells from a donor source are seedseveral of the ma jor tissues of the craniofa- ed directly onto a polymer scaffold in vitro, and the cell/scaffold construct is subsequently cial region-such as skin, bone, cartilage, implanted into the defect site in the cell transplantation approach. The transplanted cells, along with host ce that migrate into the defect, repair the site with new tissue that is strucadipose tissue, skeletal muscle, and the saliturally and functiconally integrated with the host tissue. vary glands-will be reviewed. Conductive, inductive, and cell transplantation approachto resolve some of these issues by developing skin-equivalent es are all being investigated, although a different emphasis in replacement tissues that are readily available in large quantities strategies is frequently used for each tissue.

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SKIN TISSUE ENGINEERING
Skin is a multifunctional tissue that serves as a protective barrier from the surrounding environment of the body (Teumer et al., 1998), and extensive skin loss can be life-threatening (Yannas, 1995) Skin tissue, composed of an upper epidermal layer and a lower dermal layer, prevents the entry of many toxic substances, prevents the loss of water, provides immunologic protection, and helps to regulate body temperature (Teumer et al, 1998). While the largest cause of massive skin loss over the entire body is burn injuries (Cairns et al., 1993), skin can also be lost due to toxic epidermal necrolysis syndrome, soft-tissue defects resulting from trauma or neoplasm removal, and dermatological disorders (e.g., giant hairy nevi excision, chronic ulcers, pressure sores) (Cairns et al., 1993; Dougherty and Chalabian, 1995). In addition, oral cavity tumors, trauma, and inflammatory diseases often lead to oral mucosal tissue loss (Rhee et a)., 1998) Currently, autologous meshed split-thickness skin grafts are used most often to treat deep burns on the body (Berthod and Damour, 1997) While autologous grafts successfully close these skin wounds, they cause trauma at the donor site, and often there is not enough donor skin available to cover extensive burns (Berthod and Damour, 1997). Scar formation, hypertrophy, and wound contraction are also problems resulting from autologous grafts for deep wounds (Lamme et al., 1998). Tissue engineers aim
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with limited additional surgical procedures. Engineered skin must adhere well to the defect site for nutrient diffusion (Cooper and Spielvogel, 1994), be physically tough to provide mechanical protection (Pruitt, 1997), have flexibility to allow for body movement (Teumer et al, 1998), protect from UV radiation (Yannas, 1995), control water, protein, and electrolyte loss (Cooper and Spielvogel, 1994), promote rapid healing (Berthod and Damour, 1997), and regulate heat loss (Cooper and Spielvogel, 1994).

TABLE 1
The Critical Need for Craniofacial Tissues in the United States Organ/Tissue Procedures or Patients (1 03/yr) Skin Bone Dental bone-related grafs Cartilage Dental soft tissues Reconstructive plastic surgery requiring additional tissue Oral
4750 1 343 230 1132 580
241 10,000

Adapted from Langer and Vacanti (1 993) and Lifecell Corporation Web site, http://www.lifecell.com/document/about.html

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Figure 2. Typical physical forms for tissue engineering scaffolds include fiber-based meshes (Kim et al., 1 998) (A), porous sponges (Mooney eta!., 1995) (B), and injectable hydrogels (C). Size bars are shown on (A) and (B), and the 18i/2-gauge needle utilized to inject the hydrogel in (C) gives an indication of the scale. (A) and (B) are reproduced with permission of John Wiley & Sons, Inc. and Wiley Publishers, respectively.
Obviously, an immune response or transmission of a disease must be avoided (Cooper and Spielvogel, 1994). The esthetic result is critical for craniofacial skin replacement. The ultimate skin replacement for the craniofacial region would provide the same functional and cosmetic results as an autograft Oral

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criteria mucosa replacement tissue has many of the same as those of external skin, but there are some very important differences. Oral mucosa is thinner and has more blood vessels than

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external skin, lacks hair and the sweat and sebaceous glands of external skin, and must provide a constantly moist surface with the aid of mucous and salivary glands (Smith and Karst, 2000). Several conductive materials-such as dead de-epidermized dermis (Livesey et cit., 1995; Wainwright, 1995), poly(ethylene oxide):poly(butylene terephthalate) (PEO:PBT) copolymer and poly-L-lactide (PLLA) (Beumer et cil., 1994), activated carbon cloths (Piskin and Atac, 1996), Sacchachitin (Su et al., 1999), and glutaraldehyde cross-linked collagen sponges (Dagalakis et at., 1980; Yannas and Burke, 1980; Yannas et al., 1980)-have been investigated as scaffolds for in vivo skin tissue replacement. Two of these materials, the dead de-epidermized dermis and the collagen sponges, are already commercially available as Alloderm (Lifecell Corporation, the Woodlands, TX, USA) and Integra (Integra Life Sciences Corporation, Plainsboro, NI, USA), respectively. Alloderm has a structure similar to that of normal dermis, has high wound acceptance, promotes host cell migration into the scaffold, resists wound bed collagenase activity, and promotes neovascularization (Berthod and Damour, 1997). It also has been used successfully to "resurface" patients with full-thickness intra-oral defects (Rhee et al., 1998), since several kinds of oral mucosal defects were treated with minimal short-term scarring and contracture. The downside of this model is the absence of living fibroblasts to accelerate healing, the limited availability of human cadaver skin, and the lack of an epidermal replacement (Berthod and Damour, 1997). Integra collagen sponges are produced by freeze-drying a collagen gel consisting of type bovine collagen and chondroitin-6-sulphate and attaching an upper layer of silicone rubber to the gel (Yannas and Burke, 1980). These sponges are currently applied clinically for burn treatment (Stix, 1997). The collagen sponge skin replacement has advantageous mechanical properties, can be formed in a wide variety of shapes and sizes, and can resist collagenase activity through composition alterations. However, this model also does not address epidermal replacement, and there is still a risk of disease transmission or immune response (Berthod and Damour, 1997). There have been limited attempts to utilize inductive factors to improve skin regeneration and epithelial adhesion to dental implants. Collagen sponges in combination with fibroblastic growth factor-I (FGF-I) have been applied to full-thickness skin defects in a rabbit model (Pandit et cil, 1998), and the resultant tissues demonstrated reduced contraction rate and enhanced epithelialization compared with the control. Purified laminin-5 has been used as a coating on titanium-alloy dental implants to provide a suitable matrix for the attachment of gingival epithelial cells (Tamura et al., 1997). In vivo studies are required to demonstrate if this coating will help to form a biological seal between the junctional epithelium and an implant or tooth. Cell transplantation approaches, using the addition of cultured cells to materials, have sparked an enormous amount of research and new products. One approach is to transplant only autologous epithelial cells of the skin (Green et al., 1979) or oral mucosa (de Luca et al., 1990, Ueda et al., 1998), and this approach has led to commercially available products (e.g., Epicel, Genzyme Tissue Repair, Cambridge, MA, USA). These epidermal skin replacements have the capability of providing permanent wound coverage for large defects, due to the expansion of cells obtained from a small biopsy of the patient's skin to a much larger cell mass (Phillips, 1998). However, a major limitation of these approaches
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is the two- to three-week time period needed to culture the grafts (Phillips, 1998). This issue can be bypassed through the use of cultured allogeneic cells (Rouabhia et al., 1995; Phillips, 1998). A more ambitious approach is transplantation of allogeneic cells comprising the dermis or both the epidermis and the dermis. One commercially available dermal replacement (Dermagraft, Advanced Tissue Sciences, La lolla, CA, USA), produced with neonatal foreskin fibroblasts (Hansbrough et al., 1992), has shown promise in the treatment of diabetic foot ulcers (Eaglstein, 1998) and burn injuries (Hansbrough et al., 1997). To produce composite skin grafts composed of both an epidermal and a dermal layer, fibroblasts and keratinocytes have been seeded onto various scaffolds (Ghosh et al., 1997; Zacchi et al., 1998). The only dermal-epidermal skin replacement clinically available is Apligraf (Organogenesis, Canton, MA, USA), and it is currently used to treat venous ulcers (Parenteau, 1999). The dermal component is composed of allogeneic fibroblasts seeded within a collagen gel matrix with an upper layer of allogeneic epidermal keratinocytes (Bell et al., 1981). Advantages of bilayered allogeneic skin tissues are that they are immediately availabile, no skin grafting is required, and dermal and epidermal replacement is accomplished at the same time. However, potential drawbacks to this approach include a short time span of viability, low resistance to collagenases, and possible virus transmission, since bovine collagen and allogeneic cells are used (Berthod and Damour, 1997; Phillips, 1998). A critical issue for the engineering of skin, or any tissue, is optimization of the rate and extent of blood vessel ingrowth. Vascular endothelial growth factor (VEGF) has been shown to be potently angiogenic in vivo (Breier and Risau, 1996), and might be delivered from scaffolds in a controlled manner to influence angiogenesis (Sheridan et al., 2000). In addition, endothelial cell transplantation has also been shown to increase the number of capillaries formed in scaffolds (Holder et al., 1997) and to result in new chimeric vessels comprised of both transplanted and host endothelial cells (Nor et al., 1999). It may be possible to improve vascularity in skin replacement tissues by seeding both skin cells and endothelial cells into the polymer scaffold before transplantation (Black et al., 1998). Future studies will be necessary to determine the efficacy of the approach in vivo. Combining cell transplantation and inductive gene therapy may have the potential to improve upon the successes achieved by both methods separately. Human keratinocytes have been genetically modified to overexpress platelet-derived growth factor A chain (PDGF-A) and seeded onto dead de-epidermized dermis (Eming et al., 1998). Following transplantation onto full-thickness wounds in an animal model, the grafts with genetically altered cells resulted in increased cellularity, increased type I and type IV collagen production, and decreased wound contraction compared with control grafts (Eming et al., 1998). Human oral mucosal cells have also been successfully transduced with a lacZ retroviral vector, cultured into an oral epithelial membrane, and grafted onto immunocompromised mice (Mizuno et al., 1999). This approach demonstrated that oral mucosal cells might be a feasible cell line for gene therapy approaches to skin regeneration. Skin is the tissue farthest along in the field of tissue engineering in terms of reaching clinical use. Several skin replacements are already on the market, as discussed above. There is still room for improvement on the current methods, however, since none is on par with autografts in terms of dermal repair, graft take, and cosmetic results (Teumer et al., 1998). The future may bring about skin replacements composed of non-immunogenic fibroblasts and keratinocytes or non-immunogenic xenografts produced by knocking
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out genes that express minor and major histocompatibility antigens (Berthod and Damour, 1997). Combining this technology with appropriate growth factor delivery or gene therapy may eventually lead to a more ideal skin replacement.

BONE TISSUE ENGINEERING
Bone serves several important functions in the craniofacial region and throughout the body, and there is a significant need for bone replacement due to congenital defects, trauma, and disease. The mechanical integrity of bone tissue maintains the shape and contour of the head region and protects the soft tissues of the cranial cavity (Jee, 1987). Bone is needed to augment misshapen areas and to fill gaps during repair of congenital anomalies and injuries resulting in bone deficiencies. Examples of conditions requiring bone tissue include missing alveolar bone in cleft palates, bony nasal pyramid defects following removal of a fistulous tract or cyst, extremely deficient chin, scoliosis of the mandibular arch, mandibular asymmetry, and defects following removal of sinus and mandibular tumors (Tardy and Kastenbauer, 1995). Perhaps the greatest need for bone tissue replacement arises from car accidents, sporting activities, and gunshot wounds that result in blowout fractures of the orbital floor, orbital rim fractures, craniocerebral trauma, malunited fractures, major fractures of the maxilla or mandible, osteoradionecrosis, and dento-alveolar trauma (Tardy and Kastenbauer, 1995). The 'gold standard' for bony tissue replacement is a rib, cranium, or iliac crest autograft (Parsons, 1985; Tardy and Kastenbauer, 1995), but associated problems include significant bone resorption, harvesting difficulties, donor site pain, poor contouring, and limited autogenous bone to fill a defect site adequately (Tardy and Kastenbauer, 1995). While allografts and xenografts are available in abundance, disease transmission and immunorejection remain substantial obstacles to their implementation. A tissue engineering approach utilizing polymers, bioactive factors, cells, or a combination of the three, offers the possibility of rapid tissue regeneration and integration with the host tissue. A biomaterial/cell/factor construct to be used for bony tissue replacement must satisfy specific requirements. The construct should provide an osteoconductive environment allowing for guided osteoid matrix deposition by osteoblasts and subsequent mineralization at the biomaterial interface (Ripamonti and Duneas, 1996), and/or provide osteoinductive signals such as bone-specific bioactive factors to promote bone formation (Ishaug-Riley et al., 1997). The construct must provide temporary mechanical strength to support loads imparted to the skeleton (Ripamonti and Duneas, 1996). The scaffold should degrade in a controlled manner and allow for the process of bone remodeling so that older bone is resorbed and new bone tissue is formed (Yaszemski et al., 1996). It is also desirable for the tissue-engineered construct to be easily contoured to fill irregularly shaped bone defects (Ripamonti and Duneas, 1996). Several kinds of osteoconductive materials, aimed at guiding new bone formation, have long been investigated for use as bony tissue replacements. Both naturally derived and synthetic osteoconductive materials have been found to support bone formation (Table 2). Optimization of the scaffold architecture (e.g., median pore size) may also improve conduction with these materials in vivo (Robinson et al., 1995; Whang et al., 1999). Guided bone regeneration (GBR) with the use of barrier membranes has been applied extensively to periodontal wound healing in extraction socket defects, crestal dehiscence defects, apical fenestration defects, and lateral ridge augmentation (Hermann and Buser, 1996). This osteo6

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TABLE 2
Osteoconductive Materials that Support Bone Formation
Type

Reference

Titanium Coraline hydroxyapatite Porous hydroxyapatite (HA)

r-tricalcium phosphate (r-TCP)
Injectable dahilite
HA cement Calcium sulphate

Poly(methyl methacrylate) Porous PEO/PBT copolymers Poly(dioxanone-co-glycolide) Photopolymerizable polyanhydrides Bioglass Poly(propylene fumarate)/ f-TCP composites

Wachtel et al., 1991 Ripamonti, 1991 Eggli et al., 1988 Eggli et al., 1988 Constantz et al., 1995 Friedman et al., 1998 Peltier and Jones, 1978 Yaszemski and Yasko, 1998 Radder et al., 1996 Bennett et al., 1 996 Anseth et al., 1999 Oonishi et al., 1997 Peter et al., 1998

conductive technique involves placement of a membrane over a bone defect to give osteogenic and angiogenic cells from the bone marrow cavity access to the defect, while inhibiting nonosteogenic cells of the surrounding tissues from entering the defect space (Hermann and Buser, 1996). The most prevalent barriers used in periodontal GBR are non-resorbable polytetrafluoroethylene (ePTFE) membranes; these membranes are the current gold standard (Hermann and Buser, 1996). Recently, there has been much interest in the use of resorbable membranes in the oral cavity, such as synthetic polylactic and glycolic acid and natural xenographic collagen, for periodontal applications (Hardwick et al., 1994). It is not yet clear if resorbable membranes retain their mechanical integrity long enough to provide the same success rate in periodontal GBR as ePTFE membranes (Hermann and Buser, 1996). Barrier membranes have been used in conjunction with osteoconductive materials, which fill the defect, support the membrane, and enhance bony healing (Hermann and Buser, 1996). Osteoinductive approaches, involving the delivery of bioactive factors such as growth factors or plasmid DNA, and manipulation of the scaffold have demonstrated great promise for improving upon conductive approaches to the repair of bony defects. A great many growth factors, hormones, and vitaminssuch as bone morphogenetic proteins (BMPs), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGFs), transforming growth factor-3 (TGF-3), platelet-derived growth factor (PDGF), growth hormone (GF), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D3 have been demonstrated to mediate osteoblast activity during the process of bone remodeling (Canalis, 1996; Giannobile, 1996). These bioactive factors can influence new bone formation through their effects on bone cell recruitment, proliferation, and differentiation (Canalis, 1996). Approaches involving the delivery of bioactive molecules-like bFGF from hydrogels (Tabata et al., 1998) and recombinant human bone morphogenetic protein-2 (rhBMP-2) from demineralized bone matrix (Yasko et al., 1992), poly(lactide-co-glycolide) (PLGA) (Whang et al., 1998), and P-tricalcium phosphate-monocalcium phosphate monohydrate (3-TCP-MCPM) (Ohura et al., 1999)take advantage of the molecules' regulatory properties on bone formation. Successful periodontal bone regeneration has been achieved in clinical trials with rhPDGF-BB, rhIGF-1, and rhBMP-2 (Boyne et al., 1997; Howell et al., 1997). Further clinical evaluation, on an application-specific basis, of the optimal dose, delivery

rate, and combinations of bioactive factors is needed before the full potential of this technique can be realized. The effects of these bioactive molecules can also be harnessed by gene therapy. Plasmid DNA encoding for inductive proteins can be incorporated into polymers and released in a sustained manner following implantation. Cells surrounding the polymer may then take up the released DNA. Once the cells are transfected, they may begin to produce the peptides encoded by the plasmid DNA. Delivery of plasmid DNA encoding for BMP-4 or PTH1-34 from collagen sponges was shown to induce bone formation in a critical defect model, while only fibrous tissue formed in gaps with collagen sponges alone (Fang et al., 1996). Methods have been developed to deliver plasmid DNA from polymer matrices in a controlled and sustained fashion over a time course from days to a month (Shea et al., 1999). This new technology may be applied to bone tissue regeneration in the future by allowing for the controlled release of osteogenic plasmid DNA in a time course ideal for bone formation. An alternative inductive approach utilizes Emdogain (Biora Inc., Malmo, Sweden), an enamel matrix derivative (EMD) derived from enamel matrix proteins. This osteoinductive material has been shown to induce bony tissue regeneration in periodontal defects (Heijl et al., 1997) and is being used clinically. Cell transplantation has been successfully applied to bone tissue engineering. Seeded cells with the potential for recruiting or differentiating into bone-forming cells (e.g., periosteal cells, chondrocytes, marrow stromal cells IMSCI, mouse calvarial-3T3 immortalized cells) on osteoconductive scaffolds (e.g., PLGA, polyglycolic acid IPGAI, HA, HA/N-TCP composites, HA/PLGA composites, HA-coated bioactive glass) have led to successful bone formation in vitro (Elgendy et al., 1993; Laurencin et al., 1996; El-Ghannam et al., 1997; Ishaug et al., 1997; Shea et al., 2000) and in vivo (Goshima et al., 1991 a,b; lyoda et al., 1993; Kim et al., 1994b; Puelacher et al., 1996; Ishaug-Riley et al., 1997; Breitbart et al., 1998; Peter et al., 1998; Alsberg et al., 1999; Isogai et al., 1999; Solchaga et al., 1999). MSCs have the unique capacity to differentiate into several different connective tissue cell types. When given the appropriate environmental signals, MSCs can be directed down the osteogenic lineage and cued to form bone tissue. Clinical studies are currently being planned to investigate the benefits of MSC use in dental surgery (Osiris Therapeutics, Baltimore, MD, USA). Recently, periosteal cells have been genetically modified with the bone morphogenetic protein 7 (BMP-7), seeded onto PGA matrices, and implanted into rabbit cranial critical-size defects (Breitbart et al., 1999). The combination of gene therapy, cell transplantation, and an appropriate scaffold led to increased bone formation at 12 weeks compared with controls (Breitbart et al., 1999). If cell transplantation is to achieve its potential in bone tissue engineering, however, there are many issues that must still be addressed. Vascularity is known to promote osteogenesis, and methods for the rapid induction of vascular invasion of the cell/scaffold constructs should be investigated. In addition, further studies are necessary to maximize cell viability, optimize total cell density, and design scaffolds with chemical compositions, pore sizes, and surface characteristics that allow cells to maintain their osteogenic potential. It is clear that all three tissue engineering approaches may be used to regenerate bone tissue in deficient sites. However, the utility of each technique is site-dependent. Conductive approaches are limited in that they merely create a favorable environment for bone formation, but do not play an active role in the recruitment of cells to the defect and subsequent signalBiol Med
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Figure 3. Engineering cartilage by means of chondrocytes and shaped biodegradable scaffords. (A) SEM photomicrograph of chondrocytes (indicated by arrows) adherent to and spread on a PGA scaffold following cell seeding and culture. (B) Picture of tissue engineered cartilage grown in various shapes from chondrocyte/PGA constructs, in vivo and explanted, demonstrates that neocartilage can be grown in pre-determined shapes and dimensions by means of the cell transplantation approach (Kim et al., 1 994b). (B) Reproduced with permission of Williams & Wilkins Co.
ing of cells to control their gene expression. Large defects will likely fail to heal due to lack of cellular and vascular invasion from the host tissue. In contrast, delivery of inductive signals from a matrix can incite cells to migrate into a defect and control the progression of bone formation Many inductive approaches involving one or more growth factors are in clinical trials and nearing FDA approval. Alternatively, cell transplantation is an attractive approach, since the delivery vehicle already contains cells capable of differentiating into osteoblasts and secreting osteoid matrix.
in the defect (Bentley and Greer, 1971), fibrous tissue encapsulation of newly forming matrix (Chesterman and Smith, 1968, Bentley and Greer, 1971), and lack of new tissue incorporation into the defect (Bentley and Greer, 1971). Homograft materials, such as irradiated, preserved, or lyophilized cartilage and bone, are not an option, because their implant stability over time is variable (Tardy and Kastenbauer, 1995) Thus, cartilage is a prime candidate for tissue engineering. When engineering cartilage, investigators must be aware of its unique tissue properties; specifically, cartilage has a very low metabolic rate, and it is distinctively avascular (lee, 1987). Engineered cartilage should also be easily contoured or molded into intricate shapes and have enough mechanical integrity to maintain a given form. Since the ear and nose are not load-bearing sites, the mechanical properties of cartilage meant for their replacement are not as critical as for joint replacement Attempts have been made to utilize conductive synthetic implants such as polytetrafluoroethylene (PTFE) and polyester felts (Messner and Gillquist, 1993, Messner et al., 1993). In vivo results with these materials demonstrated improved mechanical properties at the repair site when compared with biological cartilage resurfacing techniques. However, these repair materials did not integrate with the adjacent cartilage and exhibited abnormal histology at the one-year time point (Messner et al., 1993). Woven carbon fiber scaffolds have also been used clinically for deep cartilage lesions and have reconstituted the defects with a fibrocartilaginous tissue (Brittberg et al., 1994a) Initial positive results with these synthetic conductive materials have prompted cell transplantation research aimed at the creation of engineered cartilage with histologic and mechanical properties more similar to those of native cartilage. The area of cartilage engineering has focused on combining cell transplantation or periosteal grafts with biocompatible scaffolds, since little work has been performed on purely inductive approaches to the regeneration of cartilage. Polyester/HA composites (Messner, 1993) and polylactic acid (PLA) (von Schroeder et al., 1991) have been covered with a layer of autologous periosteum for cartilage repair The addition of periosteum did not increase the neocartilage compliance to that of normal cartilage. Cells with chondrogenic potential (e.g., chondrocytes, bone-marrow-derived mesenchymal cells, and periosteum-derived mesenchymal cells) have been used in conjunction with a variety of meshes and sponges (e.g., carbon fiber pads, PLA, PGA, PLGA, decalcified bone) and gels (e.g., fibrin glue, collagen gels, alginate hydrogels, fibrinogen, and poly-

CARTILAGE

TISSUE ENGINEERING

In the craniofacial region, cartilage plays two important roles. First, cartilage is present at the temporomandibular joint, and cartilage's mechanical properties allow it to resist shearing and help maintain a low-friction environment at the joint articulation (lee, 1987) Second, cartilage is the structural support of the nose and ears, providing shape and flexibility. The most common need for cartilage in the craniofacial region is for reconstruction of the nose and ears to correct congenital deformities or to replace tissue lost due to disease or injury For example, engineered cartilage could be used for correction of overdeep nasofrontal angles, rhinoplasty grafts to augment inadequate tip projection, rhinoplasty augmentation and contouring, correction of saddle nose deformity, columella reconstruction, or as replacement grafts to treat atresia and stenosis of the anterior of the nose and for treatment of the disease Ozena (Tardy and Kastenbauer, 1995). Cartilage has limited regenerative capabilities (lee, 1987) and requires replacement from an outside source. Initial efforts to regenerate cartilage were focused on cartilage transplantation (Campbell et al, 1963; Chesterman and Smith, 1968) and delivery of isolated chondrocytes (Chesterman and Smith, 1968; Bentley and Greer, 1971, Grande et a!, 1989; Brittberg et al., 1994b), but both of these techniques have significant shortcomings. Autogeneic cartilage, obtained from the nose, ear, and rib (Tardy and Kastenbauer, 1995), is limited in its supply, is difficult to form into the shape of the defect (Rodriguez and Vacanti, 1998), requires an additional invasive surgical procedure, and sometimes results in donor-site morbidity (Cao et al, 1997). Allogeneic grafts share some of the problems of autogeneic grafts with the addition of triggering immune responses. Problems associated with freshly isolated chondrocyte delivery include low cell yield, possible trauma from the isolation (Grande et al, 1989), inability to restrain the cells with-

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ethylene oxide, hyaluronic acid, extracellular matrix components) to regenerate cartilage in vitro (Buschmann et al., 1992; Homminga et al., 1993; Nixon et al., 1993; Bujia et al., 1995; Chu et al., 1995b; Ma et al., 1995; Sittinger et al., 1996; Beekman et al., 1997; Gruber et al., 1997; Aydelotte et al., 1998; Lindenhayn et al., 1999; Ma and Langer, 1999) and in vivo (Green, 1977; Itay et al., 1987; Wakitani et al., 1989, 1994, 1998; Robinson et al., 1990; Vacanti et al., 1991, 1994; Freed et al., 1993, 1994; Hendrickson et al., 1994; Kim et al., 1994a; Noguchi et al., 1994; Puelacher et al., 1994a,b,c; Chu et al., 1995a; Paige et al., 1995, 1996; Brittberg et al., 1996; Sims et al., 1996, 1998; Cao et al., 1997; Aigner et al., 1998; Rotter et al., 1998; Ting et al., 1998; de Chalain et al., 1999) (Fig. 3). Many of these cell transplantation methods have resulted in improved cartilage morphology, integration of the implant with underlying bone/cartilage, and increased mechanical properties compared with other methods of repair. Some groups have focused on specific craniomaxillofacial reconstructive and plastic surgery applications. Cartilage tissue replacements in the shape of a temporomandibular joint disc (Puelacher et al., 1994c), nasal septal cartilage (Puelacher et al., 1994b; Rotter et al., 1998; Ting et al., 1998), and a human ear (Cao et al., 1997) have been grown in vivo with chondrocytes seeded on PGA, PLGA, and PGA/PLA or in fibrin glue. The combination of chondrocytes with gels such as alginate and polyethylene oxide is particularly attractive, because these constructs are both moldable and injectable (Paige et al., 1995; Sims et al., 1996). The constructs could be delivered to defects though a syringe, providing a minimally invasive procedure. In an attempt to supply nutrients to the transplanted chondrocytes and promote parenchymal cell proliferation and differentiation, and ultimately improve cartilage repair, one group combined cell transplantation with inductive growth factor delivery. Chondrocytes seeded on collagen sponges impregnated with bFGF before chondrocyte seeding demonstrated accelerated cartilage formation (Fujisato et al., 1996). Cell transplantation has been the most successful method for engineering cartilage. As the effects of growth factors on neocartilage formation become better understood, efforts to combine bioactive factors with cell transplantation may increase. The development of methods to expand human chondrocytes in vitro while maintaining their chondrogenic phenotype is vital to the future clinical application of the cell transplantation approach (Rodriguez and Vacanti, 1998). The in vitro culture conditions of the cell/polymer constructs must also be optimized to increase the speed of neocartilage development and to improve the resultant neocartilage's biochemical, biomechanical, and morphologic properties (Freed and Vunjak-Novakovic, 1995). In addition, full graft integration within the defect site must be achieved, and the properties of the graft need to correlate well with the site-specific tissue requirements (Freed and Vunjak-Novakovic, 1995).

SKELETAL MUSCLE, SALIVARY GLAND, AND ADIPOSE TISSUE ENGINEERING There is significant craniofacial clinical need for several tissues, such as skeletal muscle, the salivary glands, and adipose tissue, that has only just begun to be addressed by the tissue engineering field. In fact, there is almost no literature pertaining to the engineering of adipose tissue, which influences energy homeostasis, steroid conversion, and sexual maturation (Mohamed-Ali et al., 1998). There is a starting point for the development of skeletal muscle and salivary gland replacements, and further improvements will eventually lead to tissues with normal physiology. Muscle enables the human body to generate movement to facilitate internal transport of materials and reaction to internal
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and environmental stimuli (Williams et al., 1989). Skeletal muscle, which is attached to the skeleton, is the most abundant type of muscle in the body (Williams et al., 1989) and, in the craniofacial area, allows for facial expression and tongue, eye, and jaw mobility. Human skeletal muscle has limited regenerative capabilities, and major damage due to trauma may result in undesirable connective tissue replacement (Williams et al., 1989). Muscle transfers are currently needed to rehabilitate the paralyzed mouth, re-animate the eye, and restore masticatory function (Tardy and Kastenbauer, 1995). Cell transplantation approaches have been pursued, sometimes in combination with inductive signaling, in attempts to alleviate this need for skeletal muscle replacement tissue. Skeletal myoblasts, seeded on materials such as Saran Wrap (Strohman et al., 1990) and in collagen disks (Okano and Matsuda, 1998), differentiate into myotubes and secrete extracellular matrix in vitro. External mechanical forces have also been applied to differentiating skeletal myoblasts in vitro to produce three-dimensional skeletal muscle organs (Vandenburgh et al., 1991). Mechanical stimulation may be vital to create aligned skeletal muscle with normal function (Petrosko et al., 1998). In addition, gene therapy has been combined with cell transplantation; skeletal muscle cells have been retrovirally transduced with recombinant human growth hormone (rhGH), and the myoblasts secreted high levels of rhGH both before and after the cells fused and aligned into multinucleated myofibers (Powell et al., 1999). This technique might eventually be used to transduce a gene that will promote the delivery of a protein beneficial to bioartificial muscle (BAM) growth and development. The production and secretion of saliva are vital functions of the salivary glands and critical to oral health. Saliva plays several roles associated with disease prevention and general health, including mucosal repair, dental remineralization, lubrication, physical protection and mechanical cleansing of the mouth, and digestion (McEwen and Sanchez, 1997; Aframian et al., 2000). The salivary glands can be damaged by neoplastic formations, a variety of non-neoplastic pathologies, and hereditary defects (e.g., Sjogren's Syndrome) (McEwen and Sanchez, 1997). Defective salivary gland function, leading to decreased salivary secretion, can result in problems such as dental decay, pain, recurrent mucosal infections, and swallowing difficulties (Fox, 1998). Tissue engineering offers the opportunity for the restoration of both form and function to the salivary glands. While a tissue engineering focus on the salivary glands is in its infancy, there are two novel approaches currently under investigation. The first approach is inductive gene therapy, in which replication-deficient recombinant adenovirus for aquaporin-1, a water channel protein, is administered intraductally or systemically to irradiated rats to improve fluid secretion from damaged or malfunctioning salivary glands (Delporte et al., 1997). While untreated rats had - 65% reduced salivary flow 4 months following radiation treatment, rats receiving the functional adenoviral vector demonstrated almost normal fluid production levels within 3 days. A cell transplantation approach is also being pursued to engineer salivary tissue. Salivary epithelial cells have been successfully cultured in vitro on two-dimensional biodegradable polymer films (e.g., PLLA, PGA) coated with specific matrix proteins (Aframian et al., in press). The subculturing of these cells on two-dimensional scaffolds is the first step toward the development of salivary gland tissue replacements for patients with compromised salivary flow.
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Conclusions
Tissue engineering is a rapidly evolving field, and several products are already being used clinically. To date, the greatest success has been achieved with relatively simple engineered tissues. The engineering of complex tissues comprised of multiple cell types remains a challenge. Current studies are focused on improving our understanding of how scaffold properties influence cellular behavior. This new information, in combination with the utilization of inductive and cell transplantation approaches, will likely lead to the development of more complex engineered tissues (e.g., vascular and neural components).

lagen sponge for maxillary sinus floor augmentation. Int I
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Biol

Acknowledgments
The authors gratefully acknowledge the NIH, especially the NIDCR. for funding the authors' laboratory. EA is supported by an NIDCR biomaterials fellowship

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