seminars in CELL & DEVELOPMENTAL BIOLOGY, Vol. 13, 2002: pp. 377383doi:10.1016/S10849521(02)00094-0, available online at http://www.idealibrary.com on

The extracellular matrix as a scaffoldfor tissue reconstruction

Stephen F. Badylak

The extracellular matrix (ECM) consists of a complexmixture of structural and functional proteins and servesan important role in tissue and organ morphogenesis,maintenance of cell and tissue structure and function, andin the host response to injury. Xenogeneic and allogeneicECM has been used as a bioscaffold for the reconstruction ofmany different tissue types in both pre-clinical and humanclinical studies. Common features of ECM-associated tissueremodeling include extensive angiogenesis, recruitment ofcirculating progenitor cells, rapid scaffold degradation andconstructive remodeling of damaged or missing tissues. TheECM-induced remodeling response is a distinctly differentphenomenon from that of scar tissue formation.

Key words: extracellular matrix / small intestinal submu-cosa (SIS) / bioscaffolds / tissue engineering / urinary blad-der submucosa (UBS)

2002 Published by Elsevier Science Ltd.

Introduction

The extracellular matrix (ECM) is a complex mixtureof structural and functional proteins, glycoproteins,and proteoglycans arranged in a unique, tissue spe-cic three-dimensional ultrastructure. These proteinsserve many functions including the provision of struc-tural support and tensile strength, attachment sites forcell surface receptors, and as a reservoir for signalingfactors that modulate such diverse host processes asangiogenesis and vasculogenesis, cell migration, cellproliferation and orientation, inammation, immuneresponsiveness and wound healing. Stated differently,

From the Department of Biomedical Engineering, Purdue University,Room 204, 1296 Potter Building, West Lafayette, IN 47907-1296, USA.E-mail: badylak@ecn.purdue.edu

2002 Published by Elsevier Science Ltd.10849521 / 02 / $ see front matter

the ECM is a vital, dynamic and indispensable compo-nent of all tissues and organs and is natures naturalscaffold for tissue and organ morphogenesis, mainte-nance, and reconstruction following injury.Until themid 1960s the cell and its intracellular con-

tents, rather than the ECM, was the focus of attentionfor most cell biologists, molecular biologists, develop-mental biologists and other life scientists. However,with the discovery that the ECM plays a role in theconversion of myoblasts to myotubes1 and that struc-tural proteins such as collagen and glyocosaminogly-cans are important in salivary gland morphogenesis2

it became obvious that the ECM is much more thana passive bystander in the events of tissue and organdevelopment and in the host response to injury. Thediscovery of cytokines, growth factors and potentfunctional proteins that reside within the ECM char-acterized it as a virtual information highway betweencells. The concept of dynamic reciprocity betweenthe ECM and intracellular cytoskeletal and nuclearelements has become widely accepted.35 The trans-lation of this phenomenon to therapeutic use of theECM as a scaffold for tissue engineering applicationshas recently been attempted.The ECM is not static. The composition and struc-

ture of the ECM are a function of location withintissues and organs, age of the host, and the physio-logic requirements of the particular tissue.68 Organsrich in parenchymal cells, such as the kidney, have rel-atively little ECM. In contrast, tissues such as tendonsand ligaments with primarily structural functions havelarge amounts of ECM relative to their cellular com-ponent. Submucosal and dermal forms of ECM residesubjacent to structures that are rich in epithelial cellssuch as the mucosa of the small intestine and epider-mis of the skin, respectively. These forms of ECM tendto be well vascularized, contain primarily type I colla-gen and site specic glycosaminoglycans, and a widevariety of growth factors including basic broblastgrowth factor (bFGF), vascular endothelial cell growthfactor (VEGF), and epidermal growth factor (EGF).

377

S.F. Badylak

In contrast, the ECM of the basement membrane thatresides immediately beneath epithelial cells such asthe urothelial cells of the urinary bladder, the en-dothelial cells of blood vessels and the hepatocytesof the liver is comprised of distinctly different collec-tions of proteins including laminin, collagen type IVand entactin. All ECMs share the common features ofproviding structural support and serving as a reservoirof growth factors and cytokines. The ECMs presentthese factors efciently to resident cell surface recep-tors, protect the growth factors from degradation,and modulate their synthesis.912 In this manner, theECM affects local concentrations and biologic activityof growth factors and cytokines and makes the ECMan ideal scaffold for tissue repair and reconstruction.

Components of the extracellular matrix thatsupport tissue reconstruction

Scaffolds for tissue reconstruction and replacementmust have both appropriate structural and functionalproperties. However, the distinction between struc-tural and functional proteins is becoming increas-ingly blurred. Domain peptides of proteins originallythought to have purely structural properties have beenidentied and found to have signicant and potentmodulating effects upon cell behavior. For example,the RGD peptide that promotes adhesion of numer-ous cell types was rst identied in the bronectinmolecule;13, 14 a molecule originally described forits structural properties. Several other peptides havesince been identied in dual function proteins in-cluding laminin, entactin, brinogen, types I andVI collagen, and vitronectin, among others.15 If oneconsiders the ECM to be a degradable bioscaffoldfor implantation, both the structural and the func-tional components are transient due to the rapidrate of degradation of ECM scaffolds in vivo.16, 17 Itis reasonable therefore, to consider ECM scaffolds astemporary controlled release vehicles for naturallyoccurring growth factors.Collagen is the most abundant protein within the

ECM.More that 20 distinct types of collagenhave beenidentied. The primary structural collagen in mam-malian tissues is type I collagen. This protein has beenwell characterized and is ubiquitous across the ani-mal and plant kingdom.18 Collagen has maintaineda highly conserved amino acid sequence through thecourse of evolution. For this reason allogeneic andxenogeneic sources of type I collagen have been longrecognized as a useful scaffold for tissue repair with

low antigenic potential. Bovine type I collagen is per-haps the most widely used biologic scaffold for thera-peutic applications due to its abundant source and itshistory of successful use.Collagen types other than type I exist in naturally oc-

curring ECM, albeit in much lower quantities. Thesealternative collagen types each provide distinct me-chanical and physical properties to the ECM and con-tribute to the utility of the intact ECM (as opposedto isolated components of the ECM) as a scaffold fortissue repair. By way of example, type IV collagen ispresent within the basement membrane of all vascularstructures and is an important ligand for endothelialcells. Type VII collagen is an important component ofthe anchoringbrils of keratinocytes to theunderlyingbasement membrane of the epidermis. Type VI colla-gen functions as a connector of functional proteinsand glycosaminoglycans to larger structural proteinssuch as type I collagen, helping to provide a gel likeconsistency to the ECM. Type III collagen exists withinselected submucosal ECMs, such as the submucosalECM of the urinary bladder, where less rigid structureis demanded for appropriate function. This diversityof collagens within a single scaffoldmaterial is partiallyresponsible for the distinctive biologic activity of ECMscaffolds and is exemplary of the difculty in recreat-ing such a composite in vitro. In summary, the ECM isa rich source of numerous types of collagen and therelative concentrations and orientation of these colla-gens to each other provide an ideal environment forcell growth both in vitro and in vivo.Fibronectin, one of the dual function proteins

mentioned earlier, represents an important compo-nent of ECM and is second only to collagen in quan-tity within the ECM. Fibronectin exists both in solubleand tissue isoforms and possesses many desirableproperties of a tissue repair scaffold including ligandsfor adhesion ofmany cell types.19, 20 Fibronectin existswithin the ECM of both submucosal structures andbasement membrane structures.21, 22 The bronectincomponent of the ECM scaffold derived from theporcine small intestinal submucosa (SIS) and urinarybladder submucosa (UBS) has been shown to bepartially responsible for the adhesion of endothelialcells during in vivo constructive remodeling of thisxenogeneic bioscaffold.23 The cell friendly character-istics of this protein have made it an attractive ligandfor use as a coating protein upon various syntheticscaffold materials to promote host biocompatibility.Laminin is a complex adhesion protein found

in the ECM; especially within basement membraneECMs.21 This trimeric cross-linked polypeptide exists

378

ECM scaffolds for tissue reconstruction

in numerous forms dependent upon the particularmixture of peptide chains (e.g. 1, 1, 1).24, 25 Theprominent role of laminin in the formation andmain-tenance of vascular structures is particularly notewor-thy when considering the ECM as a scaffold for tissuerepair.26, 27 Vascularization of scaffolds for tissue re-pair is one of the rate limiting steps in the eld oftissue engineering and proteins such as laminin arereceiving close attention as an important componentof endothelial cell friendly scaffold materials.Glycosaminoglycans (GAGs) are important compo-

nents of ECM and play important roles in bindingof growth factors and cytokines, water retention, andthe gel properties of the ECM. The heparin bindingproperties of numerous cell surface receptors and ofmany growth factors (e.g. FGF family, VEGF)make theheparin-rich GAGs extremely desirable componentsof scaffolds for tissue repair. The GAG components ofthe SIS-ECM scaffold consist of the naturally occurringmixture of chondroitin sulfates A and B, heparin, hep-aran sulfate, and hyaluronic acid.28 Hyaluronic acidhas been extensively investigated as a scaffold for der-mal reconstruction.The characteristic of the intact ECM that distin-

guishes it fromother scaffoldmaterials is its diversity ofstructural proteins and associated bioactive moleculesand their unique spatial distribution. Although cy-tokines and growth factors are present within ECM invanishingly small quantities, they act as potent modu-lators of cell behavior. The list of growth factors is ex-tensive and includes VEGF, bFGF, EGF, transforminggrowth factor beta (TGF-beta), keratinocyte growth

Figure 1. ECM harvested from porcine urinary bladder. This thin (60 uM) sheet of ECM is entirely free of any cellularcomponent, has a multidirectional tensile strength of approximately 40N, and has not been chemically cross linked ormodied from its native structure.

factor (KGF), hepatocyte growth factor (HGF) andplatelet derived growth factor (PDGF), among oth-ers. These factors tend to exist in multiple isoforms,each with its specic biologic activity. Puried formsof growth factors and biologic peptides have beeninvestigated in recent years as therapeutic means ofencouraging blood vessel formation (VEGF), inhibit-ing blood vessel formation (angiostatin), stimulatingdeposition of granulation tissue (PDGF), and encour-aging epithelialization of wounds (KGF). However,this therapeutic approach has struggled with deter-mination of optimal dose, sustained and localizedrelease at the desired site, and the inability to turnthe factor on and off as needed during the courseof tissue repair. An advantage of utilizing the ECMin its native state as a scaffold for tissue repair is thepresence of all of the attendant growth factors (andtheir inhibitors) in the relative amounts that exist innature and perhaps most importantly, in their nativethree-dimensional ultrastructure.

Sources of extracellular matrix andhost response

ECM exists in all tissues and organs but can be har-vested for use as a therapeutic scaffold from relativelyfew sources. The dermis of the skin, submucosa ofthe small intestine and urinary bladder, pericardium,basementmembrane and stroma of the decellularizedliver, and the decellularized Achilles tendon are all po-tential sources of ECM (Figure 1). The host response

379

S.F. Badylak

to ECM scaffolds is largely dependent upon the meth-ods used to process the material.Chemical and non-chemical means of cross link-

ing ECM proteins have been utilized extensively inan effort to modify the physical, mechanical, or im-munogenic properties of naturally derived scaffolds.29

Chemical cross-linking methods generally involvealdehyde or carbodiimide. Photochemical means ofprotein cross-linking have also been investigated.30

Although these cross-linking methods can result incertain desirable mechanical or physical properties,the end result is the modication of a biologicallyinteractive scaffold material into a relatively inertbioscaffold material. The functional tissue engineer-ing result of this scaffold modication is typicallya brous connective tissue response by the host tobe scaffold material, complete inhibition of scaffolddegradation, and inhibition of cellular inltrationinto the scaffold. Although there may be clinicaluses for such modied biomaterials, these propertiesare counter intuitive to many current approaches inthe eld of tissue engineering: especially those ap-proaches in which cells are seeded upon scaffoldsprior to or at the time of implantation.In contrast, ECMscaffolds that remainessentially un-

changed from native ECM elicit a host response thatpromotes cell inltration and rapid scaffold degrada-tion, deposition of host derived neomatrix, and even-tually constructive tissue remodeling with a minimumof scar tissue. Therefore, the native ECM representsa fundamentally different scaffold material than ECMthat has been chemically or otherwise modied.

Extracellular matrix scaffolds for tissue repair

There is abundant literature on the use of modiedECM scaffolds, especially chemically cross-linked bi-ologic scaffolds, for tissue repair and replacement.Porcine heart valves, decellularized and cross-linkedhuman dermis (AllodermTM), and chemically cross-linked puried bovine type I collagen (ContigenTM)are examples of such products currently available foruse in humans. Similarly modied ECM scaffolds havebeen used for the reconstitution of the cornea, skin,cartilage and bones, and nerve regeneration, amongothers.3033

Porcine derived ECM scaffolds that have not beenmodied, except for the decellurization process andterminal sterilization, have been successfully used forthe repair of numerous body tissues including muscu-lotendinous structures,3436 lower urinary tract recon-

struction,3739 dura mater replacement,40, 41 vascularreconstruction,4244 and the repair of full and partialthickness skin wounds.45 The remodeling process inall of these applications has been remarkably similar.Immediately following implantation in vivo, there is anintense cellular inltrate consisting of equal numbersof polymorphonuclear leukocytes and mononuclearcells. By 72 h post implantation, the inltrate is almostentirely mononuclear cell in appearance with early ev-idence for neovascularization. Between day 3 and 14,the number of mononuclear cells increases, vascular-ization becomes intense, and there is a progressivedegradation of the xenogeneic scaffold with associ-ated deposition of host derived neomatrix. Followingday 14, themononuclear cell inltrate diminishes andthere is the appearance of site specic parenchymalcells that orient along lines of stress. These parenchy-mal cells consist of broblasts, smooth muscle cells,skeletal muscle cells, and epithelial cells dependingupon the site in which the scaffold has been placed.It has been shown that circulating, marrow derivedprogenitor cells participate in this remodeling pro-cess when ECM scaffolds are used.46 The role of envi-ronmental stressors, such as mechanical loading, havealso been shown to be important in the remodeling ofECM scaffolds.47 Of note, there is an absence of tissuenecrosis and scar tissue formation during the remod-eling of these xenogeneic ECM scaffolds.Porcine derived ECM scaffolds derived from the

small intestinal submucosa and the urinary bladdersubmucosa have been used to replace segmental de-fects in the esophagus of a dog model.48 The esoph-agus is noteworthy for its default mechanism of scartissue formation following injury. Remodeling of thexenogeneic ECM scaffolds showed site specic de-position and organization of skeletal muscle, intactsquamous epithelial lining, and normal laminatestructure of mucosa, submucosa, and muscular lay-ers (Figures 2 and 3). Although the remodeling ofthis ECM scaffold did not result in perfectly normalesophageal tissue, the result was a functional structurewith multiple organized tissue types. In addition, theabsence of scar tissue formation suggested that thedefault mechanism of esophageal healing had beenaltered by the use of this ECM scaffold.ECM scaffolds derived from the urinary bladder sub-

mucosa (UBS) have been used for reconstruction ofthe lower urinary tract with similar constructive re-modeling results.4961 The UBS scaffolds have beeneither allogeneic or xenogeneic in origin and havebeen used both alone or with cultured autologouscells. Sections of urethra, ureter, and urinary bladder

380

ECM scaffolds for tissue reconstruction

Figure 2. Five centimeter long section of cervical esophagus in a dog that represents the site of placement of a xenogeneicECM scaffold that has now been remodeled in vivo. The scaffold was derived from the porcine urinary bladder. The scaffoldhas been replaced in 2 months by relatively normal appearing esophageal tissue without stricture, scarring or adhesions tosurrounding tissues. The arrows identify sutures that represent the original anastomosis of ECM scaffold to native esophagus.

Figure 3. Photomicrograph of tissue shown in Figure 2. There is an intact but not entirely normal appearing squamousepithelium, a lack of normal complement of submucosal glands, partially organized bundles of skeletal muscle and tissueorganization that resembles the normal laminar arrangement of tissue types found in the esophagus. Of note, there is a lackof inammatory cells or scar tissue, and there is no histologic evidence of the originally implanted scaffold.

381

S.F. Badylak

have shown excellent reconstitution with formation ororganized and innervated smooth muscle. There is asubstantial body of literature developing that supportsthe use of intact ECM as a scaffold for tissue repair.More than 100,000 human patients have now been im-planted with xenogeneic ECM scaffold derived fromthe porcine small intestinal submucosa for a variety ofapplications; scaffolds are necessary components fortissue repair and reconstitution.

Conclusions

The ECM represents natures scaffold for tissue de-velopment and tissue repair. The optimal methodsfor using this scaffold for clinically relevant tissueengineering applications have yet to be determined.Many questions remain to be answered including theoptimal source of ECM scaffolds for clinical use, theimmunologic response to allogeneic and xenogeneicscaffolds, and the optimal methods for engineeringECM scaffolds with the appropriate mechanical andphysical properties. It appears that there is a funda-mentally different host response to naturally occur-ring ECM scaffolds vs. conventional scaffold materialsand that ECM has the potential to change the defaultscar tissue response to injury in adult mammals.

References

1. Hauschka SD, Konigsberg IR (1966) The inuence of collagenon the development ofmuscle colonies. Proc Natl Acad Sci USA55:119126

2. Wessells NK, Cohen JH (1968) Effects of collagenase on devel-oping epithelia in vitro: lung, ureteric bud, and pancreas. DevBiol 18:294309

3. Bissell MJ, Hall HG, Parry G (1982) How does the extracellularmatrix direct gene expression? J Theor Biol 99:3168

4. Boudreau N, Myers C, Bissell MJ (1995) From lamini to lamin:regulationof tissue-specic gene expressionby theECM.TrendsCell Biol 5:14

5. Ingber D (1991) Extracellular matrix and cell shape: potentialcontrol points for inhibition of angiogenesis. J Cell Biochem47:236241

6. Laurie GW, Horikoshi S, Killen PD, Degui-Real B, Yamada Y(1989) In situhybridization reveals temporal and spatial changesin cellular expression of mRNA for a laminin receptor, laminin,and basement membrane (type IV) collagen in the developingkidney. J Cell Biol 109:13511362

7. Martins-Green M, Bissel MF (1995) Cellextracellular matrixinteractions in development. Semin Dev Biol 6:149159

8. Baldwin HS (1996) Early embryonic development. CardiovascRes 31:E34E45

9. Bonewald LF (1999) Regulation and regulatory activities oftransforming growth factor beta. Crit Rev Eukaryot Gene Expr9:3344

10. Kagami S, Kondo S, Loster K, Reutter W, Urushihara M, Kita-mura A, Kobayashi S, Kuroda Y (1998) Collagen type I mod-ulates the platelet-derived growth factor (PDGF) regulation ofthe growth and expression of beta 1 integrins by rat mesangialcells. Biochem Biophys Res Commun 252:728732

11. Roberts R, Gallagher J, Spooncer E, Allen TD, Bloomeld F,Dexter TM (1988) Heparan sulphate bound growth factors:a mechanism for stromal cell mediated haemopoiesis. Nature332:376378

12. Sjaastad MD, Nelson WJ (1997) Integrin-mediated calcium sig-naling and regulation of cell adhesion by intracellular calcium.BioEssays 19:4755

13. Pierschbacher MD, Ruoslahti E (1984) Cell attachment activityof bronectin can be duplicated by small synthetic fragmentsof the molecule. Nature 309:3033

14. Yamada KM, Kennedy DW (1984) Dualistic nature of adhesiveprotein function: bronectin and its biologically active peptidefragments can autoinhibit bronectin function. J Biol Chem99:2936

15. Humphries MJ, Mould AP, Yamada KM (1991)Matrix receptorsin cellmigration, inReceptors for ExtracellularMatrix (McDon-ald JA, Mecham RP, eds) pp. 195253

16. Badylak SF, Kropp B, McPherson T, Liang H, Snyder PW (1998)SIS: a rapidly resorbable bioscaffold for augmentation cysto-plasty in a dog model. Tissue Eng 4:379387

17. Rickey FA, Elmore D, Hillegonds D, Badylak S, Record R,Simmons-Byrd A (2000) Regeneration of tissue about ananimal-based scaffold: AMS studies of the fate of the scaffold.Nucl Instrum Methods Phys Res 172:904909

18. Vanderrest M, Garrone R (1991) Collagen family of proteins.FASEB J 5:28142823

19. Schwarzbauer JE (1991) Fibronectin: from gene to protein.Curr Opin Cell Biol 3:786791

20. Miyamoto S, Katz BZ, Lafrenie RM, Yamada KM (1998) Fi-bronectin and integrins in cell adhesion, signaling, and mor-phogenesis. Ann NY Acad Sci 857:119129

21. Schwarzbauer JE (1999) Basement membranes: putting up thebarriers. Curr Biol 9:R242R244

22. McPherson TB, Badylak SF (1998) Characterization of -bronectin derived fromporcine small intestinal submucosa. Tis-sue Eng 4:7583

23. Hodde J, RecordR, Tullius R, Badylak S (2002) Fibronectin pep-tides mediate HMEC adhesion to porcine-derived extracellularmatrix. Biomaterials 23:18411848

24. Timpl R (1996) Macromolecular organization of basementmembranes. Curr Opin Cell Biol 8:618624

25. Timpl R, Brown J (1996) Supramolecular assembly of basementmembranes. BioEssays 18:123132

26. Ponce M, Nomizu M, Delgado MC, Kuratomi Y, Hoffman MP,Powell S, Yamada Y, Kleinman HK, Malinda KM (1999) Identi-cation of endothelial cell binding sites on the laminin gamma-1chain. Circ Res 84:688694

27. Werb Z, Cu TH, Rinkenberger JL, Coussens LM (1999)Matrix-degrading proteases and angiogenesis during develop-ment and tumor formation. Acta Pathol Microbiol ImmunolScand 107:1118

28. Hodde JP, Badylak SF, Brightman AO, Voytik-Harbin SL (1996)Glycosaminoglycan content of small intestinal submucosa: abioscaffold for tissue replacement. Tissue Eng 2:209217

29. Bellamkondra R, Raniere JP, Bouche N, Aebischer P (1995)Hydrogel-based here dimensional matrix for neuronal cells. JBiomed Mater Res 29:633671

382

ECM scaffolds for tissue reconstruction

30. Bouhadir KH, Mooney DJ (1998) In vitro and in vivomodels forthe reconstruction of intracellular signaling. Ann NY Acad Sci842:188194

31. Kim BS, Mooney DJ (1998) Engineering smooth muscle tissuewith a predened structure. J Biomed Mater Res 41:322332

32. Aiken SW, Badylak SF, Toombs JP, Shelbourne KD, Hiles MC,Lantz GC, Van Sickle D (1994) Small intestinal submucosa asan intra-articular ligamentous repair material: a pilot study indogs. Vet Comp Orthop Traumatol 7:124128

33. Badylak SF, Arnoczky S, Plouhar P, Haut R, Mendenhall V, Hor-vath C (1999) Naturally-occurring ECMs as scaffolds for muscu-loskeletal repair. Clin Orthop Relat Res 367S:S333S343

34. Kropp BP, Sawyer BD, Shannon HE, Ripy MK, Badylak SF,AdamsMC,KeatingMA,RinkRC,ThorKB(1996)Characteriza-tion of small intestinal submucosa-regenerated canine detrusor:assessment of reinnervation, in vitro compliance and contractil-ity. J Urol 156:599607

35. Kropp BP, Rippy MK, Badylak SF, Adams MC, Keating MA,Rink RC, Thor KB (1996) Regenerative urinary bladder aug-mentation using small intestinal submucosa: urodynamic andhistopathologic assessment in long term canine bladder aug-mentations. J Urol 155:20982104

36. Cobb MA, Badylak SF, Janas W, Boop FA (1996) Histology af-ter dural grafting with small intestinal submucosa. Surg Neurol46:389394

37. Cobb MA, Badylak SF, Janas W, Simmons-Byrd A, Boop FA(1999) Porcine small intestinal submucosa as a dural substitute.Surg Neurol 51(1):99104

38. SanduskyGE, LantzGC, Badylak SF (1995)Healing comparisonof small intestine submucosa and ePTFE grafts in the caninecarotid artery. J Surg Res 58:415420

39. Prevel CD, Eppley BL, McCarty M, Harruff R, Brock C,Badylak SF (1994) Experimental evaluation of small intestinesubmucosa as a microvascular graft material. J Microsurg 15:588591

40. Badylak SF, Lantz G, Coffey A, Geddes LA (1989) Small intesti-nal submucosa as a large diameter vascular graft in the dog.J Surg Res 47:7480

41. Badylak SF, Park K, McCabe G, Yoder M (2001) Marrow-derivedcells populate scaffolds composed of xenogeneic extracellularmatrix. Exp Hematol 29:13101318

42. Prevel CD, Eppley BL, Summerlin DJ, Jackson JR, McCarty M,Badylak SF (1995) Small intestinal submucosa (SIS): utilizationas a wound dressing in full-thickness rodent wounds. Ann PlastSurg 35:381388

43. Hodde JP, Badylak SF, Shelbourne KD (1997) The effect ofrange of motion on remodeling of small intestinal submucosa(SIS) when used as an Achilles tendon repair material in therabbit. Tissue Eng 3:2737

44. Vaught JD, Kropp BP, Sawyer BD, Rippy MK, Badylak SF, Shan-nonHE, Thor KB (1996) Detrusor regeneration in the rat usingporcine small intestinal submucosal grafts: functional innerva-tion and receptor expression. J Urol 155:374378

45. Badylak SF, Meurling S, Chen M, Spievack A, Simmons-Byre A(2000) Resorbable bioscaffold for esophageal repair in a dogmodel. J Pediatr Surg 35:10971103

46. Atala A, Guzman L, Retik AB (1999) A novel inert collagenmatrix for hypospadias repair. J Urol 162:11481151

47. Chen F, Yoo JJ, Atala A (1999) A cellular collagen matrix as apossible off the shelf biomaterial for urethral repair. Urology54:407410

48. Dahms SE, Piechota HJ, Dahiya R, Gleason CA, HohenfellnerM, Tanagho EA (1998) Bladder acellular matrix graft in rats: itsneurophysiologic properties and mRNA expression of growthfactors TGF-alpha and TGF-beta. Neurourol Urodyn 17:3754

49. Dahms SE, Piechota HJ, Dahiya R, Lue TF, Tanagho EA (1998)Composition and biomechanical properties of the bladder acel-lular matrix graft: comparative analysis in rat, pig and human.Br J Urol 82:411419

50. Dahms SE, Piechota HJ, Nunes L, Dahiya R, Lue TF, TanaghoEA (1997) Free ureteral replacement in rats: regeneration ofureteral wall components in the acellular matrix graft. Urology50:818825

51. Merguerian PA, Reddy PP, Barrieras DJ, Wilson GJ, WoodhouseK, Bagli DJ, McLorie GA, Khoury AE (2000) A cellular blad-dermatrix allografts in the regeneration of functional bladders:evaluation of large-segment (>24 cm) substitution in a porcinemodel.. Br J Urol 85(7):894898

52. Piechota HJ, Dahms SE, Nunes LS, Dahiya R, Lue TF, TanaghoEA (1998) In vitro functional properties of the rat bladder regen-erated by the bladder acellular matrix graft. J Urol 159:17171724

53. Piechota HJ, Dahms SE, Probst M, Gleason CA, Nunes LS,Dahiya R, Lue TF, Tanagho EA (1998) Functional rat bladderregeneration through xenotransplantation of the bladder acel-lular matrix graft. Br J Urol 81:548559

54. Piechota HJ, Gleason CA, Dahms SE, Dahiya R, Nunes LS, LueTF, Tanagho EA (1999) Bladder acellular matrix graft: in vivofunctional properties of the regenerated rat bladder. Urol Res27:206213

55. Probst M, Dahiya R, Carrier S, Tanagho EA (1997) Reproduc-tion of functional smooth muscle tissue and partial bladder re-placement. Br J Urol 79:505515

56. Probst M, Piechota HJ, Dahiya R, Tanagho EA (2000) Homol-ogous bladder augmentation in dog with the bladder acellularmatrix graft. Br J Urol 85:362371

57. Reddy PP, Barrieras DJ,WilsonG, Bagli DJ,McLorieGA, KhouryAE, Merguerian PA (2000) Regeneration of functional bladdersubstitutes using large segment acellular matrix allografts in aporcine model. J Urol 164:936941

58. Sutherland RS, Baskin LS, Hayward SW, Cunha GR (1996) Re-generation of bladder urothelium smoothmuscle, blood vesselsand nerves into an acellular tissue matrix. J Urol 156:571577

59. Wu HY, Baskin LS, Liu W, Li YW, Hayward S, Cunha GR(1999) Understanding bladder regeneration: smooth muscleontogeny. J Urol 162:11011105

60. Yoo JJ, Meng J, Oberpenning F, Atala A (1998) Bladder aug-mentation using allogenic bladder submucosa seededwith cells.Urology 51:221225

61. Badylak SF (2002) Modication of natural polymers: collagen,in Methods of Tissue Engineering, Chapter 42 (Atala A, LanzaRP, eds) pp. 505514

383

The extracellular matrix as a scaffold for tissue reconstructionIntroductionComponents of the extracellular matrix that support tissue reconstructionSources of extracellular matrix and host responseExtracellular matrix scaffolds for tissue repairConclusionsReferences