Engineering complex tissues - PubMed (original) (raw)

Review

. 2006 Dec;12(12):3307-39.

doi: 10.1089/ten.2006.12.3307.

Susan W Herring, Pannee Ochareon, Jennifer Elisseeff, Helen H Lu, Rita Kandel, Frederick J Schoen, Mehmet Toner, David Mooney, Anthony Atala, Mark E Van Dyke, David Kaplan, Gordana Vunjak-Novakovic

Affiliations

Review

Engineering complex tissues

Antonios G Mikos et al. Tissue Eng. 2006 Dec.

Abstract

This article summarizes the views expressed at the third session of the workshop "Tissue Engineering--The Next Generation," which was devoted to the engineering of complex tissue structures. Antonios Mikos described the engineering of complex oral and craniofacial tissues as a "guided interplay" between biomaterial scaffolds, growth factors, and local cell populations toward the restoration of the original architecture and function of complex tissues. Susan Herring, reviewing osteogenesis and vasculogenesis, explained that the vascular arrangement precedes and dictates the architecture of the new bone, and proposed that engineering of osseous tissues might benefit from preconstruction of an appropriate vasculature. Jennifer Elisseeff explored the formation of complex tissue structures based on the example of stratified cartilage engineered using stem cells and hydrogels. Helen Lu discussed engineering of tissue interfaces, a problem critical for biological fixation of tendons and ligaments, and the development of a new generation of fixation devices. Rita Kandel discussed the challenges related to the re-creation of the cartilage-bone interface, in the context of tissue engineered joint repair. Frederick Schoen emphasized, in the context of heart valve engineering, the need for including the requirements derived from "adult biology" of tissue remodeling and establishing reliable early predictors of success or failure of tissue engineered implants. Mehmet Toner presented a review of biopreservation techniques and stressed that a new breakthrough in this field may be necessary to meet all the needs of tissue engineering. David Mooney described systems providing temporal and spatial regulation of growth factor availability, which may find utility in virtually all tissue engineering and regeneration applications, including directed in vitro and in vivo vascularization of tissues. Anthony Atala offered a clinician's perspective for functional tissue regeneration, and discussed new biomaterials that can be used to develop new regenerative technologies.

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Figures

FIG. 1

FIG. 1

Lateral surface of the zygomatic bone, coronal section, epifluorescent illumination. Light color is the 3-hour calcein label in a continuous layer of newly mineralized matrix. Vascular fill (red) is seen in the periosteal vessels and in cross-sectioned vessels within the calcein-labeled layer (arrows). Color images available online at

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FIG. 2

FIG. 2

Lateral surface of the temporal bone, coronal section, epifluorescent illumination. The 3-hour calcein label is discontinuous and forms the tips of bony spicules. Vascular fill (red) shows that the radially arranged vessels of this layer are continuous with intraosseous vessels (arrows) and differ in orientation from the periosteal vessels. Color images available online at

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FIG. 3

FIG. 3

Lateral portion of the zygomatic bone, parasagittal section. An intraosseous vessel near the surface can be seen encased in a bony tube (arrow). Color images available online at

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FIG. 4

FIG. 4

Cartilage has been engineered using a number of different cell types. Primary bovine chondrocytes (A), caprine MSCs (B), mouse EBs (C), and human EBs (D) demonstrate Safranin-O positive proteoglycan production in polyethylene glycol (PEG) gels with the exception of human EBs, which did not undergo chondrogenesis. Human embryonic stem (ES) cells were aggregated into EBs and either encapsulated directly (2A) or disaggregated and cultured for five passages (1) before encapsulation (2B). The hEBs that were encapsulated into PEG gels did not stain positive for Safranin-O (D). Cells derived from the hEBs (1) encapsulated in PEG gels also did not stain positive for Safranin-O when cultured in chondrogenic medium with TGF-β1 (E). Incorporation of the adhesion peptide sequence YRGDS into the PEG gels promoted homogenous differentiation and formation of cartilage-like tissue from hES-derived cells (F), confirming the unique requirements for human ES cell differentiation. Reproduced with permission from Annals of Biomedical Engineering. Color images available online at

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FIG. 5

FIG. 5

Cells labeled with colored dyes encapsulated in a bilayered hydrogel. Organized tissue can be created or interactions of coculture environments can be studied. Reproduced with permission from Annals of Biomedical Engineering. Color images available online at

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FIG. 6

FIG. 6

Anatomy and matrix organization of the ligament-to-bone insertion site. (A) The anterior cruciate ligament (ACL) connects to the femur and tibia through two insertion sites (posterior view). (B) The multitissue organization of the tibial insertion, transiting from the ACL to fibrocartilage (FC) region, and then to the bone region (modified Goldner’s Masson Trichrome, bar = 500 μm). (C) The fibrocartilage interface is further divided into the nonmineralized fibrocartilage (NFC) and mineralized fibrocartilage (MFC) zones (von Kossa, bar = 200 μm). Color images available online at

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FIG. 7

FIG. 7

Coculture models to evaluate interaction of interface-relevant cells. (A-i) In vitro coculture model of fibroblasts (Fb) and osteoblasts (Ob) permit heterotypic and homotypic cell-cell interactions. (A-ii) Fibroblast (CFDA-SE, green) and osteoblast (CM-DiI, orange-red) distribution at day 7, bar = 100 μm. (B) In vitro coculture model of chondrocytes (Ch) and osteoblasts (Ob), established by forming an osteoblast monolayer on top of the chondrocyte micromass. Glycosaminoglycan distribution was restricted to the chondrocytes micromass during coculture (day 10, Alcian blue, bar = 100 μm). Color images available online at

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FIG. 8

FIG. 8

Structure-function relationship at the ligament-to-bone insertion. (A-i) Elastographic analysis of the ACL-to-bone insertion (TI) under applied uniaxial tension. Displacement map calculated from ultrasound radio frequency data (Increase in magnitude in mm: blue to red, bar = 5 mm). A region-dependent decrease in displacement is a result of increasing tissue stiffness from the ligament to fibrocartilage region and to the bone region. (A-ii) Microcompression testing of the ACL-to-bone insertion also revealed region-specific increase in tissue stiffness from the nonmineralized (NFC) to mineralized fibrocartilage (MFC) and to bone. In the displacement curve, slope of the curve in each region represents the strain, with a less steeper slope for MFC, indicating decreased strain compared to the NFC zone. (B) The increase in tissue stiffness across the interface may be related to the higher calcium phosphate distribution from the NFC to MFC, and to bone (i von Kossa and ii Elemental analysis of the MFC revealed presence of Ca and P at the insertion104). Color images available online at

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FIG. 9

FIG. 9

Biomimetic multiphasic scaffold for interface tissue engineering: Design, in vitro and in vivo testing. (A) Triphasic scaffold modeled after the three regions of the interface: Phase A for soft tissue, Phase B for the fibrocartilage region, and Phase C for bone. Phase A consists of knitted degradable polymer mesh, Phase B of sintered degradable polymer microspheres, and Phase C of osteointegrative polymer-ceramic composite microspheres. (B) In vitro coculture of fibroblasts and osteoblasts on the triphasic scaffold resulted in phase-specific cell distribution and controlled matrix heterogeneity. Fibroblasts (Calcein AM, green) were localized in Phase A and osteoblasts (CM-DiI, red) were found in Phase C at day 1 (i) and day 28 (ii). Both osteoblasts and fibroblasts migrated into Phase B by day 28. (C) In vivo evalution of the triphasic scaffold cocutlured with fibroblasts and osteoblasts revealed abundant tissue infiltration and matrix production at 4 weeks postimplantation. (modified Goldner’s MassonTrichrome, bar = 200 μm). Color images available online at

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FIG. 10

FIG. 10

(A) Line drawing of biphasic construct. (B) Histological appearance of biphasic construct at 8 weeks of culture. The cartilage is integrated with the upper aspect of substrate and has a nonmineralized zone and a mineralized zone (arrowhead) adjacent to the substrate (von Kossa and toluidine blue, ×50 original magnification). Color images available online at

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FIG. 11

FIG. 11

Paradigm for translating research in heart valve tissue engineering from the laboratory to the clinic. Biomarkers for cell and tissue characterization in conjunction with structural, chemical, and molecular information obtained via in vitro and in vivo models are necessary for understanding key biological processes in tissue engineering and regenerative medicine. These concepts and data can be used to predict and measure patient success and failure. Data from clinical experience further informs the development of appropriate biomarkers, which may result in reassessment of the appropriate characterization parameters. Reproduced and modified with permission from Mendelson et al. Color images available online at

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FIG. 12

FIG. 12

Long-term storage of cells is critical for the successful applications of tissue engineered products. Cell and tissue banks are needed at various steps in the development of tissue engineered products. Reprinted with permission from Acker, J.P., Chen, T., Fowler, A., and Toner, M. Engineering dessication tolerance in mammalian cells: tools and techniques. In: Fuller, B.J., Lane, N., and Benson, E.E., eds. Life in the Frozen State. Boca Raton, FL: CRC Press, 2004. Color images available online at

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