Frontiers of Engineering Reports on Leading Edge Engineering From the 1998 NAE Symposium on Frontiers of Engineering (1999) / Chapter Skim
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Biomaterials and Optical Imaging for Biomedicine
Biomaterials and Optical Imaging for Biomedicine
Pages 1-34
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tissue or foreign tissue that would be discarded after surgical procedures such as circumcision. In every case the approach is to break the donor material down to the level of individual cells and then coax the isolated cells into forming a tissue structure of the appropriate size and/or shape by using a physical "scaffold" to organize cells on a macrosopic scale and providing molecular cues to stimulate appropriate cell growth, migration, and differentiation.
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Our lab and many others have focused on synthetic bioresorbable polyesters in the polylactide/polyglycolide family as materials for scaffold construction in tissue engineering, as these materials have good mechanical properties, a long and favorable clinical record, are processable by solvent or thermal techniques, and break down by hydrolysis in body fluids to yield natural metabolites. In a collaboration initiated by a plastic surgeon at Boston Children's Hospital, we demonstrated that cartilage-like tissue in the shape of a human outer ear could be formed either in culture or by implanting beneath the skin a porous ear-shaped
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Highly vascularized tissues also tend to comprise several cell types arranged in a hierarchical structure, further complicating their reproduction by tissue engineering approaches. Cells derived from such tissues, such as hepatocytes from liver, often lose tissue-related functions when placed in culture; presumably, the hierarchy of structure also conveys a hierarchy of molecular control of cell behavior.
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It is becoming more apparent that the molecular signals from ECM may at least partially govern cell behavior by measurable biophysical outcomes such as the relative magnitude of adhesive bonds (Lauffenburger and Horwitz, 1996~. For example, the morphology of aggregates of hepatocytes in culture spread or spheriodal can be predicted on the basis of the relative magnitudes of cell-substrate adhesion strength and cell contractile forces, and the morphology of more complex structures obtained from mixed hepatocyte/endothelial cultures can also be predicted based on relative cell-cell and cell-substrate adhesion strengths (Powers et al., 1997~.
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1992. Tissue engineered growth of new cartilage in the shape of a human ear using synthetic polymers seeded with chondrocytes.
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The molecular architectural features that underlie these disparate patterns of behavior are strikingly different: proteins and nucleic acids are characterized by precisely defined chain lengths and sequences, whereas synthetic polymeric materials consist of complex mixtures of chain molecules in which length, sequence, and stereochemistry (molecular shape) vary widely from chain to chain.
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It has also been demonstrated that the protein biosynthetic apparatus can accommodate monomers other than the 20 amino acids normally used to build cellular proteins. The materials engineer is thus presented with an important new opportunity that of designing polymeric materials of precisely controlled architectures without sacrificing the versatility characteristic of synthetic polymers.
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The messenger RNA template that guides protein synthesis in this approach is derived not from any natural gene but rather from an artificial gene that specifies the sequence of amino acids dictated by the materials design process. The template polymerization that nature uses to build cellular proteins is co-opted by the materials engineer for his or her own purposes.
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In a recent example, socalled leucine-zipper peptide domains were attached to the ends of a watersoluble polypeptide to create tnblock chimenc proteins in which the leucine zippers control polymer-polymer interactions in a manner that leads to reversible "elation of the protein solution in response to changes in pH or temperature (Petka et al., 1998~. REFERENCES Krejchi, M
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is a new technology for performing high-resolution cross-sectional imaging. OCT functions as a type of optical biopsy that provides cross-sectional images of tissue structure on the micron scale.
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OCT is a promising and powerful medical imaging technology because it can permit real-time in situ visualization of tissue microstructure without the need to excisionally remove and process a specimen, as in conventional biopsy and histopathology. The concept of "nonexcisional optical biopsy" provided by OCT and the ability to visualize tissue morphology in real time under operator guidance can be used both for diagnostic imaging and to guide surgical intervention.
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This dataset represents the backscattering or back reflection through a cross-section of the object being imaged and can be displayed as a gray scale or false color image. The axial resolution in OCT images is determined by the coherence length of the light source.
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Thus, broad-bandwidth optical sources are required to achieve high axial resolution. The transverse resolution achieved with an OCT imaging system is determined by the focused spot size in analogy with conventional microscopy.
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For clinical applications, compact superluminescent diodes or semiconductor-based light sources can be used. The laser source for many of our studies was a short-pulse Cr4+:Forsterite laser, which operates near 1,300 rim and achieves an axial resolution of 5 to 10 ,um with a signal-to-noise ratio of 110 dB (Boppart et al., 1998~.
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The middle image shows the structure of the normal intestinal mucosal tissue, which has a vertically organized columnar epithelial structure. Even at modest resolutions of 15 ,um, the differences between the architectural morphology of these tissue types is evident.
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Changes in architectural morphology such as these can be used for the screening and diagnosis of early neoplastic changes. Conventional excisional biopsy often suffers from high false-negative rates because the biopsy process relies on sampling tissue and the diseased tissues can easily be missed.
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These studies demonstrate the feasibility of performing OCT imaging of internal organ systems and suggest the possibility of its application clinically (Tearney et al., 1997a)
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One of the keys to achieving high resolution is the use of short-pulsed lasers to obtain short coherence length. High-resolution OCT imaging has been demonstrated in vivo in developmental biology specimens.
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a powerful technique for optical biopsy because it can perform micron-scale imaging of cellular and architectural morphology in situ and in real time. Imaging information is available in real time without the need for excision and histological processing of a specimen.
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1995. Biomedical imaging and optical biopsy using optical coherence tomography.
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1997b. Optical biopsy in human gastrointestinal tissue using optical coherence tomography.
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Between 1991 and 1996, scientists at L'Oreal in France demonstrated confocal imaging of living human skin with a white-light tandem scanning microscope (Bertrand and Corcuff, 1994; Corcuff et al., 1993,1996; Corcuff and Leveque, 1993; New et al., 1991~. In 1995 we developed a confocal scanning laser microscope for real-time imaging of human tissues (Rajadhyaksha et 24
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25 al., 1995~. Cellular and nuclear microstructures in normal human skin and skin cancers, and dynamic events such as circulating blood flow, the response of skin to ultraviolet light, and wound healing were investigated (Rajadhyaksha and Zavislan, 1998~.
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A confocal microscope thus allows noninvasive imaging of a thin plane (section) within a scattering object with high axial (and also lateral)
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DEVELOPMENT OF CONFOCAL SCANNING LASER MICROSCOPES Laboratory Prototype At Wellman Laboratories, Massachusetts General Hospital (MGH) , we built a video-rate confocal scanning laser microscope (CSLM)
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Confocal imaging of living tissue is most useful if the resolution is similar to that of conventional microscopy (histology) , so that cellular and nuclear microstructures can be seen.
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FIGURE 5 Commercial confocal scanning laser microscope (VivaScope_) for imaging living human skin.
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Morphological features included thickness of stratum corneum and epidermis and modulation depth of the epidermal-dermal junction. A group at L'Oreal has demonstrated similar imaging in normal human skin with their white light tandem scanning confocal microscope (Bertrand and Corcuff, 1994; Corcuff and Leveque, 1993; Corcuff et al., 1993, 1996; New et al., 1991~.
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the use of dyes to stain specific cell types enhances tissue contrast, so that critical information necessary for diagnosis can be easily read in histology, whereas confocal microscopy relies on the natural (low) reflectance contrast of tissue without the advantages of stains.
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, the combination of confocal microscopy with other techniques such as laparoscopy should enable imaging of internal organs. Ultimately, optical imaging must be combined with nonoptical imaging modalities to create a noninvasive diagnostic tool kit for the medical profession.
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1995. In vivo confocal scanning laser microscopy of human skin: Melanin provides strong contrast.
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