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50 years of scanning electron microscopy of bone—a comprehensive overview of the important discoveries made and insights gained into bone material properties in health, disease, and taphonomy

Shah, Furqan A., Ruscsák, Krisztina, Palmquist, Anders·2019·Bone Research
DOI 10.1038/s41413-019-0053-zPMC PMC6531483
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Abstract

Bone is an architecturally complex system that constantly undergoes structural and functional optimisation through renewal and repair. The scanning electron microscope (SEM) is among the most frequently used instruments for examining bone. It offers the key advantage of very high spatial resolution coupled with a large depth of field and wide field of view. Interactions between incident electrons and atoms on the sample surface generate backscattered electrons, secondary electrons, and various other signals including X-rays that relay compositional and topographical information. Through selective removal or preservation of specific tissue components (organic, inorganic, cellular, vascular), their individual contribution(s) to the overall functional competence can be elucidated. With few restrictions on sample geometry and a variety of applicable sample-processing routes, a given sample may be conveniently adapted for multiple analytical methods. While a conventional SEM operates at high vacuum conditions that demand clean, dry, and electrically conductive samples, non-conductive materials (e.g., bone) can be imaged without significant modification from the natural state using an environmental scanning electron microscope. This review highlights important insights gained into bone microstructure and pathophysiology, bone response to implanted biomaterials, elemental analysis, SEM in paleoarchaeology, 3D imaging using focused ion beam techniques, correlative microscopy and in situ experiments. The capacity to image seamlessly across multiple length scales within the meso-micro-nano-continuum, the SEM lends itself to many unique and diverse applications, which attest to the versatility and user-friendly nature of this instrument for studying bone. Significant technological developments are anticipated for analysing bone using the SEM.

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Figures

Fig. 1 Parts of a scanning electron microscope (SEM) and the typical signals that are recorded from bone. BSE backscattered electrons, SE secondary electrons, EDX energy-dispersive X-ray spectroscopy
Fig. 1 Parts of a scanning electron microscope (SEM) and the typical signals that are recorded from bone. BSE backscattered electrons, SE secondary electrons, EDX energy-dispersive X-ray spectroscopyCC BY · PubMed Central
Fig. 2 Imaging bone in the SEM. a BSE-SEM photomontage of a human rib viewed in cross-section. Local variations in mineralisation density, Haversian canals, resorption spaces, and osteocyte lacunae can be detected. From Bereshiem et al. Adapted with permission from John Wiley and Sons. Copyright 2019 7. b Osteocyte lacunar density determined using BSE imaging. From Bach-Gansmo et al.12. Adapted with permission from Elsevier. Copyright 201512. c A cement line between osteonal bone and interstitial bone. From Skedros et al. Adapted with permission from John Wiley and Sons. Copyright 200520. d The intertrabecular spaces in antler bone are occupied by primary osteons. Trabeculae (asterisks) and unremodelled islands of calcified cartilage (arrow) can be identified. From Kierdorf et al. Adapted with permission from John Wiley and Sons. Copyright 201330. e Topographical BSE-SEM. For each 90° sector of an annular BSE detector, a separate image is recorded containing information sensitive to the direction of apparent illumination (arrows). From Boyde A. Adapted with permission from John Wiley and Sons. Copyright 200331. f Osteon pull-out under cyclic mechanical loading observed using SE imaging. From Hiller et al. Adapted with permission from John Wiley and Sons. Copyright 200347. g Cell surface detail of osteoblasts on the surface of parietal bone. From Jones S. J. Adapted with permission from Springer Nature. Copyright 197457. h Osteoblasts appear to organise collagen fibrils through flat basal processes. From Pazzaglia U.E. et al. Adapted with permission from Springer Nature. Copyright 201061. i Hypermineralised osteocyte lacuna containing mineralised apoptotic debris. From Shah et al. Adapted with permission from the American Chemical Society. Copyright 2017.69 j Severely disorganised bone microstructure in melorheostosis. From Fratzl-Zelman et al. Adapted with permission from John Wiley and Sons. Copyright 201972. k Bone with (right) and without (left) osteocytes. From Atkins et al. Adapted with permission from the National Academy of Sciences. Copyright 201477. l An osteocyte and associated canalicular network exposed by resin cast etching. From Feng et al. Adapted with permission from John Wiley and Sons. Copyright 200679. m Howship’s lacunae: longitudinally extended resorption (LER; left) and reticulate patch resorption (RPR; right) lacunae. From Gentzsch et al. Adapted with permission from Springer Nature. Copyright 200384. n Cryo-SEM. The combination of SE (above) and BSE (below) imaging provides morphological and compositional information. From Mahamid et al. Adapted with permission from the National Academy of Sciences. Copyright 201097
Fig. 2 Imaging bone in the SEM. a BSE-SEM photomontage of a human rib viewed in cross-section. Local variations in mineralisation density, Haversian canals, resorption spaces, and osteocyte lacunae can be detected. From Bereshiem et al. Adapted with permission from John Wiley and Sons. Copyright 2019 7. b Osteocyte lacunar density determined using BSE imaging. From Bach-Gansmo et al.12. Adapted with permission from Elsevier. Copyright 201512. c A cement line between osteonal bone and interstitial bone. From Skedros et al. Adapted with permission from John Wiley and Sons. Copyright 200520. d The intertrabecular spaces in antler bone are occupied by primary osteons. Trabeculae (asterisks) and unremodelled islands of calcified cartilage (arrow) can be identified. From Kierdorf et al. Adapted with permission from John Wiley and Sons. Copyright 201330. e Topographical BSE-SEM. For each 90° sector of an annular BSE detector, a separate image is recorded containing information sensitive to the direction of apparent illumination (arrows). From Boyde A. Adapted with permission from John Wiley and Sons. Copyright 200331. f Osteon pull-out under cyclic mechanical loading observed using SE imaging. From Hiller et al. Adapted with permission from John Wiley and Sons. Copyright 200347. g Cell surface detail of osteoblasts on the surface of parietal bone. From Jones S. J. Adapted with permission from Springer Nature. Copyright 197457. h Osteoblasts appear to organise collagen fibrils through flat basal processes. From Pazzaglia U.E. et al. Adapted with permission from Springer Nature. Copyright 201061. i Hypermineralised osteocyte lacuna containing mineralised apoptotic debris. From Shah et al. Adapted with permission from the American Chemical Society. Copyright 2017.69 j Severely disorganised bone microstructure in melorheostosis. From Fratzl-Zelman et al. Adapted with permission from John Wiley and Sons. Copyright 201972. k Bone with (right) and without (left) osteocytes. From Atkins et al. Adapted with permission from the National Academy of Sciences. Copyright 201477. l An osteocyte and associated canalicular network exposed by resin cast etching. From Feng et al. Adapted with permission from John Wiley and Sons. Copyright 200679. m Howship’s lacunae: longitudinally extended resorption (LER; left) and reticulate patch resorption (RPR; right) lacunae. From Gentzsch et al. Adapted with permission from Springer Nature. Copyright 200384. n Cryo-SEM. The combination of SE (above) and BSE (below) imaging provides morphological and compositional information. From Mahamid et al. Adapted with permission from the National Academy of Sciences. Copyright 201097CC BY · PubMed Central
Fig. 3 Sources of osteogenesis around implant biomaterials. 1. Contact osteogenesis. 2. Distance osteogenesis. 3. De novo formed woven bone. 4. Autogenous bone fragments
Fig. 3 Sources of osteogenesis around implant biomaterials. 1. Contact osteogenesis. 2. Distance osteogenesis. 3. De novo formed woven bone. 4. Autogenous bone fragmentsCC BY · PubMed Central
Fig. 4 Imaging bone around implant biomaterials. a BSE imaging of bone formed around laser-ablated titanium. From Palmquist et al. Adapted with permission from John Wiley and Sons. Copyright 2011115. b BSE imaging of HAp-coated titanium implants. From Merolli et al. Adapted by permission from Springer Nature. Copyright 2000132. c Local bisphosphonate delivery (BP; 16 µg/implant. Ctrl; 0 µg/implant) from HAp-coated cp-Ti implants (3 mm diameter) promotes bone formation. From Peter et al. Adapted with permission from John Wiley and Sons. Copyright 2006135. d Ingrowth of mineralised tissue into 3D printed polycaprolactone + β-tricalcium phosphate (80:20) scaffolds with a repeating 0°/90° strut laydown pattern. From Paris et al. Adapted with permission from Elsevier. Copyright 2017153. e Resin cast etching for direct visualisation of osteocyte attachment to various implant surfaces. Example #1: Ti6Al4V. From Shah et al. Adapted with permission from Elsevier. Copyright 201674. Example #2: CoCr. From Shah et al. Adapted with permission from John Wiley and Sons. Copyright 201873
Fig. 4 Imaging bone around implant biomaterials. a BSE imaging of bone formed around laser-ablated titanium. From Palmquist et al. Adapted with permission from John Wiley and Sons. Copyright 2011115. b BSE imaging of HAp-coated titanium implants. From Merolli et al. Adapted by permission from Springer Nature. Copyright 2000132. c Local bisphosphonate delivery (BP; 16 µg/implant. Ctrl; 0 µg/implant) from HAp-coated cp-Ti implants (3 mm diameter) promotes bone formation. From Peter et al. Adapted with permission from John Wiley and Sons. Copyright 2006135. d Ingrowth of mineralised tissue into 3D printed polycaprolactone + β-tricalcium phosphate (80:20) scaffolds with a repeating 0°/90° strut laydown pattern. From Paris et al. Adapted with permission from Elsevier. Copyright 2017153. e Resin cast etching for direct visualisation of osteocyte attachment to various implant surfaces. Example #1: Ti6Al4V. From Shah et al. Adapted with permission from Elsevier. Copyright 201674. Example #2: CoCr. From Shah et al. Adapted with permission from John Wiley and Sons. Copyright 201873CC BY · PubMed Central
Fig. 5 Elemental analysis. a BSE image and Ca (magenta), P (yellow), and Sr (cyan) elemental maps demonstrate Sr incorporation into the fracture callus after therapeutic administration. From Brüel et al. Adapted with permission from Springer Nature. Copyright 2011166. b Colour-merge image C (red), Ca (green), and Ti (blue) elemental maps reveals highly mineralised bone around laser-ablated titanium implants. From Palmquist et al. Adapted with permission from John Wiley and Sons. Copyright 2011115
Fig. 5 Elemental analysis. a BSE image and Ca (magenta), P (yellow), and Sr (cyan) elemental maps demonstrate Sr incorporation into the fracture callus after therapeutic administration. From Brüel et al. Adapted with permission from Springer Nature. Copyright 2011166. b Colour-merge image C (red), Ca (green), and Ti (blue) elemental maps reveals highly mineralised bone around laser-ablated titanium implants. From Palmquist et al. Adapted with permission from John Wiley and Sons. Copyright 2011115CC BY · PubMed Central
Fig. 6 Selective removal and/or preservation of specific tissue components. a Osteonal lamellar pattern enhanced by etching with citric acid. From Congiu and Pazzaglia. Adapted with permission from John Wiley and Sons. Copyright 2011.176 b Osteoblastic-osteocyte lacunae on the surface of trabecular bone treated with NaOCl. From Shah et al. Adapted with permission from Springer Nature. Copyright 2016.60 c Heat-deproteinised and fractured surface. Ordered layout of mineral crystal aggregates arranged in a concentric sequence of crests and grooves. From Pazzaglia et al. Adapted with permission from John Wiley and Sons. Copyright 2016.180 d After OsO4 and K4Fe(CN)6 treatment, a portion of lining cells is detached by ultrasonication and the underlying surface is exposed. Two morphological types of cells are recognised here: (i) convex dome-shaped cells with a non-adhering border (denoted as “ostC1”; mean surface area of 52.5 µm2 per cell), and (ii) flattened cells on the bone surface with spreading equatorial, cytoplasmic processes (denoted as “ostC2”; mean surface area of 179 µm2 per cell). From Pazzaglia et al. Adapted with permission from John Wiley and Sons. Copyright 2014.59 e Multi-layered cast of the osteocyte network and vasculature obtained by prolonged, repeated exposure to HCl and KOH solutions. From Pazzaglia and Congiu. Adapted with permission from John Wiley and Sons. Copyright 2013.184 f Directly opposing an implant surface, collagen is exposed by etching with HCl after mechanically separating the implant from a resin embedded bone-implant specimen. From Traini et al. Adapted with permission from John Wiley and Sons. Copyright 2005.103 g Resin cast etching reveals osteocyte attachment to the surface of a laser-ablated cp-Ti implant. Fine topographical features of the implant surface remain intact after H3PO4 and NaOCl exposure. From Shah et al. Adapted with permission from the American Chemical Society. Copyright 2015.159
Fig. 6 Selective removal and/or preservation of specific tissue components. a Osteonal lamellar pattern enhanced by etching with citric acid. From Congiu and Pazzaglia. Adapted with permission from John Wiley and Sons. Copyright 2011.176 b Osteoblastic-osteocyte lacunae on the surface of trabecular bone treated with NaOCl. From Shah et al. Adapted with permission from Springer Nature. Copyright 2016.60 c Heat-deproteinised and fractured surface. Ordered layout of mineral crystal aggregates arranged in a concentric sequence of crests and grooves. From Pazzaglia et al. Adapted with permission from John Wiley and Sons. Copyright 2016.180 d After OsO4 and K4Fe(CN)6 treatment, a portion of lining cells is detached by ultrasonication and the underlying surface is exposed. Two morphological types of cells are recognised here: (i) convex dome-shaped cells with a non-adhering border (denoted as “ostC1”; mean surface area of 52.5 µm2 per cell), and (ii) flattened cells on the bone surface with spreading equatorial, cytoplasmic processes (denoted as “ostC2”; mean surface area of 179 µm2 per cell). From Pazzaglia et al. Adapted with permission from John Wiley and Sons. Copyright 2014.59 e Multi-layered cast of the osteocyte network and vasculature obtained by prolonged, repeated exposure to HCl and KOH solutions. From Pazzaglia and Congiu. Adapted with permission from John Wiley and Sons. Copyright 2013.184 f Directly opposing an implant surface, collagen is exposed by etching with HCl after mechanically separating the implant from a resin embedded bone-implant specimen. From Traini et al. Adapted with permission from John Wiley and Sons. Copyright 2005.103 g Resin cast etching reveals osteocyte attachment to the surface of a laser-ablated cp-Ti implant. Fine topographical features of the implant surface remain intact after H3PO4 and NaOCl exposure. From Shah et al. Adapted with permission from the American Chemical Society. Copyright 2015.159CC BY · PubMed Central
Fig. 7 SEM in paleoarchaeology. a Defects of active osteomalacia visible in archaeological bone from the adult rib. Multiple areas of incomplete mineralisation (IM) and defect cement lines (DCL) are noted. From Brickley et al. Adapted with permission from John Wiley and Sons. Copyright 2007.195 b Pyrite deposits within Haversian canals in human tibia from 2 000 years ago. From Tjelldén et al. Adapted with permission from John Wiley and Sons. Copyright 2018.202 c A number of high-density foci within a single secondary osteonal system in archaeological human tibia (left). Bacterial ingress seen extending from a single osteocyte lacuna. Other osteocytes exhibit demineralisation boundaries or enlargement (right). From Bell LS. 2012. Forensic Microscopy for Skeletal Tissues. Adapted with permission from Springer Nature. Copyright 2012.196 d Mycelia mineralised with Fe/Mn oxides and calcite. Here, the mycelia (white) are seen as sunflower-like aggregates and networks of hyphae filling the resorption canals inside the compact bone tissue. From Owocki et al. Reproduced under the terms of the Creative Commons Attribution License (CC BY 4.0)204
Fig. 7 SEM in paleoarchaeology. a Defects of active osteomalacia visible in archaeological bone from the adult rib. Multiple areas of incomplete mineralisation (IM) and defect cement lines (DCL) are noted. From Brickley et al. Adapted with permission from John Wiley and Sons. Copyright 2007.195 b Pyrite deposits within Haversian canals in human tibia from 2 000 years ago. From Tjelldén et al. Adapted with permission from John Wiley and Sons. Copyright 2018.202 c A number of high-density foci within a single secondary osteonal system in archaeological human tibia (left). Bacterial ingress seen extending from a single osteocyte lacuna. Other osteocytes exhibit demineralisation boundaries or enlargement (right). From Bell LS. 2012. Forensic Microscopy for Skeletal Tissues. Adapted with permission from Springer Nature. Copyright 2012.196 d Mycelia mineralised with Fe/Mn oxides and calcite. Here, the mycelia (white) are seen as sunflower-like aggregates and networks of hyphae filling the resorption canals inside the compact bone tissue. From Owocki et al. Reproduced under the terms of the Creative Commons Attribution License (CC BY 4.0)204CC BY · PubMed Central
Fig. 8 Focused ion beam (FIB) techniques for 3D imaging and sample preparation. a FIB tomography of collagen fibrils in bone. From Reznikov et al. Adapted with permission from the American Association for the Advancement of Science. Copyright 2018.211 b FIB tomography of implanted demineralised dentin matrix and surrounding new bone where osteocytes form an interconnected network of cellular processes. From Tanoue et al. Reproduced under the terms of the Creative Commons Attribution License (CC BY 4.0).216 c Sample preparation for transmission electron microscopy using the in situ lift-out technique, starting with deposition of a 30 µm long, 2 µm wide, and 1 µm-thick protective layer, followed by sequential milling, lift-out, and thinning to electron transparency. From Grandfield et al. Adapted with permission from John Wiley and Sons. Copyright 2012.217 d Sample preparation for ptychographic X-ray computed tomography. From Dierolf et al. Adapted with permission from Springer Nature. Copyright 2010.229 e Micropillars and nanopillars prepared for uniaxial compression testing. From Tertuliano and Greer. Adapted with permission from Springer Nature. Copyright 2016231
Fig. 8 Focused ion beam (FIB) techniques for 3D imaging and sample preparation. a FIB tomography of collagen fibrils in bone. From Reznikov et al. Adapted with permission from the American Association for the Advancement of Science. Copyright 2018.211 b FIB tomography of implanted demineralised dentin matrix and surrounding new bone where osteocytes form an interconnected network of cellular processes. From Tanoue et al. Reproduced under the terms of the Creative Commons Attribution License (CC BY 4.0).216 c Sample preparation for transmission electron microscopy using the in situ lift-out technique, starting with deposition of a 30 µm long, 2 µm wide, and 1 µm-thick protective layer, followed by sequential milling, lift-out, and thinning to electron transparency. From Grandfield et al. Adapted with permission from John Wiley and Sons. Copyright 2012.217 d Sample preparation for ptychographic X-ray computed tomography. From Dierolf et al. Adapted with permission from Springer Nature. Copyright 2010.229 e Micropillars and nanopillars prepared for uniaxial compression testing. From Tertuliano and Greer. Adapted with permission from Springer Nature. Copyright 2016231CC BY · PubMed Central

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Metadata

Authors
Shah, F. A., Ruscsák, K., & Palmquist, A.
Venue
Bone Research
Publisher
Springer Science and Business Media LLC
Published
2019-05-22
Volume
7
Issue
1
ISSN
2095-6231
DOI
10.1038/s41413-019-0053-z
PMC
PMC6531483
Cited by
115
References
3
Language
en
Licence

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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