A new tool is necessary to explore the nanoscale mechanisms that contribute to tissue mechanical properties. These nanoscale mechanisms are of key importance in understanding bone fragility, intervertebral disc degeneration, osteoarthritis, and other diseases. The Atomic Force Microscope, AFM, with its ability to both image and manipulate nanostructures, has been a powerful tool in this area. But it has a major limitation for studying tissue samples: most tissue samples are too rough to be imaged with AFM cantilevers. Here we propose to move beyond cantilevers to a novel Deep AFM probe that enables a vertical approach deep into the topography of tissue samples. The objectives of the proposed research are to build the first prototypes of a new generation of Atomic Force Microscopes, Deep AFMs, that will increase imaging range of AFMs by at least one order of magnitude, and then to use these Deep AFMs to explore tissue structures and nanomechanics with a goal of understanding the molecules and nanoscale processes involved in tissue degeneration at a sufficient level of detail to inform development of new therapies. The overall impact and relevance of the proposed work is broad due to the numerous potential applications, however, because of our current progress and work on bone diagnostics, we will focus primarily on the nanoscale fracture mechanics of bone. We propose three related aims that include both the development and characterization of this new class of AFMs as well as their application in clinically relevant bone tissue samples.
Specific Aim 1 is to develop Deep AFM I for very large scale scanning and nanomechanics. It will enable imaging of crack propagation in bone submerged in buffer as well as spatially resolved force spectroscopy, nanomanipulation and indentation to measure local nanomechanical properties.
Specific Aim 2 is to develop Deep AFM II for high resolution, large scale scanning and nanomechanics. The higher resolution of Deep AFM II will enable imaging the nanoscale origin of bone fracture cracks with resolution comparable to Scanning Electron Microscopy, but without ever removing the sample from buffer. Thus it will be possible to image nanoscale processes that occur at intermediate stages of the crack growth process. It will also be possible to perform spatially resolved force spectroscopy, nanomanipulation and indentation to measure local nanomechanical properties.
Specific Aim 3 is to use Deep AFM to move forward in our understanding of the nanoscale mechanisms of bone fracture and ways to reduce bone fracture risk. With Deep AFM, we can continue to move toward a long term goal of clinically decreasing the component of bone fracture risk by understanding the molecules and nanoscale mechanisms that resist bone fracture.

Public Health Relevance

Bone fragility, intervertebral disc degeneration, cancer, atherosclerosis, osteoarthritis, and tooth decay all involve changes in tissue mechanical properties at the nanoscale. The proposed Deep Atomic Force Microscope, Deep AFM, is designed to investigate these changes with the goal of understanding how to prevent and even reverse undesirable changes for tissues in general and bone in particular. This work will be synergistic with our ongoing collaboration with physicians on diagnosing bone fragility due to bone tissue degeneration in patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Lewis, Catherine D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
Zip Code
Lescun, Timothy B; Hoffseth, Kevin; Yang, Henry T et al. (2016) Effect of various testing conditions on results for a handheld reference point indentation instrument in horses. Am J Vet Res 77:39-49
Drake, Barney; Randall, Connor; Bridges, Daniel et al. (2014) A new ion sensing deep atomic force microscope. Rev Sci Instrum 85:083706
Farr, Joshua N; Drake, Matthew T; Amin, Shreyasee et al. (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29:787-95
Szabo, M E; Thurner, P J (2013) Anisotropy of bovine cortical bone tissue damage properties. J Biomech 46:2-6
Randall, Connor; Bridges, Daniel; Guerri, Roberto et al. (2013) Applications of a New Handheld Reference Point Indentation Instrument Measuring Bone Material Strength. J Med Device 7:410051-410056
Guerri-Fernandez, Roberto C; Nogues, Xavier; Quesada Gomez, Jose M et al. (2013) Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res 28:162-8
Barnard, H; Drake, B; Randall, C et al. (2013) Deep atomic force microscopy. Rev Sci Instrum 84:123701
Bridges, Daniel; Randall, Connor; Hansma, Paul K (2012) A new device for performing reference point indentation without a reference probe. Rev Sci Instrum 83:044301
Barnard, H; Randall, C; Bridges, D et al. (2012) The long range voice coil atomic force microscope. Rev Sci Instrum 83:023705
Szabo, M E; Taylor, M; Thurner, P J (2011) Mechanical properties of single bovine trabeculae are unaffected by strain rate. J Biomech 44:962-7

Showing the most recent 10 out of 45 publications