Optimizing Mechanical Loading in Bone Formation
Two Northeastern professors recently received a $650K NSF grant for “Manipulating Fluid Flow in Mechanoadaptation of Bone.” Principal Investigator, MIE/BioE Professor Sandra Shefelbine, said that one of the project’s main goals is to learn how to improve bone strength, especially as individuals age.
Bones are sensitive to mechanical loads, meaning that increased loading can make more bone, and decreased loading can take it away. Exposing bone tissue to a mechanical load, such as through an exercise training program, can improve bone strength.
“As you age, bones are not as responsive to loading,” Shefelbine explained. “It’s part of the reason why older people have weak bones.” She added that physical therapies to improve bone strength in the elderly are not very effective.
COS Associate Professor James Monaghan is a co-investigator on the grant, which will focus on analyzing bone at the tissue, cellular, and molecular level.
Time to bone up
Lifting weights is known to build up muscle mass and increase strength, but how do you strengthen bone? Shefelbine explained that most of her lab work is delving into how that process happens.
For example, tennis players have more bone in their serving arm than in their non-serving arm, she said.
“How we can use that characteristic in a therapeutic technique?” she posited. “We also examine how bones respond to load during growth. If loading is incorrect while an individual is growing, you can get a huge number of bone deformities.”
With the NSF grant, Shefelbine and her team will be using mice for research. She explained that they have determined that older mice can form new bone. But it’s necessary to determine the specific conditions to ensure that the process of forming new bone can more regularly occur.
“We’re doing some work with novel imaging,” she said. “ We will image the bone cells and watch them receive the mechanical signal. We will use a mouse that has bone cells that will glow when stimulated. With the mouse in a microscope, we will apply the load and watch bone cells respond. We’re watching the process of cells translating mechanical signals into a biological response.
“We will use a labeling technique (fluorescence in situ hybridization) to find out what proteins the cells make in response to the loading,” Shefelbine added.
Interweaving science and art
Another part of the NSF grant aims to have a broader impact: showing the similarities – and beauty – in both science and art.
Shefelbine has previously worked with Lincoln, MA-based artist Colleen Pearce, and said and they are excited to collaborate together again.
“Initially, I was surprised how similar the artistic process was to the scientific process,” Shefelbine said. “They both involve questioning, conducting a trial, and then a retrial.
“We both experiment, collect data. If she does a piece and it doesn’t work, [she adjusts] and does another piece. It was eye opening for me to see how similar [our approaches] were.”
Abstract Source: NSF
Bone is sensitive to mechanical loads, or “mechano-sensitive”. It responds to increased loading by making more bone and to decreased loading by taking away bone. This project will study how mechanical signals are translated into a biological response using analysis at the tissue, cellular, and molecular level. Investigations will reveal how to optimize the mechanical signal by adjusting the speed and magnitude of a load applied to the tibia bone of a living mouse. Evaluation of where new bone is made in response to the loading will be made by imaging methods. These include high resolution 3D x-ray tomography and fluorescent labeling that can indicate where new bone has formed. The in-flux of calcium signaling into bone cells in a mouse tibia will also be measured under different mechanical loading conditions. These measurements will indicate how the cell-level response changes with different loading protocols. A molecular imaging technique will be used to determine what proteins are being made by the bone cells in response to loading. Bones from old mice and younger mice will be compared to see how the response changes with age. This work will provide insight about how to optimize mechanical loading to cause bone formation, which can help to inform exercise and rehabilitation therapies to keep bone healthy.
This project will use the in vivo murine tibial loading model to explore two potential fluid based stimuli: peak fluid velocity and fluid signal (integral of fluid velocity over time). By exploring the effects of loading profiles in a computational poroelastic finite element models, loading profiles will be designed to optimize each stimuli separately as well as both together in mature and aged bone. The effects of the loading profile on the tissue level will be observed by measuring the amount of bone formation. Cellular signaling during mechanical loading will be determined by using in vivo multi-photon imaging of calcium reporter osteocytes. This will indicate if cells are sensitive to peak fluid velocity or fluid signal (the amount of time there is fluid-induced shear stress). Fluorescence in situ hybridization (FISH) will be used to quantitatively assess intracellular signaling of genes involved in mechanoadaptation (mechano-RNA). This study will not only provide a mechanistic understanding of adaptation to load but will also advance imaging and assessment techniques for exploring mechanoadaptation at the cellular and molecular level. This work is co-funded by the Biomechanics & Mechanobiology and the Physiological Mechanisms & Biomechanics programs.
This award reflects NSF’s statutory mission and has been deemed worthy of support through evaluation using the Foundation’s intellectual merit and broader impacts review criteria.