| NSF Org: |
CMMI Division of Civil, Mechanical, and Manufacturing Innovation |
| Recipient: |
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| Initial Amendment Date: | January 18, 2017 |
| Latest Amendment Date: | May 16, 2019 |
| Award Number: | 1653216 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Wendy C. Crone
CMMI Division of Civil, Mechanical, and Manufacturing Innovation ENG Directorate for Engineering |
| Start Date: | April 1, 2017 |
| End Date: | March 31, 2023 (Estimated) |
| Total Intended Award Amount: | $500,000.00 |
| Total Awarded Amount to Date: | $507,992.00 |
| Funds Obligated to Date: |
FY 2019 = $7,992.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
3451 WALNUT ST STE 440A PHILADELPHIA PA US 19104-6205 (215)898-7293 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
3450 Hamilton Walk Philadelphia PA US 19104-6205 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
CAREER: FACULTY EARLY CAR DEV, BMMB-Biomech & Mechanobiology |
| Primary Program Source: |
01001920DB NSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.041 |
ABSTRACT
During pregnancy and breastfeeding, the maternal skeleton serves as an important source of calcium for fetal/infant growth. This results in a substantial loss of maternal bone mass. However, at the same time, the skeleton must also continue to perform its mechanical function, bearing the loads applied during everyday activities. This balance is achieved through adaptations during pregnancy and lactation and partial recovery of bone mass after weaning, which allow the mechanical strength of the maternal skeleton to be preserved. The mechanisms behind the skeleton's amazing ability to balance these metabolic and mechanical functions during female reproduction are not clear. By elucidating the underlying mechanisms, this Faculty Early Career Development (CAREER) Program project will increase our scientific knowledge on the changes in bone structure, mechanical properties, and bone cells' responses to mechanical forces that occur as a result of childbearing. Through the education program, this project will inspire interest in bone biology and mechanics among high school students, foster interdisciplinary learning and research in musculoskeletal engineering and science in undergraduate students, and enhance communication with the general public on the educational context of bone biology, structure and mechanics.
The first objective of this project is to quantify the effects of physiological load-bearing and determine the effects of bone's mechano-sensitivity on skeletal responses to pregnancy and lactation. Trabecular and cortical bone structure, mechanics, and remodeling activities will be compared among multiple skeletal sites that undergo various amounts of load-bearing during daily activities. The extent of bone formation in response to a range of low to high peak strains applied through axial tibial loading in virgin rats and rats at different reproductive stages will be compared. The second objective of the project is to define mechanisms by which pregnancy and lactation modulate the osteocyte micro-mechanical environment and mechano-sensitivity. This will be achieved by integrating advanced imaging, mechanical testing, and simulation techniques for assessment of changes in lacunar and canalicular structure, peri-lacunar bone tissue material properties, and load-induced fluid flow stimulation experienced by osteocytes and their processes in response to different stages of female reproduction. The proposed study will discover and understand novel functions of the osteocyte in modulating its micro-mechanical environment and mechano-sensitivity to maintain the integrity of the maternal skeleton, and provide insight into prevention and management of osteoporosis during pregnancy and lactation.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
The female skeleton undergoes dramatic physiological alterations as a result of reproduction, where 5-10% loss in bone mineral density occurs during pregnancy and lactation. While weaning induces substantial bone recovery, reproduction-induced bone loss is only partially recovered after weaning. Nevertheless, pregnancy or lactation-associated fracture is rare. By using state-of-the-art imaging and mechanical approaches, we identified several innate compensatory mechanisms that allow for the maintenance of skeletal mechanical integrity during reproduction and lactation. The balance between the mechanical and metabolic functions of skeleton during reproduction and lactation was achieved by: 1) adaptations in cortical bone structure and load-sharing by the cortical compartment to allow for rapid calcium release from the trabecular compartment while maintaining whole-bone mechanics; 2) optimizing variations in the extent of lactation-induced bone loss and weaning-induced recovery according to bone’s load-bearing capacity to maintain the mechanical integrity of the critical load-bearing sites; 3) “buffer” with more trabecular bone than mechanically necessary in the female skeleton to offset future reproductive bone loss; 4) Enhanced mechano-sensitivity in maternal bone that results from altered osteocyte microenvironment through peri-lacunar/canalicular remodeling (PLR). Using a multiscale poroelastic model of the lacunar-canalicular system, we further demonstrated that the PLR-induced alterations in the osteocyte pericellular environment would amplify the mechanical and biochemical signal transduction to osteocyte, which could in turn enhance the mechanical adaptation of maternal bone to maintain its load-bearing function. Moreover, we discovered that a positive correlation and supportive interactions between bone and bone marrow adipose tissue (BMAT) during reproduction and lactation: both bone and BMAT undergo significant reduction during lactation and increase substantially after weaning. This unexpected finding is contradictory to the commonly reported, reciprocal relationship between bone mass and BMAT that has been found in numerous clinical and animal studies, suggesting a novel and unique bone adaptation mechanism for regulation of calcium and energy homeostasis during reproduction and lactation.
Last Modified: 05/08/2024
Modified by: Xiaowei Sherry Liu
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