The general purpose of this study is to establish, validate and translate to clinical protocol, MR imaging biomarkers that non-invasively reflect structure, function, and adaptive relationships between meniscus, cartilage and subchondral bone based upon structural, histologic, and biomechanical reference standards. This proposal incorporates our experience from past cartilage and meniscus research to develop a unified theory, that of the meniscal osteochondral unit (M-OCU). This theory emphasizes the dynamic relationship between meniscus, cartilage, subchondral bone and bone marrow. It is supported by structural and mechanical relationships in the meniscus covered and uncovered osteochondral surfaces of the tibia, as well as by pathologic phenotypes in knee OA. The development of a single study protocol that allows non-invasive evaluation of the components of the M-OCU will facilitate understanding the degree and type of adaptation that occurs in these tissues in the setting of an altered mechanical axis in meniscus-injured patients. The overall hypothesis is that the intact M-OCU preserves a normal mechanical axis in the knee, and further that the pattern of meniscal failure (acuity, location, character) will predict the response of the subjacent osteochondral surface (adaptive response versus failure).
Four specific aims are proposed: 1) cadaveric knees, we will determine if high resolution 3D Cube MR measures of the subchondral bone and trabecular bone can serve as biomarkers for structure and biomechanical function of tissue, for characterizing the structures of the subchondral (SC) bone plate and SC trabecular bone using micro CT as a reference standard, 2) cadaveric knees, will determine if MR measures of bone marrow can serve as biomarkers for marrow composition, and together with bone structure, improve the prediction of biomechanical function of the surrounding trabecular bone, 3) to evaluate the M-OCU (meniscus, cartilage, SC bone plate, SC trabecular bone, and bone marrow) using morphologic and quantitative MR sequences with histologic, imaging, and biomechanical reference standards, and 4) to translate MR imaging evaluation of the M-OCU with a novel load-bearing technique, to 2 meniscal repair cohorts pre- and post-treatment over time to characterize degree and patterns of adaptive remodeling.
Aims 1 and 2 will establish sensitivity of MR techniques, magnified by novel hardware and software optimization, to structure and function of SC bone plate and SC trabecular bone.
Aim 3 will be a translational aim, to perform whole-joint MR analysis of M-OCU in normal vs. pathologic knees of cadavers.
Aim 4 will apply all of the developed techniques to meniscus-deficient patient cohorts, one receiving traditional meniscectomy vs. another receiving meniscus-conserving treatments, which is hypothesized to better preserve mechanical axis, lead to gradual adaptation of M-OCU, and better clinical outcome.

Public Health Relevance

This project has exciting implications for clinical use. It focuses on novel MR hardware development and MR pulse sequence optimization that allow non-invasive interrogation of earliest structural alterations in cartilage, meniscus, subchondral bone, and bone marrow (meniscal osteochondral unit, or M-OCU), providing imaging biomarkers reflecting integrity of major knee components. The project explores the relationship of meniscal pathology and cartilage degeneration as well as bone remodeling, focusing on the concept that the whole joint must be considered when identifying factors affecting progression of osteoarthrosis. Further, the project analyzes differential effects of meniscectomy vs. meniscus-conserving surgery on cartilage degeneration, and bone remodeling. In addition, this work explores the concept that noninvasive MRI techniques may reflect tissue function as expressed with biomechanical testing. The information from this study could be instrumental in understanding and monitoring progression of degenerative joint disease, and guiding clinical therapy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01CX000625-05A1
Application #
9345715
Study Section
Endocrinology B (ENDB)
Project Start
2012-10-01
Project End
2021-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161
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