Douglas R. Pedersen

Purpose: Early-stage osteoarthritis (OA) includes glycosaminoglycan (GAG) loss and collagen disruption that cannot be seen on morphological magnetic resonance imaging (MRI). T1ρ MRI is a measurement that probes the low-frequency rate of exchange between protons of free water and those from water associated with macromolecules in the cartilage's extracellular matrix. While it has been hypothesized that increased water mobility resulting from early osteoarthritic changes cause elevated T1ρ MRI values, there remain several unknown mechanisms influencing T1ρ measurements in cartilage. The purpose of this work was to relate histological and biochemical metrics directly measured from osteochondral biopsies and fluid specimens with quantitative MRI-detected changes of in vivo cartilage composition. Patients and methods: Six young patients were enrolled an average of 41 days after acute anterior cruciate ligament (ACL) rupture. Femoral trochlear groove osteochondral biopsies, serum, and synovial fluid were harvested during ACL reconstruction to complement a presurgery quantitative MRI study (T1ρ, T2, delayed gadolinium-enhanced MRI of cartilage [dGEMRIC] relaxation times). A high-resolution MRI scan of the excised osteochondral biopsy was also collected. Analyses of in vivo T1ρ images were compared with ex vivo T1ρ imaging, GAG assays and histological GAG distribution in the osteochondral biopsies, and direct measures of bone and cartilage turnover markers and "OA marker" 3B3 in serum and synovial fluid samples. Conclusion: T1ρ relaxation times in patients with a torn ACL were elevated from normal, indicating changes consistent with general fluid effusion after blunt joint trauma. Increased chondrogenic progenitor cell (CPC) production of chondroprotective lubricin may relate to cartilage surface disruption by blunt trauma and CPC amplification of joint inflammation. Disparity between ex vivo and matched in vivo MRI of trochlear cartilage suggests MRI signal differences that may be related to the synovial fluid environment. T1ρ is emerging as a promising MRI biomarker to relate noninvasive measures of whole-joint condition and cartilage composition to direct measures of cartilage changes in the acute phase of joint injuries.

Investigation of femoral head osteonecrosis would benefit from an animal model whose natural history includes progression to bony collapse of a segmental necrotic lesion. The bipedal emu holds attraction for systematic organ‐level study of collapse mechanopathology. One established method of experimentally inducing segmental lesions is liquid nitrogen cryoinsult. Four cryoinsult parameters—hold temperature, freeze duration, freeze/thaw repetition, and thaw duration—were investigated to determine their individual and combined effects on resulting necrotic lesion morphology. 3D distributions of histologically apparent osteocyte necrosis from 24 emus receiving varying cryoinsults were used to develop univariate and multivariate linear regression models relating resulting necrotic lesion morphology to particular cryoinsult input parameters. These models were then applied to predict lesion size in four additional emus receiving differing input cryoinsults. The best multivariate regression model predicted lesion volumes that were accurate to better than 8% of overall emu femoral head volume. The hold temperature during cryoinsult was by far the most influential cryoinsult input parameter. The utility of this information is to enhance the consistency and predictability of cryoinsult‐induced segmental lesion size for the purposes of systematic laboratory studies at the whole‐organ level. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:931–937

Systematic studies of treatment options for femoral head osteonecrosis have been hindered by the lack of an animal model that mimics the human event of femoral head collapse. The (bipedal) emu model of osteonecrosis has proven to progress to collapse following an external insult. Since osteonecrosis clinically has multiple etiologies, various alternatives are seemingly appropriate to initiate lesions for research purposes. This study compared osteonecrosis initiated by a local cryoinsult, to that initiated by a large systemic dose of steroid (methylprednisolone acetate), and by a combination of steroid and cryoinsult. One year post-insult, the animals were sacrificed and their femoral heads harvested. A custom-written computer program was used to expedite analysis of the global distribution of histologically apparent osteonecrosis, as determined by the Ficat scale. Following whole-head analysis, grade distributions were calculated, and a measure of spatial clustering of histologic abnormality was calculated using Moran's I statistic. Normal femoral heads showed very small amounts of histological abnormality, and no significant spatial clustering. Femoral heads receiving isolated cryoinsult had a greater incidence of high-grade abnormality, as well as statistically significant spatial clustering of that abnormality. Steroid-only animals had a higher percentage of diffuse, low-grade abnormality. The group receiving both steroid and cryoinsult showed the highest overall abnormality, with statistically significant clustering of that high-grade abnormality. Cryoinsult, both in isolation and in combination with a steroid regimen, appeared necessary to mimic the clinically typical focal lesions of osteonecrosis.

A new fluid/structure-interaction finite element formulation is reported, by means of which reactive fluid stresses can be determined for what is currently the most widely used laboratory apparatus (; the Flexercell Strain Unit ) for delivering controlled in vitro mechanical stimuli to cultured cells. The apparatus functions by means of cyclic vacuum application to the undersurface of a membrane-like circular rubber substrate. When operated in Us original embodiment ( i.e., without axial constraint to substrate motion), the pulsatile vacuum causes appreciable pulsatile excursions ( often several millimeters) of the substrate. The mechanical stimuli experienced by cells attached atop the substrate include not only substrate distention, but also potentially confounding reactive fluid stresses due to coupled motions of the overlying liquid culture nutrient medium. Since it is impractical to directly measure reactive fluid stress in such environments, a corresponding mathematical model has been developed. The formulation involves transient continuum finite element solutions for the nutrient medium flow field and for the deformation of the substrate, coupled at their mutual interface ( the substrate culture surface) Besides the nonlinearities inherent in the flow field and substrate treatments per se, the numerical problem is complicated by the presence of moving boundaries at the nutrient free surface and at the nutrient/substrate interface, as well as by the need to enforce fluid/structure interaction throughout the duty cycle. Algorithmic considerations appropriate to achieving physically realistic numerical performance are reported, and a confirmatory laboratory validation experiment is described.