Publications by authors named "Marjolein C H van der Meulen"

75 Publications

Ceramic composite with gentamicin decreases persistent infection and increases bone formation in a rat model of debrided osteomyelitis.

J Bone Jt Infect 2021 20;6(7):283-293. Epub 2021 Jul 20.

Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, NY 10021, USA.

: Current methods of managing osteomyelitic voids after debridement are inadequate and result in significant morbidity to patients. Synthetic ceramic void fillers are appropriate for non-infected bone defects but serve as a nidus of re-infection in osteomyelitis after debridement. CERAMENT G (CG) is an injectable ceramic bone void filler which contains gentamicin and is currently being evaluated for use in osteomyelitic environments after debridement due to its theoretical ability to serve as a scaffold for healing while eliminating residual bacteria after debridement through the elution of antibiotics. The goal of this study was to evaluate (1) the rate of persistent infection and (2) new bone growth of a debrided osteomyelitic defect in a rat model which has been treated with either gentamicin-impregnated ceramic cement (CERAMENT G) or the same void filler without antibiotics (CERAMENT, CBVF). : Osteomyelitis was generated in the proximal tibia of Sprague Dawley rats, subsequently debrided, and the defect filled with either (1) CG ( ), (2) CBVF ( ), or (3) nothing ( ). Each group was euthanized after 6 weeks. Infection was detected through bacterial culture and histology. Bone growth was quantified using microCT. : Infection was not detected in defects treated with CG as compared with 35 % of defects ( ) treated with CBVF and 50 % ( ) of empty defects ( ). Bone volume in the defect of CG-treated rats was greater than the CBVF (0.21 vs. 0.17, ) and empty groups (0.21 vs. 0.11, ) at 6 weeks after implantation. : Ceramic void filler with gentamicin (CERAMENT G) decreased the rate of persistent infection and increased new bone growth as compared to the same void filler without antibiotics (CERAMENT) and an empty defect in a rat model of debrided osteomyelitis.
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http://dx.doi.org/10.5194/jbji-6-283-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320378PMC
July 2021

Low bone mass resulting from impaired estrogen signaling in bone increases severity of load-induced osteoarthritis in female mice.

Bone 2021 11 24;152:116071. Epub 2021 Jun 24.

Cornell University, Ithaca, NY, United States of America; Hospital for Special Surgery, New York, NY, United States of America. Electronic address:

Objective: Reduced subchondral bone mass and increased remodeling are associated with early stage OA. However, the direct effect of low subchondral bone mass on the risk and severity of OA development is unclear. We sought to determine the role of low bone mass resulting from a bone-specific loss of estrogen signaling in load-induced OA development using female osteoblast-specific estrogen receptor-alpha knockout (pOC-ERαKO) mice.

Methods: Osteoarthritis was induced by cyclic mechanical loading applied to the left tibia of 26-week-old female pOC-ERαKO and littermate control mice at peak loads of 6.5N, 7N, or 9N for 2 weeks. Cartilage damage and thickness, osteophyte development, and joint capsule fibrosis were assessed from histological sections. Subchondral bone morphology was analyzed by microCT. The correlation between OA severity and intrinsic bone parameters was determined.

Results: The loss of ERα in bone resulted in an osteopenic subchondral bone phenotype, but did not directly affect cartilage health. Following two weeks of cyclic tibial loading to induce OA pathology, pOC-ERαKO mice developed more severe cartilage damage, larger osteophytes, and greater joint capsule fibrosis compared to littermate controls. Intrinsic bone parameters negatively correlated with measures of OA severity in loaded limbs.

Conclusions: Subchondral bone osteopenia resulting from bone-specific loss of estrogen signaling was associated with increased severity of load-induced OA pathology, suggesting that reduced subchondral bone mass directly exacerbates load-induced OA development. Bone-specific changes associated with estrogen loss may contribute to the increased incidence of OA in post-menopausal women.
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http://dx.doi.org/10.1016/j.bone.2021.116071DOI Listing
November 2021

Early inhibition of subchondral bone remodeling slows load-induced posttraumatic osteoarthritis development in mice.

J Bone Miner Res 2021 Oct 16;36(10):2027-2038. Epub 2021 Jul 16.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

Posttraumatic osteoarthritis (PTOA) is associated with abnormal and increased subchondral bone remodeling. Inhibiting altered remodeling immediately following joint damage can slow PTOA progression. Clinically, however, inhibiting remodeling when significant joint damage is already present has minimal effects in slowing further disease progression. We sought to determine the treatment window following PTOA initiation in which inhibiting remodeling can attenuate progression of joint damage. We hypothesized that the most effective treatment would be to inhibit remodeling immediately after PTOA initiation. We used an animal model in which a single bout of mechanical loading was applied to the left tibia of 26-week-old male C57Bl/6 mice at a peak load of 9 N to initiate load-induced PTOA development. Following loading, we inhibited bone remodeling using daily alendronate (ALN) treatment administered either immediately or with 1 or 2 weeks' delay up to 3 or 6 weeks post-loading. A vehicle (VEH) treatment group controlled for daily injections. Cartilage and subchondral bone morphology and osteophyte development were analyzed and compared among treatment groups. Inhibiting remodeling using ALN immediately after load-induced PTOA initiation reduced cartilage degeneration, slowed osteophyte formation, and preserved subchondral bone volume compared to VEH treatment. Delaying the inhibition of bone remodeling at 1 or 2 weeks similarly attenuated cartilage degeneration at 6 weeks, but did not slow the development of osteoarthritis (OA)-related changes in the subchondral bone, including osteophyte formation and subchondral bone erosions. Immediate inhibition of subchondral bone remodeling was most effective in slowing PTOA progression across the entire joint, indicating that abnormal bone remodeling within the first week following PTOA initiation played a critical role in subsequent cartilage damage, subchondral bone changes, and overall joint degeneration. These results highlight the potential of anti-resorptive drugs as preemptive therapies for limiting PTOA development after joint injury, rather than as disease-modifying therapies after joint damage is established. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4397DOI Listing
October 2021

Systemic osteoprotegerin does not improve peri-implant bone volume or osseointegration in rabbits.

J Orthop Res 2021 Aug 27;39(8):1611-1621. Epub 2020 Oct 27.

Hospital for Special Surgery, New York, New York, USA.

Anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agents function by blocking the differentiation of osteoclasts, thereby proving useful in the clinical management of postmenopausal osteoporosis. The effects of such agents on osseointegration is less well understood. The purpose of the current study was to investigate whether osteoprotegerin (OPG), an osteoclast inhibitor, enhances the known anabolic effects of mechanical loading (VEH) and intermittent PTH (iPTH) using a well-established rabbit model of osseointegration. In the first set of experiments, OPG was administered either alone or combined with iPTH to study its effects on measured bone mass. The second set of experiments was conducted using a higher dosage of OPG (10 mg/kg) to explore its early impact at the cellular and molecular levels. All subjects had mechanical load applied to the implant on one extremity, and no load applied on the contralateral side. In the first set of experiments, OPG alone decreased peri-implant bone mass compared to the mechanical loading group, whereas OPG + iPTH increased peri-implant bone mass compared to the OPG group. In the second set of experiments, high-dose OPG significantly decreased osteoclast number (-74.3%) at 1 week. However, this effect was not sustained as osteoclast number returned to baseline by 2 weeks. These results suggest that systemic administration of OPG does not enhance osseointegration, but rather has a detrimental effect.
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http://dx.doi.org/10.1002/jor.24884DOI Listing
August 2021

Obesity and load-induced posttraumatic osteoarthritis in the absence of fracture or surgical trauma.

J Orthop Res 2021 05 17;39(5):1007-1016. Epub 2020 Jul 17.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York.

Osteoarthritis is increasingly viewed as a heterogeneous disease with multiple phenotypic subgroups. Obesity enhances joint degeneration in mouse models of posttraumatic osteoarthritis (PTOA). Most models of PTOA involve damage to surrounding tissues caused by surgery/fracture; it is unclear if obesity enhances cartilage degeneration in the absence of surgery/fracture. We used a nonsurgical animal model of load-induced PTOA to determine the effect of obesity on cartilage degeneration 2 weeks after loading. Cartilage degeneration was caused by a single bout of cyclic tibial loading at either a high or moderate load magnitude in adult male mice with severe obesity (C57Bl6/J + high-fat diet), mild obesity (toll-like receptor 5 deficient mouse [TLR5KO]), or normal adiposity (C57Bl6/J mice + normal diet and TLR5KO mice in which obesity was prevented by manipulation of the gut microbiome). Two weeks after loading, cartilage degeneration occurred in limbs loaded at a high magnitude, as determined by OARSI scores (P < .001). However, the severity of cartilage damage did not differ among groups. Osteophyte width and synovitis of loaded limbs did not differ among groups. Furthermore, obesity did not enhance cartilage damage in limbs evaluated 6 weeks after loading. Constituents of the gut microbiota differed among groups. Our findings suggest that, in the absence of surgery/fracture, obesity may not influence cartilage loss after a single mechanical insult, suggesting that either damage to surrounding tissues or repeated mechanical insult is necessary for obesity to influence cartilage degeneration. These findings further illustrate heterogeneity in PTOA phenotypes and complex interactions between mechanical/metabolic factors in cartilage loss.
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http://dx.doi.org/10.1002/jor.24799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855296PMC
May 2021

Increased anabolic bone response in Dkk1 KO mice following tibial compressive loading.

Bone 2020 02 12;131:115054. Epub 2019 Sep 12.

Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address:

A viable Dkk1 knockout (KO) mouse strain in which embryonic lethality is rescued by developmental Wnt3 heterozygosity (Dkk1:Wnt3) exhibits increased bone formation and a high bone mass phenotype. We hypothesized that in vivo mechanical loading would further augment the bone formation response in Dkk1 KO mice, comparable to results from Sost KO mice. A cyclic loading protocol was applied to Dkk1 KO mice, wild type mice (WT; Dkk1:Wnt3), and Wnt3 heterozygote (Wnt3; Dkk1:Wnt3) controls. The left tibiae of 10-week-old female mice were dynamically loaded in vivo with 7N maximum compressive force 5 days/week for 2 weeks. Dkk1 KO bones were significantly stiffer, and so an additional group of Dkk1 KO received 12N maximum compressive force to achieve an equivalent +1200με strain at the mid-diaphysis. MicroCT and bone histomorphometry analyses were subsequently performed. All groups responded to tibial loading with increased mid-diaphyseal bone volume. The largest effect size was in the Dkk1 KO -12N group. Thus, Dkk1 KO animals had enhanced sensitivity to mechanical loading. Increases in cortical bone volume reflected increased periosteal bone formation. Bone volume and formation were not altered between WT and Wnt3 controls. These data support the concept that agonists of Wnt/β-catenin signaling can act synergistically with load-bearing exercise. Notably, Sost expression decreased with loading in Dkk1 KO and WT mice, independent of genotype. These data suggest that a compensatory downregulation of Sost in Dkk1 KO mice is not likely the primary mechanism for the augmented response to mechanical load.
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http://dx.doi.org/10.1016/j.bone.2019.115054DOI Listing
February 2020

Murine Axial Compression Tibial Loading Model to Study Bone Mechanobiology: Implementing the Model and Reporting Results.

J Orthop Res 2020 02 23;38(2):233-252. Epub 2019 Oct 23.

Department of Pediatric Surgery, Research Centre, Shriners Hospital for Children-Canada, McGill University, Montreal, Canada.

In vivo, tibial loading in mice is increasingly used to study bone adaptation and mechanotransduction. To achieve standardized and defined experimental conditions, loading parameters and animal-related factors must be considered when performing in vivo loading studies. In this review, we discuss these loading and animal-related experimental conditions, present methods to assess bone adaptation, and suggest reporting guidelines. This review originated from presentations by each of the authors at the workshop "Developing Best Practices for Mouse Models of In Vivo Loading" during the Preclinical Models Section at the Orthopaedic Research Society Annual Meeting, San Diego, CA, March 2017. Following the meeting, the authors engaged in detailed discussions with consideration of relevant literature. The guidelines and recommendations in this review are provided to help researchers perform in vivo loading experiments in mice, and thus further our knowledge of bone adaptation and the mechanisms involved in mechanotransduction. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:233-252, 2020.
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http://dx.doi.org/10.1002/jor.24466DOI Listing
February 2020

Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis.

Regen Biomater 2019 Aug 22;6(4):211-219. Epub 2019 Apr 22.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a 'mechanical pillow' to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an load-induced OA mouse model.
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http://dx.doi.org/10.1093/rb/rbz013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683954PMC
August 2019

Mechanobiological Mechanisms of Load-Induced Osteoarthritis in the Mouse Knee.

J Biomech Eng 2019 07;141(7)

Meinig School of Biomedical Engineering, Cornell University, 113 Weill Hall, Ithaca, NY 14853.

Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide, yet its disease mechanism is not clearly understood. Animal models have been established to study disease progression by initiating OA through modified joint mechanics or altered biological activity within the joint. However, animal models often do not have the capability to directly relate the mechanical environment to joint damage. This review focuses on a novel in vivo approach based on controlled, cyclic tibial compression to induce OA in the mouse knee. First, we discuss the development of the load-induced OA model, its different loading configurations, and other techniques used by research laboratories around the world. Next, we review the lessons learned regarding the mechanobiological mechanisms of load-induced OA and relate these findings to the current understanding of the disease. Then, we discuss the role of specific genetic and cellular pathways involved in load-induced OA progression and the contribution of altered tissue properties to the joint response to mechanical loading. Finally, we propose using this approach to test the therapeutic efficacy of novel treatment strategies for OA. Ultimately, elucidating the mechanobiological mechanisms of load-induced OA will aid in developing targeted treatments for this disabling disease.
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http://dx.doi.org/10.1115/1.4043970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611469PMC
July 2019

Dynamic structure and composition of bone investigated by nanoscale infrared spectroscopy.

PLoS One 2018 4;13(9):e0202833. Epub 2018 Sep 4.

Hospital for Special Surgery, Research Institute, New York, New York, United States of America.

Bone is a highly organized tissue in which each structural level influences the macroscopic and microscopic mechanical behavior. In particular, the quantity, quality, and distribution of the different bone components, i.e. collagen matrix and hydroxyapatite crystals, are associated with bone strength or fragility. Common spectroscopic techniques used to assess bone composition have resolutions limited to the micrometer range. In this study, our aims were two-fold: i) to develop and validate the AFM-IR methodology for skeletal tissues and ii) to apply the methodology to sheep cancellous bone with the objective to obtain novel findings on the composition and structure of trabecular packets.To develop the methodology, we assessed spatial and temporal reproducibility using a known homogeneous material (polymethylmethacrylate, PMMA). We verified that the major peak positions were similar and not shifted when compared to traditional Fourier Transform Infrared imaging (FTIRI). When AFM-IR was applied to sheep cancellous bone, the mineral-to-matrix ratio increased and the acid phosphate substitution ratio decreased as a function of tissue maturity. The resolution of the technique enabled visualization of different stages of the bone maturation process, particularly newly-formed osteoid prior to mineralization. We also observed alternating patterns of IR parameters in line and imaging measurements, suggesting the apposition of layers of alternating structure and / or composition that were not visible with traditional spectroscopic methods. In conclusion, nanoscale IR spectroscopy demonstrates novel compositional and structural changes within trabecular packets in cancellous bone. Based on these results, AFM-IR is a valuable tool to investigate cancellous bone at the nanoscale and, more generally, to analyze small dynamic areas that are invisible to traditional spectroscopic methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202833PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122783PMC
April 2019

Mouse models to evaluate the role of estrogen receptor α in skeletal maintenance and adaptation.

Ann N Y Acad Sci 2017 12 17;1410(1):85-92. Epub 2017 Nov 17.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.

Estrogen signaling and mechanical loading have individual and combined effects on skeletal maintenance and adaptation. Previous work investigating estrogen signaling both in vitro and in vivo using global estrogen receptor α (ERα) gene knockout mouse models has provided information regarding the role of ERα in regulating bone mass and adaptation to mechanical stimulation. However, these models have inherent limitations that confound interpretation of the data. Therefore, recent studies have focused on mice with targeted deletion of ERα from specific bone cells and their precursors. Cell stage, tissue type, and mouse sex all influence the effects of ERα gene deletion. Lack of ERα in osteoblast progenitor and precursor cells generally affects the periosteum of female and male mice. The absence of ERα in differentiated osteoblasts, osteocytes, and osteoclasts in mice generally resulted in reduced cancellous bone mass, with differing reports of the effect by animal sex and greater deficiencies in bone mass typically occurring in cancellous bone in female mice. Limited data exist for the role of bone cell-specific ERα in skeletal adaptation in vivo. Cell-specific ERα gene knockout mice provide an excellent platform for investigating the function of ERα in regulating skeletal phenotype and response to mechanical loading by sex and age.
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http://dx.doi.org/10.1111/nyas.13523DOI Listing
December 2017

An in vivo model of a mechanically-induced bone marrow lesion.

J Biomech 2017 11 13;64:258-261. Epub 2017 Oct 13.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA; Hospital for Special Surgery, New York, NY, USA. Electronic address:

Bone marrow lesions (BMLs) are radiologic abnormalities in magnetic resonance images of subchondral bone that are correlated with osteoarthritis. Little is known about the physiologic processes within a BML, although BMLs are associated with mechanical stress, bone tissue microdamage and increased bone remodeling. Here we establish a rabbit model to study the pathophysiology of BMLs. We hypothesized that in vivo loads that generate microdamage in cancellous bone would also create BMLs and increase bone remodeling. In vivo cyclic loading (0.2-2.0 MPa in compression for 10,000 cycles at 2 Hz) was applied to epiphyseal cancellous bone in the distal femurs of New Zealand white rabbits (n=3, right limb loaded, left limb controls experienced surgery but no loading). Magnetic resonance images were collected using short tau inversion recovery (STIR) and T1 weighted sequences at 1 and 2 weeks after surgery/loading and histological analysis of the BML was performed after euthanasia to examine tissue microdamage and remodeling. Loaded limbs displayed BMLs while control limbs showed only a small BML-like signal caused by surgery. Histological analysis of the BML at 2 weeks after loading showed increased tissue microdamage (p=0.03) and bone resorption (p=0.01) as compared to controls. The model described here displays the hallmarks of load-induced BMLs, supporting the use of the model to examine changes in bone during the development, progression and treatment of BMLs.
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http://dx.doi.org/10.1016/j.jbiomech.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694366PMC
November 2017

Collagen XI mutation lowers susceptibility to load-induced cartilage damage in mice.

J Orthop Res 2018 02 31;36(2):711-720. Epub 2017 Oct 31.

Meinig School of Biomedical Engineering, Cornell University, 113 Weill Hall, Ithaca, 14853, New York.

Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018.
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http://dx.doi.org/10.1002/jor.23731DOI Listing
February 2018

Kinematics of meniscal- and ACL-transected mouse knees during controlled tibial compressive loading captured using roentgen stereophotogrammetry.

J Orthop Res 2017 02 3;35(2):353-360. Epub 2016 Oct 3.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.

Pre-clinical studies of post-traumatic OA have examined the pathways that lead to disease after injury by using surgical models such as the destabilization of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT). While the morphological, molecular, and genetic pathways leading to OA have been examined extensively; the effects of these injuries on joint kinematics, and thus disease progression, have yet to be fully characterized. To this end, we sought to understand the kinematics in the DMM and ACLT joints compared to intact joints subjected to controlled tibial compressive loading. We hypothesized that the DMM and ACLT models would result in different patterns of joint instability compared to intact joints, thus explaining the different patterns of OA initiation and severity in these models. Cadaver adult C57BL/6 mice were subjected to either a DMM or ACLT in their right knee joints, while the left limbs remained as intact controls. All limbs were labeled with fiducial markers, and the rigid body kinematics of the tibia and femur were examined using roentgen stereophotogrammetry (RSA) with application of compressive loads from 0 to 9 N. DMM and intact joints demonstrated similar kinematics under compressive loading, in contrast to ACLT joints, which dislocated even before load application. These results demonstrate the importance of rigorous kinematic analysis in defining the role of joint instability in animal models of OA and suggest significant differences in DMM and ACLT joint instabilities in the context of controlled mechanical loading. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:353-360, 2017.
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http://dx.doi.org/10.1002/jor.23285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349862PMC
February 2017

Osteoarthritis: Pathology, Mouse Models, and Nanoparticle Injectable Systems for Targeted Treatment.

Ann Biomed Eng 2016 06 4;44(6):2062-75. Epub 2016 Apr 4.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, 14853-7501, USA.

Osteoarthritis (OA) is a progressive, degenerative disease of articulating joints that not only affects the elderly, but also involves younger, more active individuals with prolonged participation in high physical-demand activities. Thus, effective therapies that are easy to adopt clinically are critical in limiting the societal burden associated with OA. This review is focused on intra-articular injectable regimens and provides a comprehensive look at existing in vivo models of OA that might be suitable for developing, testing, and finding a cure for OA by intra-articular injections. We first discuss the pathology, molecular mechanisms responsible for the initiation and progression of OA, and challenges associated with disease-specific targeting of OA. We proceed to discuss available animal models of OA and provide a detailed perspective on the use of mouse models in studies of experimental OA. We finally provide a closer look at intra-articular injectable treatments for OA, focusing on biomaterials-based nanoparticles, and provide a comprehensive overview of the various nanometer-size ranges studied.
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http://dx.doi.org/10.1007/s10439-016-1600-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880528PMC
June 2016

Effect of the Proximal Abducting Ulnar Osteotomy on Intra-Articular Pressure Distribution and Contact Mechanics of Congruent and Incongruent Canine Elbows Ex Vivo.

Vet Surg 2016 Apr 23;45(3):347-55. Epub 2016 Mar 23.

Department of Clinical Sciences, Cornell University, Ithaca, New York.

Objective: To determine the effects of the Proximal Abducting Ulnar Osteotomy (PAUL) on contact pressures of congruent and incongruent (short radius) canine elbows.

Study Design: Ex vivo biomechanical study.

Sample Population: Unpaired normal cadaveric canine forelimbs (n=16).

Methods: A servohydraulic testing frame and thin-film sensors were utilized to measure intra-articular contact area (CA), mean contact pressure (mCP), and peak contact pressure (pCP) for medial and lateral elbow compartments. Percent contribution of the medial compartment relative to the whole (%Med) was also examined. Baseline data were collected in 9 congruent elbows and 7 incongruent elbows where the radius was shortened. Both sets of elbows were tested following ulnar osteotomy and sequential placement of 2 and 3 mm PAUL plates and paw repositioning (to account for any medial to lateral shift of transarticular forces). Paired t-tests compared sequential procedural steps. P<.05 was significant.

Results: For congruent elbows, the 2 mm PAUL plate decreased CA in both compartments compared to baseline; lateral pCP increased with subsequent paw repositioning. Induction of radio-ulnar incongruity decreased CA and increased mCP medially, decreased pCP laterally, and increased %MedCA and %MedmCP compared to baseline. Both PAUL plates decreased mCP and pCP medially, with no effect laterally. Paw repositioning had no effect.

Conclusion: The PAUL procedure had no effect on medial compartment pressure in the congruent elbow. It may ameliorate increased medial compartment pressure in the incongruent elbow. This change does not result from a medial to lateral compartmental shift and deserves further investigation.
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http://dx.doi.org/10.1111/vsu.12456DOI Listing
April 2016

Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading.

J Orthop Res 2016 11 21;34(11):1941-1949. Epub 2016 Mar 21.

Meinig School of Biomedical Engineering, Sibley School of Mechanical and Aerospace Engineering, Cornell University, 219 Upson Hall, Ithaca, New York 14853.

We previously showed that repetitive cyclic loading of the mouse knee joint causes changes that recapitulate the features of osteoarthritis (OA) in humans. By applying a single loading session, we characterized the temporal progression of the structural and compositional changes in subchondral bone and articular cartilage. We applied loading during a single 5-minute session to the left tibia of adult (26-week-old) C57Bl/6 male mice at a peak load of 9.0N for 1,200 cycles. Knee joints were collected at times 0, 1, and 2 weeks after loading. The changes in articular cartilage and subchondral bone were analyzed by histology, immunohistochemistry (caspase-3 and cathepsin K), and microcomputed tomography. At time 0, no change was evident in chondrocyte viability or cartilage or subchondral bone integrity. However, cartilage pathology demonstrated by localized thinning and proteoglycan loss occurred at 1 and 2 weeks after the single session of loading. Transient cancellous bone loss was evident at 1 week, associated with increased osteoclast number. Bone loss was reversed to control levels at 2 weeks. We observed formation of fibrous and cartilaginous tissues at the joint margins at 1 and 2 weeks. Our findings demonstrate that a single session of noninvasive loading leads to the development of OA-like morphological and cellular alterations in articular cartilage and subchondral bone. The loss in subchondral trabecular bone mass and thickness returns to control levels at 2 weeks, whereas the cartilage thinning and proteoglycan loss persist. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1941-1949, 2016.
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http://dx.doi.org/10.1002/jor.23204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349861PMC
November 2016

Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression.

Bone 2016 May 12;86:22-9. Epub 2016 Feb 12.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, 105 Upson Hall, Ithaca, NY 14853, USA; Nancy E and Peter C Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, Ithaca, NY 14853, USA; Research Division, Hospital for Special Surgery, 541 East 71st St., New York, NY 10021, USA. Electronic address:

Mechanical loading is an anabolic stimulus that increases bone mass, and thus a promising method to counteract osteoporosis-related bone loss. The mechanism of this anabolism remains unclear, and needs to be established for both cortical and cancellous envelopes individually. We hypothesized that cortical and cancellous bone display different gene expression profiles at baseline and in response to mechanical loading. To test this hypothesis, the left tibiae of 10-week-old female C57Bl/6 mice were subjected to one session of axial tibial compression (9N, 1200cycles, 4Hz triangle waveform) and euthanized 3 and 24h following loading. The right limb served as the contralateral control. We performed RNA-seq on marrow-free metaphyseal samples from the cortical shell and the cancellous core to determine differential gene expression at baseline (control limb) and in response to load. Differential expression was verified with qPCR. Cortical and cancellous bone exhibited distinctly different transcriptional profiles basally and in response to mechanical loading. More genes were differentially expressed with loading at 24h with more genes downregulated at 24h than at 3h in both tissues. Enhanced Wnt signaling dominated the response in cortical bone at 3 and 24h, but in cancellous bone only at 3h. In cancellous bone at 24h many muscle-related genes were downregulated. These findings reveal key differences between cortical and cancellous genetic regulation in response to mechanical loading. Future studies at different time points and multiple loading sessions will add to our knowledge of cortical and cancellous mechanotransduction with the potential to identify new targets for mouse genetic knockout studies and drugs to treat osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2016.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833881PMC
May 2016

Intermittent Parathyroid Hormone Enhances Cancellous Osseointegration of a Novel Murine Tibial Implant.

J Bone Joint Surg Am 2015 Jul;97(13):1074-83

Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for X. Yang:

Background: Long-term fixation of uncemented joint implants requires early mechanical stability and implant osseointegration. To date, osseointegration has been unreliable and remains a major challenge in cementless total knee arthroplasty. We developed a murine model in which an intra-articular proximal tibial titanium implant with a roughened stem can be loaded through the knee joint. Using this model, we tested the hypothesis that intermittent injection of parathyroid hormone (iPTH) would increase proximal tibial cancellous osseointegration.

Methods: Ten-week-old female C57BL/6 mice received a subcutaneous injection of PTH (40 μg/kg/day) or a vehicle (n = 45 per treatment group) five days per week for six weeks, at which time the baseline group was killed (n = 6 per treatment group) and an implant was inserted into the proximal part of the tibiae of the remaining mice. Injections were continued until the animals were killed at one week (n = 7 per treatment group), two weeks (n = 14 per treatment group), or four weeks (n = 17 per treatment group) after implantation. Outcomes included peri-implant bone morphology as analyzed with micro-computed tomography (microCT), osseointegration percentage and bone area fraction as shown with backscattered electron microscopy, cellular composition as demonstrated by immunohistochemical analysis, and pullout strength as measured with mechanical testing.

Results: Preimplantation iPTH increased the epiphyseal bone volume fraction by 31.6%. When the data at post-implantation weeks 1, 2, and 4 were averaged for the iPTH-treated mice, the bone volume fraction was 74.5% higher in the peri-implant region and 168% higher distal to the implant compared with the bone volume fractions in the same regions in the vehicle-treated mice. Additionally, the trabecular number was 84.8% greater in the peri-implant region and 74.3% greater distal to the implant. Metaphyseal osseointegration and bone area fraction were 28.1% and 70.1% higher, respectively, in the iPTH-treated mice than in the vehicle-treated mice, and the maximum implant pullout strength was 30.9% greater. iPTH also increased osteoblast and osteoclast density by 65.2% and 47.0%, respectively, relative to the values in the vehicle group, when the data at post-implantation weeks 1 and 2 were averaged.

Conclusions: iPTH increased osseointegration, cancellous mass, and the strength of the bone-implant interface.

Clinical Relevance: Our murine model is an excellent platform on which to study biological enhancement of cancellous osseointegration.
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http://dx.doi.org/10.2106/JBJS.N.01052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574908PMC
July 2015

Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones.

J Bone Miner Res 2015 Jun;30(6):951-66

Department of Biomedical Engineering and Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, NY, USA.

Mice are widely used in studies of skeletal biology, and assessment of their bones by mechanical testing is a critical step when evaluating the functional effects of an experimental perturbation. For example, a gene knockout may target a pathway important in bone formation and result in a "low bone mass" phenotype. But how well does the skeleton bear functional loads; eg, how much do bones deform during loading and how resistant are bones to fracture? By systematic evaluation of bone morphological, densitometric, and mechanical properties, investigators can establish the "biomechanical mechanisms" whereby an experimental perturbation alters whole-bone mechanical function. The goal of this review is to clarify these biomechanical mechanisms and to make recommendations for systematically evaluating phenotypic changes in mouse bones, with a focus on long-bone diaphyses and cortical bone. Further, minimum reportable standards for testing conditions and outcome variables are suggested that will improve the comparison of data across studies. Basic biomechanical principles are reviewed, followed by a description of the cross-sectional morphological properties that best inform the net cellular effects of a given experimental perturbation and are most relevant to biomechanical function. Although morphology is critical, whole-bone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and work-to-fracture are reviewed. Because bone and body size are often strongly related, strategies to adjust whole-bone properties for body mass are detailed. Finally, a comprehensive framework is presented using real data, and several examples from the literature are reviewed to illustrate how to synthesize morphological, tissue-level, and whole-bone mechanical properties of mouse long bones.
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http://dx.doi.org/10.1002/jbmr.2539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794979PMC
June 2015

Effects of Deletion of ERα in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice.

J Bone Miner Res 2015 Aug 22;30(8):1468-80. Epub 2015 May 22.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA.

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell-specific ERαKO mice. Therefore, we crossed ERα floxed (ERα(fl/fl)) and osteocalcin-Cre (OC-Cre) mice to generate animals lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro-CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERα in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ERαKO mice had decreased cortical and cancellous bone mass, whereas male pOC-ERαKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ERαKO female L(5) vertebrae and with increased maximum moment in pOC-ERαKO male femora. Female pOC-ERαKO mice responded more to mechanical loading, whereas the response of pOC-ERαKO male animals was similar to their littermate controls.
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http://dx.doi.org/10.1002/jbmr.2488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506717PMC
August 2015

The Effect of Osteoporosis Treatments on Fatigue Properties of Cortical Bone Tissue.

Bone Rep 2015 Jun;2:8-13

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY ; Musculoskeletal Integrity Program, Hospital for Special Surgery, New York, NY.

Bisphosphonates are commonly prescribed for treatment of osteoporosis. Long-term use of bisphosphonates has been correlated to atypical femoral fractures (AFF). AFFs arise from fatigue damage to bone tissue that cannot be repaired due to pharmacologic treatments. Despite fatigue being the primary damage mechanism of AFFs, the effects of osteoporosis treatments on fatigue properties of cortical bone are unknown. To examine if fatigue-life differences occur in bone tissue after different pharmacologic treatments for osteoporosis, we tested bone tissue from the femurs of sheep given a metabolic acidosis diet to induce osteoporosis, followed by treatment with a selective estrogen reception modulator (raloxifene), a bisphosphonate (alendronate or zoledronate), or parathyroid hormone (teriparatide, PTH). Beams of cortical bone tissue were created and tested in four-point bending fatigue to failure. Tissues treated with alendronate had reduced fatigue life and less modulus loss at failure compared to other treatments, while tissue treated with PTH had a prolonged fatigue life. No loss of fatigue life occurred with zoledronate treatment despite its greater binding affinity and potency compared to alendronate. Tissue mineralization measured by microCT did not explain the differences seen in fatigue behavior. Increased fatigue life with PTH suggests that current treatment methods for AFF could have beneficial effects for restoring fatigue life. These results indicate that fatigue life differs with each type of osteoporosis treatment.
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http://dx.doi.org/10.1016/j.bonr.2014.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306187PMC
June 2015

Tissue-level remodeling simulations of cancellous bone capture effects of in vivo loading in a rabbit model.

J Biomech 2015 Mar 29;48(5):875-82. Epub 2014 Dec 29.

Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, NY, USA; Hospital for Special Surgery, New York, NY, USA. Electronic address:

The adaptation of cancellous bone to mechanical stimuli occurs throughout normal skeletal growth and aging, as well as in response to surgery, disease and device implantation. Previously we developed an in vivo cancellous loading model in the distal lateral femur of the rabbit. In response to daily in vivo loading for four weeks, bone mass increased, trabeculae thickened and the apparent modulus of the underlying cancellous bone increased. Here, we simulated our prior in vivo rabbit loading experiment using a cell-based tissue remodeling algorithm (Mullender et al., 1994) and compared the results to the in vivo experimental data published previously. Cancellous bone tissue was added or removed from the surface of trabeculae in regions of high and low mechanical stimulus, respectively. To examine the effect of material properties on mechanically regulated adaptation, we implemented both a homogeneous material model and a model where the relative density of tissue was lower for new and surface bone tissue compared to interior tissue. The simulations captured the changes in histomorphometric parameters and mechanical properties measured in the in vivo experiment illustrating the ability of computational simulations to predict the effect of mechanically regulated adaptation on cancellous bone histomorphometry and apparent modulus.
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http://dx.doi.org/10.1016/j.jbiomech.2014.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361179PMC
March 2015

Intermittent PTH administration and mechanical loading are anabolic for periprosthetic cancellous bone.

J Orthop Res 2015 Feb 18;33(2):163-73. Epub 2014 Nov 18.

Laboratory for Mineralized Tissue Research, Hospital for Special Surgery, 535 East 70th Street, New York, 10021, New York; Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, 44195, Ohio.

The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and µCT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro-osteoblastic/anti-adipocytic direction, and (2) controlling bone turnover by modulating the RANKL-OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, p < 0.05) and iPTH (+54%, p < 0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, p > 0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies.
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http://dx.doi.org/10.1002/jor.22748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776647PMC
February 2015

In vivo axial loading of the mouse tibia.

Methods Mol Biol 2015 ;1226:99-115

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA,

Noninvasive methods to apply controlled, cyclic loads to the living skeleton are used as anabolic procedures to stimulate new bone formation in adults and enhance bone mass accrual in growing animals. These methods are also invaluable for understanding bone signaling pathways. Our focus here is on a particular loading model: in vivo axial compression of the mouse tibia. An advantage of loading the tibia is that changes are present in both the cancellous envelope of the proximal tibia and the cortical bone of the tibial diaphysis. To load the tibia of the mouse axially in vivo, a cyclic compressive load is applied up to five times a week to a single tibia per mouse for a duration lasting from 1 day to 6 weeks. With the contralateral limb as an internal control, the anabolic response of the skeleton to mechanical stimuli can be studied in a pairwise experimental design. Here, we describe the key parameters that must be considered before beginning an in vivo mouse tibial loading experiment, including methods for in vivo strain gauging of the tibial midshaft, and then we describe general methods for loading the mouse tibia for an experiment lasting multiple days.
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http://dx.doi.org/10.1007/978-1-4939-1619-1_9DOI Listing
June 2015

A method for isolating high quality RNA from mouse cortical and cancellous bone.

Bone 2014 Nov 26;68:1-5. Epub 2014 Jul 26.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, 105 Upson Hall, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, 101 Weill Hall, Ithaca, NY 14853, USA; Research Division, Hospital for Special Surgery, 541 East 71st St., New York, NY 10021, USA. Electronic address:

The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4, a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap, while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites.
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http://dx.doi.org/10.1016/j.bone.2014.07.022DOI Listing
November 2014

Reduced tissue-level stiffness and mineralization in osteoporotic cancellous bone.

Calcif Tissue Int 2014 Aug 3;95(2):125-31. Epub 2014 Jun 3.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, 219 Upson Hall, Ithaca, NY, 14853, USA,

Osteoporosis alters bone mass and composition ultimately increasing the fragility of primarily cancellous skeletal sites; however, effects of osteoporosis on tissue-level mechanical properties of cancellous bone are unknown. Dual-energy X-ray absorptiometry (DXA) scans are the clinical standard for diagnosing osteoporosis though changes in cancellous bone mass and mineralization are difficult to separate using this method. The goal of this study was to investigate possible difference in tissue-level properties with osteoporosis as defined by donor T scores. Spine segments from Caucasian female cadavers (58-92 years) were used. A T score for each donor was calculated from DXA scans to determine osteoporotic status. Tissue-level composition and mechanical properties of vertebrae adjacent to the scan region were measured using nanoindentation and Raman spectroscopy. Based on T scores, six samples were in the Osteoporotic group (58-74 years) and four samples were in the Not Osteoporotic group (65-92 years). The indentation modulus and mineral to matrix ratio (mineral:matrix) were lower in the Osteoporotic group than the Not Osteoporotic group. Mineral:matrix ratio decreased with age (r (2) = 0.35, p = 0.05), and the indentation modulus increased with areal bone mineral density (r (2) = 0.41, p = 0.04). This study is the first to examine cancellous bone composition and mechanical properties from a fracture prone location with osteoporosis. We found differences in tissue composition and mechanical properties with osteoporosis that could contribute to increased fragility in addition to changes in trabecular architecture and bone volume.
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http://dx.doi.org/10.1007/s00223-014-9873-4DOI Listing
August 2014

Load-induced changes in bone stiffness and cancellous and cortical bone mass following tibial compression diminish with age in female mice.

J Exp Biol 2014 May 27;217(Pt 10):1775-83. Epub 2014 Feb 27.

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA Laboratory for Biomedical Mechanics and Materials, Hospital for Special Surgery, New York, NY 10021, USA.

The vertebrate skeleton is an adaptive structure that responds to mechanical stimuli by increasing bone mass under increased mechanical loads. Although experimental animal models have shown the anabolic cortical bone response to applied load decreases with age, no consensus exists regarding whether this adaptive mechanism is affected by age in cancellous bone, the tissue most impacted by age-related bone loss. We used an established murine in vivo tibial loading model to characterize the load-induced cancellous, cortical and whole-bone responses to mechanical stimuli in growing and mature female mice at 6, 10 and 16 weeks of age. The effects of applied load on tibial morphology and stiffness were determined using microcomputed tomography and in vivo bone strains measured at the medial tibial midshaft during applied loading. At all ages, 2 weeks of applied load produced larger midshaft cortical cross-sectional properties (+13-72%) and greater cancellous bone volume (+21-107%) and thicker trabeculae (+31-68%) in the proximal metaphyses of the loaded tibiae. The relative anabolic response decreased from 6 to 16 weeks of age in both the cancellous and cortical envelopes. Load-induced tibial stresses decreased more in 6-week-old mice following loading, which corresponded to increased in vivo tibial stiffness. Stiffness in the loaded tibiae of 16-week-old mice decreased despite moderately increased cortical cross-sectional geometry, suggesting load-induced changes in bone material properties. This study shows that the cancellous and cortical anabolic responses to mechanical stimuli decline with age into adulthood and that cortical cross-sectional geometry alone does not necessarily predict whole-bone functional stiffness.
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http://dx.doi.org/10.1242/jeb.085522DOI Listing
May 2014

Effect of ulnar ostectomy on intra-articular pressure mapping and contact mechanics of the congruent and incongruent canine elbow ex vivo.

Vet Surg 2014 Mar 27;43(3):339-46. Epub 2014 Jan 27.

Department of Clinical Sciences, Cornell University, Ithaca, New York.

Objective: To determine (1) the effect of elbow incongruity on contact mechanics and (2) the effect of treatment of this incongruity with 1 of 2 ulnar ostectomies in the canine elbow.

Study Design: Ex vivo biomechanical study.

Sample Population: Unpaired cadaveric canine forelimbs (n = 17).

Methods: In a servohydraulic testing frame, thin-film pressure sensors were placed into the lateral and medial compartments of the elbow. Specimens were tested in 135° of elbow joint flexion at 200 N of cyclic axial force, followed by a 20 seconds hold. Intra-articular contact area (CA), mean contact pressure (mCP) and peak contact pressure (pCP) were measured in each compartment. After radial shortening, testing was repeated and limbs randomized into proximal ulnar ostectomy with IM pin (PUO) or sequential distal ulnar ostectomy (DUO), interosseous ligament release (DUO-L), and ulnar attachment of the abductor pollicis longus muscle and interosseous membrane release (DUO-ML). Paired t-tests were used to compare each treatment to baseline values. Differences between treatment groups were evaluated with a mixed model with random effect to adjust for the clustering of limbs within dog. P < .05 was considered significant.

Results: Radial shortening resulted in shift of mCP and pCP from the lateral to the medial compartment. The PUO group resulted in normalization of medial compartment mCP and decrease of pCP, whereas in the DUO group return to baseline was achieved only after DUO-ML.

Conclusion: PUO is effective in unloading medial compartment pCP in an incongruent joint.
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http://dx.doi.org/10.1111/j.1532-950X.2014.12137.xDOI Listing
March 2014
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