Papers by Marnie Saunders
Medical Engineering & Physics, Oct 1, 2016
Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. ... more Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. This is normally a paired process, although it can be disrupted by changes in mechanical load. One theory is that osteocytes play a key role in the cellular regulation of this process. Mechanotransduction studies, which investigate how cells convert mechanical stimuli into biophysical effects and cellular activity, offer one way to investigate this theory. Mechanotransduction work is commonly done by applying an isolated mechanical load to cells grown in vitro, and quantifying the response. While in vitro work does not fully replicate the natural environment, it does allow the study of isolated factors. In this study, a mechanical loading platform was designed, fabricated, and characterized for bone mechanotransduction studies. This platform was designed to tent cell-seeded substrates from below, loading using out of plane distension. This introduced a nonuniform strain profile, enabling the study of cells cultured under identical conditions and variable strains as a function of substrate location. An alphanumerically gridded polydimethylsiloxane well substrate was designed and fabricated for cellular loading experiments. Following initial characterization, a study was run to quantify the cellular activity of osteocyte-like MLO-Y4 cells as a function of strain field. The results indicated that regions with lower strains led to an increase in cellular activity while higher strains led to a reduction in cellular activity. This demonstrated that cells could be exposed to mechanically-induced microdamage using the microloading platform.
Medical Engineering & Physics, Oct 1, 2016
Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. ... more Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. This is normally a paired process, although it can be disrupted by changes in mechanical load. One theory is that osteocytes play a key role in the cellular regulation of this process. Mechanotransduction studies, which investigate how cells convert mechanical stimuli into biophysical effects and cellular activity, offer one way to investigate this theory. Mechanotransduction work is commonly done by applying an isolated mechanical load to cells grown in vitro, and quantifying the response. While in vitro work does not fully replicate the natural environment, it does allow the study of isolated factors. In this study, a mechanical loading platform was designed, fabricated, and characterized for bone mechanotransduction studies. This platform was designed to tent cell-seeded substrates from below, loading using out of plane distension. This introduced a nonuniform strain profile, enabling the study of cells cultured under identical conditions and variable strains as a function of substrate location. An alphanumerically gridded polydimethylsiloxane well substrate was designed and fabricated for cellular loading experiments. Following initial characterization, a study was run to quantify the cellular activity of osteocyte-like MLO-Y4 cells as a function of strain field. The results indicated that regions with lower strains led to an increase in cellular activity while higher strains led to a reduction in cellular activity. This demonstrated that cells could be exposed to mechanically-induced microdamage using the microloading platform.
Synthesis Lectures on Biomedical Engineering, Jan 5, 2015
Medical Engineering & Physics, Oct 1, 2016
Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. ... more Bone remodeling is a process in which bone is resorbed by osteoclasts and formed by osteoblasts. This is normally a paired process, although it can be disrupted by changes in mechanical load. One theory is that osteocytes play a key role in the cellular regulation of this process. Mechanotransduction studies, which investigate how cells convert mechanical stimuli into biophysical effects and cellular activity, offer one way to investigate this theory. Mechanotransduction work is commonly done by applying an isolated mechanical load to cells grown in vitro, and quantifying the response. While in vitro work does not fully replicate the natural environment, it does allow the study of isolated factors. In this study, a mechanical loading platform was designed, fabricated, and characterized for bone mechanotransduction studies. This platform was designed to tent cell-seeded substrates from below, loading using out of plane distension. This introduced a nonuniform strain profile, enabling the study of cells cultured under identical conditions and variable strains as a function of substrate location. An alphanumerically gridded polydimethylsiloxane well substrate was designed and fabricated for cellular loading experiments. Following initial characterization, a study was run to quantify the cellular activity of osteocyte-like MLO-Y4 cells as a function of strain field. The results indicated that regions with lower strains led to an increase in cellular activity while higher strains led to a reduction in cellular activity. This demonstrated that cells could be exposed to mechanically-induced microdamage using the microloading platform.
Medical Engineering & Physics, Jun 1, 2005
The current method for graft fixation in bone tendon-bone anterior cruciate ligament (ACL) recons... more The current method for graft fixation in bone tendon-bone anterior cruciate ligament (ACL) reconstruction is the interference screw. Although this method of fixation provides for adequate graft fixation with respect to strength, intraoperative placement is difficult and the failure rate is high. To address these concerns, we have designed and fabricated prototype expansion anchors that could be expanded to anchor the graft in the bone tunnel. As a first step in assessing the validity of this concept, in the current work, we demonstrate that these systems are of comparable fixation strength (biomechanical pullout testing) to the standard interference screw, are smaller at the time of insertion and thus provide for increased visibility and ease of placement. The increased visibility should result in better placement and reduced failure rates. The increased ease of placement should result in significant savings in decreased OR time.
Journal of Biomimetics, Biomaterials, and Tissue Engineering, Dec 1, 2012
In the body, osteocytes reside in lacunae, lenticular shaped cavities within mineralized bone. Th... more In the body, osteocytes reside in lacunae, lenticular shaped cavities within mineralized bone. These cells are linked to each other and surface-residing osteoblasts via physical channels known as gap junctions. It has been suggested that osteocytes sense mechanical load applied to bone and relay that signal to osteoclasts and osteoblasts. Current in vitro and in vivo models of mechanotransduction face temporal and spatial barriers. Recent advances in polydimethylsiloxane (PDMS) based microfabrication techniques may be able to overcome some of these hurdles. However, before the bone research field can effectively utilize microsystems techniques, fundamental groundwork must be completed. This study characterized the behaviour of osteocytes on PDMS coated with collagen type I (CTI) and provides the framework for bone cell mechanotransduction studies using microsystems. The goal was to determine whether osteocytes were adversely affected by the substrate material by comparing their behaviour to a standard glass substrate. In addition, optimal culture conditions and time points for growing osteocytes on PDMS substrates were determined. Results of this study suggested that use of PDMS does not adversely affect osteocyte behaviour. Furthermore, the results demonstrated that osteocytes should be cultured for no less than 72 hours prior to experimentation to allow the establishment and maintenance of phenotypic characteristics. These results completed essential groundwork necessary for further studies regarding osteocytes in microsystems modelling utilizing PDMS.
Atlas of the oral and maxillofacial surgery clinics of North America, Sep 1, 2008
Review of bone mechanics To begin to understand the effects of mechanical forces on bone, such as... more Review of bone mechanics To begin to understand the effects of mechanical forces on bone, such as those that occur during distraction osteogenesis (DO), it is necessary to consider the makeup of the bone and the features that enable it to respond to mechanical loading. Bone is a dynamic organ and, as such, it is in a constant state of change as affected by factors including nutrition, disease, and mechanical environment. Whether these changes alter the quantity or quality of the bone depends upon considerations such as their severity and duration. For practical purposes, bone can be considered a composite material. That is, in addition to water, bone is comprised of organic materials and inorganic matrix. While the organic material, such as collagen, gives bone its resilience and tensile strength, the mineralized matrix gives bone its compressive strength. The mineralized matrix also serves as the structural housing for the osteocytes. The osteocytes are the most abundant bone cells in the body and before becoming encased in their own matrix were bone-forming osteoblasts. These osteocytes reside in lenticular cavities called lacunae. In turn, the lacunae are connected to each other by way of a network of interconnecting channels called canaliculi. While the osteocyte bodies reside in the lacunae, their long, slender processes reside in the canaliculi. Interstitial fluid bathes the lacuno-canalicular network providing for nutrient exchange. This network may also play an important role in transducing mechanical signals. The osteocytes are able to physically link with each other through this porous environment and, many believe, amplify the mechanosensory response at the cellular level such that, among other functions, minimal loading can maintain bone integrity. These bone cells not only link and form networks with each other, but they also maintain contact with the surface-residing osteoblasts. It is hypothesized that the osteocytes act as strain gauges sensing mechanical deformation and communicate this signal to bone-forming osteoblasts that coordinate their activity with boneresorbing osteoclasts, possibly by way of soluble signaling (Fig. 1). Two important bone types emerge, distinguishable largely by the level of porosity. Cortical (or compact) bone, comprising the hollow shafts of long bones and the thin cortices surrounding trabecular bone, typically has a porosity on the order of 5% to 10%; whereas cancellous (or spongy or trabecular) bone forming the bodies of flat and cuboidal bones typically has a porosity on the order of 75% to 95%. With the interstitial fluid running throughout these porous bone networks, bone is characterized not only by its porous mineral matrix, but also its fluid constituents, giving rise to the distinction that bone is also referred to as a poroelastic material. When a bone is under mechanical load, its performance is governed by its size, shape, and the material that comprises it. Collectively, these features determine the mechanical properties
Bone reports, Jun 1, 2018
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a dramatic disintegration of the jaw t... more Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a dramatic disintegration of the jaw that affects patients treated with bisphosphonates (BPs) for diseases characterized by bone loss. These diseases are often metastasizing cancers (like multiple myeloma, breast cancer and prostate cancer (Aragon-Ching et al., 2009)) as well as osteoporosis. BRONJ is incompletely understood, although it is believed to arise from a defect in bone remodeling-the intricate process by which sensory osteocytes signal to osteoclasts and osteoblasts to resorb and form bone in response to stimuli. Further, tooth extraction and infection have been overwhelmingly linked to BRONJ (Ikebe, 2013). Because bone cells are highly networked, the importance of multicellular interactions and mechanotransduction during the onset of these risk factors cannot be overstated. As such, this perspective addresses current research on the effects of BPs, mechanical load and inflammation on bone remodeling and on development of BRONJ. Our investigation has led us to conclude that improved in vitro systems capable of adequately recapitulating multicellular communication and incorporating effects of osteocyte mechanosensing on bone resorption and formation are needed to elucidate the mechanism(s) by which BRONJ ensues.
PubMed, Mar 1, 2001
Breast cancer progresses toward increasingly malignant behavior in tumorigenic and metastatic sta... more Breast cancer progresses toward increasingly malignant behavior in tumorigenic and metastatic stages. In the series of events in the metastatic stage, tumor cells leave the primary tumor in breast and travel to distant sites where they establish secondary tumors, or metastases. In this report, we demonstrate that cell-cell communication via gap junctions is restored in the metastatic human breast carcinoma cell line MDA-MB-435 when it is transfected with breast metastasis suppressor 1 (BRMS1) cDNA. Furthermore, the expression profile of connexins (Cxs), the protein subunits of gap junctions, changes. Specifically, the expression of BRMS1 in MDA-MB-435 cells increases Cx43 expression and reduces Cx32 expression, resulting in a gap junction phenotype more similar to normal breast tissue. Taken together, these results suggest that gap junctional communication and the Cx expression profile may contribute to the metastatic potential of these breast cancer cells.
Springer eBooks, 2015
Lectures in Biomedical Engineering will be comprised of 75-to 150-page publications on advanced a... more Lectures in Biomedical Engineering will be comprised of 75-to 150-page publications on advanced and state-of-the-art topics that span the field of biomedical engineering, from the atom and molecule to large diagnostic equipment. Each lecture covers, for that topic, the fundamental principles in a unified manner, develops underlying concepts needed for sequential material, and progresses to more advanced topics. Computer software and multimedia, when appropriate and available, are included for simulation, computation, visualization and design. The authors selected to write the lectures are leading experts on the subject who have extensive background in theory, application and design. The series is designed to meet the demands of the 21st century technology and the rapid advancements in the all-encompassing field of biomedical engineering that includes biochemical processes, biomaterials, biomechanics, bioinstrumentation, physiological modeling, biosignal processing, bioinformatics, biocomplexity, medical and molecular imaging, rehabilitation engineering, biomimetic nano-electrokinetics, biosensors, biotechnology, clinical engineering, biomedical devices, drug discovery and delivery systems, tissue engineering, proteomics, functional genomics, and molecular and cellular engineering.
Conference proceedings of the Society for Experimental Mechanics, Jul 7, 2014
Mechanosensitive cells, such as osteocytes in bone, are capable of translating mechanical stimuli... more Mechanosensitive cells, such as osteocytes in bone, are capable of translating mechanical stimuli into cellular responses. This phenomenon can be widely found in cells throughout the body, and yet little is known about the mechanisms and pathways by which this occurs. Research in this field has focused on creating in vitro models that better reflect the in vivo environment in order to study these mechanisms and pathways. Where many variations on these systems exists, one major goal in improving these models is to use fewer cells in order to observe the response of specific cells and possibly more meaningful data. Using an uniaxial loading device, a substrate with cells seeded onto it can be mechanically strained and the response of these fewer cells can be quantified. In this study, two substrates of varying geometry are proposed that allow for a gradient of mechanical strains to be applied to cultured cells. These designs are characterized and compared using both physical and simulated testing. Utilizing designs, such as the ones used for these substrates, enables the effects of a wide range of mechanical strains on cells to be observed and studied under identical culture and loading environments.
Mathematical biosciences, Apr 1, 2017
Bone remodeling is an elegantly orchestrated process by which osteocytes, osteoblasts and osteocl... more Bone remodeling is an elegantly orchestrated process by which osteocytes, osteoblasts and osteoclasts function as a syncytium to maintain or modify bone. On the microscopic level, bone consists of cells that create, destroy and monitor the bone matrix. These cells interact in a coordinated manner to maintain a tightly regulated homeostasis. It is this regulation that is responsible for the observed increase in bone gain in the dominant arm of a tennis player and the observed increase in bone loss associated with spaceflight and osteoporosis. The manner in which these cells interact to bring about a change in bone quality and quantity has yet to be fully elucidated. But efforts to understand the multicellular complexity can ultimately lead to eradication of metabolic bone diseases such as osteoporosis and improved implant longevity. Experimentally validated mathematical models that simulate functional activity and offer eventual predictive capabilities offer tremendous potential in understanding multicellular bone remodeling. Here we undertake the initial challenge to develop a mathematical model of bone formation validated with in vitro data obtained from osteoblastic bone cells induced to mineralize and quantified at 26 days of culture. A cellular automata model was constructed to simulate the in vitro characterization. Permutation tests were performed to compare the distribution of the mineralization in the cultures and the distribution of the mineralization in the mathematical models. The results of the permutation test show the distribution of mineralization from the characterization and mathematical model come from the same probability distribution, therefore validating the cellular automata model.
Synthesis Lectures on Biomedical Engineering, Jan 5, 2015
Lectures in Biomedical Engineering will be comprised of 75-to 150-page publications on advanced a... more Lectures in Biomedical Engineering will be comprised of 75-to 150-page publications on advanced and state-of-the-art topics that span the field of biomedical engineering, from the atom and molecule to large diagnostic equipment. Each lecture covers, for that topic, the fundamental principles in a unified manner, develops underlying concepts needed for sequential material, and progresses to more advanced topics. Computer software and multimedia, when appropriate and available, are included for simulation, computation, visualization and design. The authors selected to write the lectures are leading experts on the subject who have extensive background in theory, application and design. The series is designed to meet the demands of the 21st century technology and the rapid advancements in the all-encompassing field of biomedical engineering that includes biochemical processes, biomaterials, biomechanics, bioinstrumentation, physiological modeling, biosignal processing, bioinformatics, biocomplexity, medical and molecular imaging, rehabilitation engineering, biomimetic nano-electrokinetics, biosensors, biotechnology, clinical engineering, biomedical devices, drug discovery and delivery systems, tissue engineering, proteomics, functional genomics, and molecular and cellular engineering.
American Journal of Sports Medicine, Nov 1, 2000
Graft-tunnel mismatch during arthroscopically assisted anterior cruciate ligament reconstruction ... more Graft-tunnel mismatch during arthroscopically assisted anterior cruciate ligament reconstruction using the central-third patellar tendon results in less than 20 mm of bone plug remaining in the tibial tunnel. We decided to evaluate the strength of bone plug fixation using interference fit screws that were less than 20 mm in length. Biomechanical testing was performed on 48 porcine hindquarters using 9-mm diameter interference fit screws that measured 12.5, 15, and 20 mm in length. No significant difference was noted between the different-length screws for insertion torque, divergence, stiffness, displacement, or load to failure. We believe, therefore, that comparable graft fixation can be achieved in the tibial tunnel using 9-mm diameter interference fit screws that are less than 20 mm long, and that these shorter screws may be useful in cases of graft-tunnel mismatch.
Uploads
Papers by Marnie Saunders