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IN THIS ISSUE


Editorial

J Biomech Eng. 2017;139(2):020201-020201-1. doi:10.1115/1.4035641.
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JBME continues to thrive. Over 520 manuscripts were received in 2016, and our acceptance rate was 15%. We continue to streamline all the stages of the review and publication process, with time to first decision now average 1.8 months and immediate online availability of accepted manuscripts. The tremendous effort of the Associate Editors (AEs) on this front, and on all the aspects of the journal operation, is acknowledged here with our profound thanks—JBME would not work without them! We especially thank the retiring AE Frank Loth and welcome our new AE Ching-Long Lin.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):020202-020202-3. doi:10.1115/1.4035652.
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Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):020203-020203-1. doi:10.1115/1.4035653.
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Each year, the Editors-in-Chief and the editorial board members of the ASME Journal of Biomechanical Engineering identify the most meritorious papers published in the journal in the previous calendar year, and an external committee selects the top paper of the year from that list. The authors of this paper are the recipients of the Richard Skalak Award, named after an early leader within the ASME Bioengineering community. Richard Skalak (1923–1997) played a leadership role in the formative decades of the discipline of biomedical engineering through his technical contributions in biomechanics, his educational influence on students, and his service to many developing societies and journals. Richard Skalak believed in several central approaches to bioengineering and several central values in working with people. In bioengineering, these were: (1) the useful combination of mathematical and computational modeling with experimental results, to better inform the new biological understanding that is derived and (2) the inclusion of both microscale and macroscale phenomena in understanding complex biological systems. In terms of mentoring students and collaborating with colleagues, these were: (1) share ideas freely, (2) listen to ideas of others and integrate the best into new developments, and (3) show tolerance and respect for others at all times. These tenets help guide us as a community and as a journal, and we are honored by the opportunity to contribute to Richard Skalak's legacy by giving an award bearing his name. The Editors thank the 2016 Skalak Award committee: Ross Ethier (chair), Gerard Ateshian, Alison Marsden, David Merryman, and Lori Setton.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):020204-020204-1. doi:10.1115/1.4035680.
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As part of the Annual Special Issue, the JBME Associate Editors selected the top papers published in the journal during 2016. Those Editors' Choice papers, listed below in chronological order, exemplified both the high quality and the breadth of papers published in the journal. Congratulations to these authors and to all the authors whose work appeared in the JBME over the past year!

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):020205-020205-2. doi:10.1115/1.4035645.
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Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):020206-020206-1. doi:10.1115/1.4035642.
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The Journal of Biomechanical Engineering has been in continuous production since 1977. To honor papers published at least 30 years ago that have had a long-lasting impact on the field, we present a paper starting from the early years of the journal that has had lasting impact, as assessed by metrics such as the total number of citations accumulated since publication. Looking at the papers from the journal's first 5 years, we are pleased to present the following paper as this year's Legacy Paper:

Commentary by Dr. Valentin Fuster

Research Papers

J Biomech Eng. 2017;139(2):021001-021001-11. doi:10.1115/1.4034430.

This review was prepared for the American Society of Mechanical Engineers Lissner Medal. It specifically discusses research performed in the Orthopaedic Biomechanics Laboratories on pediatric cranial bone mechanics and patterns of fracture in collaboration with the Forensic Anthropology Laboratory at Michigan State University. Cranial fractures are often an important element seen by forensic anthropologists during the investigation of pediatric trauma cases litigated in courts. While forensic anthropologists and forensic biomechanists are often called on to testify in these cases, there is little basic science developed in support of their testimony. The following is a review of studies conducted in the above laboratories and supported by the National Institute of Justice to begin an understanding of the mechanics and patterns of pediatric cranial bone fracture. With the lack of human pediatric specimens, the studies utilize an immature porcine model. Because much case evidence involves cranial bone fracture, the studies described below focus on determining input loading based on the resultant bone fracture pattern. The studies involve impact to the parietal bone, the most often fractured cranial bone, and begin with experiments on entrapped heads, progressing to those involving free-falling heads. The studies involve head drops onto different types and shapes of interfaces with variations of impact energy. The studies show linear fractures initiating from sutural boundaries, away from the impact site, for flat surface impacts, in contrast to depressed fractures for more focal impacts. The results have been incorporated into a “Fracture Printing Interface (FPI),” using machine learning and pattern recognition algorithms. The interface has been used to help interpret mechanisms of injury in pediatric death cases collected from medical examiner offices. The ultimate aim of this program of study is to develop a “Human Fracture Printing Interface” that can be used by forensic investigators in determining mechanisms of pediatric cranial bone fracture.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021002-021002-10. doi:10.1115/1.4034932.

Cerebral aneurysms are pathological focal evaginations of the arterial wall at and around the junctions of the circle of Willis. Their tenuous walls predispose aneurysms to leak or rupture leading to hemorrhagic strokes with high morbidity and mortality rates. The endovascular treatment of cerebral aneurysms currently includes the implantation of fine-mesh stents, called flow diverters, within the parent artery bearing the aneurysm. By mitigating flow velocities within the aneurysmal sac, the devices preferentially induce thrombus formation in the aneurysm within hours to days. In response to the foreign implant, an endothelialized arterial layer covers the luminal surface of the device over a period of days to months. Organization of the intraneurysmal thrombus leads to resorption and shrinkage of the aneurysm wall and contents, eventually leading to beneficial remodeling of the pathological site to a near-physiological state. The devices' primary function of reducing flow activity within aneurysms is corollary to their mesh structure. Complete specification of the device mesh structure, or alternately device permeability, necessarily involves the quantification of two variables commonly used to characterize porous media—mesh porosity and mesh pore density. We evaluated the flow alteration induced by five commercial neurovascular devices of varying porosity and pore density (stents: Neuroform, Enterprise, and LVIS; flow diverters: Pipeline and FRED) in an idealized sidewall aneurysm model. As can be expected in such a model, all devices substantially reduced intraneurysmal kinetic energy as compared to the nonstented case with the coarse-mesh stents inducing a 65–80% reduction whereas the fine-mesh flow diverters induced a near-complete flow stagnation (∼98% reduction). We also note a trend toward greater device efficacy (lower intraneurysmal flow) with decreasing device porosity and increasing device pore density. Several such flow studies have been and are being conducted in idealized as well as patient-derived geometries with the overarching goals of improving device design, facilitating treatment planning (what is the optimal device for a specific aneurysm), and predicting treatment outcome (will a specific aneurysm treated with a specific device successfully occlude over the long term). While the results are generally encouraging, there is poor standardization of study variables between different research groups, and any consensus will only be reached after standardized studies are conducted on collectively large datasets. Biochemical variables may have to be incorporated into these studies to maximize predictive values.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021003-021003-13. doi:10.1115/1.4035647.

Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the body's load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021004-021004-10. doi:10.1115/1.4034991.

Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021005-021005-9. doi:10.1115/1.4035121.

Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.

Topics: Tumors , Cancer , Stress
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021006-021006-16. doi:10.1115/1.4035350.

Biophysical stimuli presented to cells via microenvironmental properties (e.g., alignment and stiffness) or external forces have a significant impact on cell function and behavior. Recently, the cell nucleus has been identified as a mechanosensitive organelle that contributes to the perception and response to mechanical stimuli. However, the specific mechanotransduction mechanisms that mediate these effects have not been clearly established. Here, we offer a comprehensive review of the evidence supporting (and refuting) three hypothetical nuclear mechanotransduction mechanisms: physical reorganization of chromatin, signaling at the nuclear envelope, and altered cytoskeletal structure/tension due to nuclear remodeling. Our goal is to provide a reference detailing the progress that has been made and the areas that still require investigation regarding the role of nuclear mechanotransduction in cell biology. Additionally, we will briefly discuss the role that mathematical models of cell mechanics can play in testing these hypotheses and in elucidating how biophysical stimulation of the nucleus drives changes in cell behavior. While force-induced alterations in signaling pathways involving lamina-associated polypeptides (LAPs) (e.g., emerin and histone deacetylase 3 (HDAC3)) and transcription factors (TFs) located at the nuclear envelope currently appear to be the most clearly supported mechanism of nuclear mechanotransduction, additional work is required to examine this process in detail and to more fully test alternative mechanisms. The combination of sophisticated experimental techniques and advanced mathematical models is necessary to enhance our understanding of the role of the nucleus in the mechanotransduction processes driving numerous critical cell functions.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021007-021007-13. doi:10.1115/1.4035557.

The function of the heart valve interstitial cells (VICs) is intimately connected to heart valve tissue remodeling and repair, as well as the onset and progression of valvular pathological processes. There is yet only very limited knowledge and extant models for the complex three-dimensional VIC internal stress-bearing structures, the associated cell-level biomechanical behaviors, and how they change under varying activation levels. Importantly, VICs are known to exist and function within the highly dynamic valve tissue environment, including very high physiological loading rates. Yet we have no knowledge on how these factors affect VIC function. To this end, we extended our previous VIC computational continuum mechanics model (Sakamoto, et al., 2016, “On Intrinsic Stress Fiber Contractile Forces in Semilunar Heart Valve Interstitial Cells Using a Continuum Mixture Model,” J. Mech. Behav. Biomed. Mater., 54(244–258)). to incorporate realistic stress-fiber geometries, force-length relations (Hill model for active contraction), explicit α-smooth muscle actin (α-SMA) and F-actin expression levels, and strain rate. Novel micro-indentation measurements were then performed using cytochalasin D (CytoD), variable KCl molar concentrations, both alone and with transforming growth factor β1 (TGF-β1) (which emulates certain valvular pathological processes) to explore how α-SMA and F-actin expression levels influenced stress fiber responses under quasi-static and physiological loading rates. Simulation results indicated that both F-actin and α-SMA contributed substantially to stress fiber force generation, with the highest activation state (90 mM KCL + TGF-β1) inducing the largest α-SMA levels and associated force generation. Validation was performed by comparisons to traction force microscopy studies, which showed very good agreement. Interestingly, only in the highest activation state was strain rate sensitivity observed, which was captured successfully in the simulations. These unique findings demonstrated that only VICs with high levels of αSMA expression exhibited significant viscoelastic effects. Implications of this study include greater insight into the functional role of α-SMA and F-actin in VIC stress fiber function, and the potential for strain rate-dependent effects in pathological states where high levels of α-SMA occur, which appear to be unique to the valvular cellular in vivo microenvironment.

Topics: Fibers , Stress , Simulation
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021008-021008-13. doi:10.1115/1.4035120.

We review recent advances in multiscale modeling of the biomechanical characteristics of red blood cells (RBCs) in hematological diseases, and their relevance to the structure and dynamics of defective RBCs. We highlight examples of successful simulations of blood disorders including malaria and other hereditary disorders, such as sickle-cell anemia, spherocytosis, and elliptocytosis.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021009-021009-11. doi:10.1115/1.4035436.

The translation of many tissue engineering/regenerative medicine (TE/RM) therapies that demonstrate promise in vitro are delayed or abandoned due to reduced and inconsistent efficacy when implemented in more complex and clinically relevant preclinical in vivo models. Determining mechanistic reasons for impaired treatment efficacy is challenging after a regenerative therapy is implanted due to technical limitations in longitudinally measuring the progression of key environmental cues in vivo. The ability to acquire real-time measurements of environmental parameters of interest including strain, pressure, pH, temperature, oxygen tension, and specific biomarkers within the regenerative niche in situ would significantly enhance the information available to tissue engineers to monitor and evaluate mechanisms of functional healing or lack thereof. Continued advancements in material and fabrication technologies utilized by microelectromechanical systems (MEMSs) and the unique physical characteristics of passive magnetoelastic sensor platforms have created an opportunity to implant small, flexible, low-power sensors into preclinical in vivo models, and quantitatively measure environmental cues throughout healing. In this perspective article, we discuss the need for longitudinal measurements in TE/RM research, technical progress in MEMS and magnetoelastic approaches to implantable sensors, the potential application of implantable sensors to benefit preclinical TE/RM research, and the future directions of collaborative efforts at the intersection of these two important fields.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;139(2):021010-021010-7. doi:10.1115/1.4035644.

Diarthrodial joint function is mediated by a complex interaction between bones, ligaments, capsules, articular cartilage, and muscles. To gain a better understanding of injury mechanisms and to improve surgical procedures, an improved understanding of the structure and function of diarthrodial joints needs to be obtained. Thus, robotic testing systems have been developed to measure the resulting kinematics of diarthrodial joints as well as the in situ forces in ligaments and their replacement grafts in response to external loading conditions. These six degrees-of-freedom (DOF) testing systems can be controlled in either position or force modes to simulate physiological loading conditions or clinical exams. Recent advances allow kinematic, in situ force, and strain data to be measured continuously throughout the range of joint motion using velocity-impedance control, and in vivo kinematic data to be reproduced on cadaveric specimens to determine in situ forces during physiologic motions. The principle of superposition can also be used to determine the in situ forces carried by capsular tissue in the longitudinal direction after separation from the rest of the capsule as well as the interaction forces with the surrounding tissue. Finally, robotic testing systems can be used to simulate soft tissue injury mechanisms, and computational models can be validated using the kinematic and force data to help predict in vivo stresses and strains present in these tissues. The goal of these analyses is to help improve surgical repair procedures and postoperative rehabilitation protocols. In the future, more information is needed regarding the complex in vivo loads applied to diarthrodial joints during clinical exams and activities of daily living to serve as input to the robotic testing systems. Improving the capability to accurately reproduce in vivo kinematics with robotic testing systems should also be examined.

Commentary by Dr. Valentin Fuster

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