J Biomech Eng. 2015;137(2):020201-020201-1. doi:10.1115/1.4029297.

In the last year, Journal of Biomechanical Engineering (JBME) has continued to thrive, with increasing submissions and decreasing review times. The number of manuscripts submitted each year remains on the rise and our acceptance rate continues to become more selective, while our review times continue to improve. The continued selectivity and improved review speed is a credit to all of our Associate Editors and reviewers. In the last year, we have added three new Associate Editors which has helped to keep up with the increased submissions and reduced review time. We are grateful to all of them for their service and dedication to quality science and this journal!

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020202-020202-3. doi:10.1115/1.4029233.
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020203-020203-2. doi:10.1115/1.4029296.
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020204-020204-1. doi:10.1115/1.4029299.

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. Following on last year's legacy paper, “Biphasic Creep and Stress Relaxation of Articular Cartilage in Compression: Theory and Experiments,” by V. C. Mow, S. C. Kuei, W. M. Lai and C. G. Armstrong (JBME102(1):73, 1980), we present this year's choice for the Legacy paper:

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020205-020205-1. doi:10.1115/1.4029298.

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 micro- 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 2014 Skalak Award committee: Jimmy Moore (chair), Ross Ethier, Michael Sacks, and Jennifer Wayne.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020206-020206-1. doi:10.1115/1.4029300.

As part of the Annual Special Issue, the Journal of Biomechanical Engineering (JBME) Associate Editors selected the top papers published in the journal during 2014. 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 authors whose work appeared in JBME over the past year!

Commentary by Dr. Valentin Fuster

Technical Forum

J Biomech Eng. 2015;137(2):020901-020901-14. doi:10.1115/1.4028825.

As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020902-020902-6. doi:10.1115/1.4029551.

Osteogenic lineage commitment is often evaluated by analyzing gene expression. However, many genes are transiently expressed during differentiation. The availability of genes for expression is influenced by epigenetic state, which affects the heterochromatin structure. DNA methylation, a form of epigenetic regulation, is stable and heritable. Therefore, analyzing methylation status may be less temporally dependent and more informative for evaluating lineage commitment. Here we analyzed the effect of mechanical stimulation on osteogenic differentiation by applying fluid shear stress for 24 hr to osteocytes and then applying the osteocyte-conditioned medium (CM) to progenitor cells. We analyzed gene expression and changes in DNA methylation after 24 hr of exposure to the CM using quantitative real-time polymerase chain reaction and bisulfite sequencing. With fluid shear stress stimulation, methylation decreased for both adipogenic and osteogenic markers, which typically increases availability of genes for expression. After only 24 hr of exposure to CM, we also observed increases in expression of later osteogenic markers that are typically observed to increase after seven days or more with biochemical induction. However, we observed a decrease or no change in early osteogenic markers and decreases in adipogenic gene expression. Treatment of a demethylating agent produced an increase in all genes. The results indicate that fluid shear stress stimulation rapidly promotes the availability of genes for expression, but also specifically increases gene expression of later osteogenic markers.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020903-020903-6. doi:10.1115/1.4029115.

Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder characterized by the formation of calcific nodules (CN) on the valve. In vitro assays studying the formation of these nodules were developed and have led to many significant mechanistic findings; however, the biophysical properties of CNs have not been clearly defined. A thorough analysis of dystrophic and osteogenic nodules utilizing scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), and atomic force microscopy (AFM) was conducted to describe calcific nodule properties and provide a link between calcific nodule morphogenesis in vitro and in vivo. Unique nodule properties were observed for dystrophic and osteogenic nodules, highlighting the distinct mechanisms occurring in valvular calcification.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020904-020904-12. doi:10.1115/1.4029258.

Musculoskeletal (MS) models should be able to integrate patient-specific MS architecture and undergo thorough validation prior to their introduction into clinical practice. We present a methodology to develop subject-specific models able to simultaneously predict muscle, ligament, and knee joint contact forces along with secondary knee kinematics. The MS architecture of a generic cadaver-based model was scaled using an advanced morphing technique to the subject-specific morphology of a patient implanted with an instrumented total knee arthroplasty (TKA) available in the fifth “grand challenge competition to predict in vivo knee loads” dataset. We implemented two separate knee models, one employing traditional hinge constraints, which was solved using an inverse dynamics technique, and another one using an 11-degree-of-freedom (DOF) representation of the tibiofemoral (TF) and patellofemoral (PF) joints, which was solved using a combined inverse dynamic and quasi-static analysis, called force-dependent kinematics (FDK). TF joint forces for one gait and one right-turn trial and secondary knee kinematics for one unloaded leg-swing trial were predicted and evaluated using experimental data available in the grand challenge dataset. Total compressive TF contact forces were predicted by both hinge and FDK knee models with a root-mean-square error (RMSE) and a coefficient of determination (R2) smaller than 0.3 body weight (BW) and equal to 0.9 in the gait trial simulation and smaller than 0.4 BW and larger than 0.8 in the right-turn trial simulation, respectively. Total, medial, and lateral TF joint contact force predictions were highly similar, regardless of the type of knee model used. Medial (respectively lateral) TF forces were over- (respectively, under-) predicted with a magnitude error of M < 0.2 (respectively > −0.4) in the gait trial, and under- (respectively, over-) predicted with a magnitude error of M > −0.4 (respectively < 0.3) in the right-turn trial. Secondary knee kinematics from the unloaded leg-swing trial were overall better approximated using the FDK model (average Sprague and Geers' combined error C = 0.06) than when using a hinged knee model (C = 0.34). The proposed modeling approach allows detailed subject-specific scaling and personalization and does not contain any nonphysiological parameters. This modeling framework has potential applications in aiding the clinical decision-making in orthopedics procedures and as a tool for virtual implant design.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020905-020905-24. doi:10.1115/1.4029304.

Computational modeling and simulation of neuromusculoskeletal (NMS) systems enables researchers and clinicians to study the complex dynamics underlying human and animal movement. NMS models use equations derived from physical laws and biology to help solve challenging real-world problems, from designing prosthetics that maximize running speed to developing exoskeletal devices that enable walking after a stroke. NMS modeling and simulation has proliferated in the biomechanics research community over the past 25 years, but the lack of verification and validation standards remains a major barrier to wider adoption and impact. The goal of this paper is to establish practical guidelines for verification and validation of NMS models and simulations that researchers, clinicians, reviewers, and others can adopt to evaluate the accuracy and credibility of modeling studies. In particular, we review a general process for verification and validation applied to NMS models and simulations, including careful formulation of a research question and methods, traditional verification and validation steps, and documentation and sharing of results for use and testing by other researchers. Modeling the NMS system and simulating its motion involves methods to represent neural control, musculoskeletal geometry, muscle–tendon dynamics, contact forces, and multibody dynamics. For each of these components, we review modeling choices and software verification guidelines; discuss variability, errors, uncertainty, and sensitivity relationships; and provide recommendations for verification and validation by comparing experimental data and testing robustness. We present a series of case studies to illustrate key principles. In closing, we discuss challenges the community must overcome to ensure that modeling and simulation are successfully used to solve the broad spectrum of problems that limit human mobility.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020906-020906-19. doi:10.1115/1.4029278.

Anterior cruciate ligament (ACL) injury is a common and potentially catastrophic knee joint injury, afflicting a large number of males and particularly females annually. Apart from the obvious acute injury events, it also presents with significant long-term morbidities, in which osteoarthritis (OA) is a frequent and debilitative outcome. With these facts in mind, a vast amount of research has been undertaken over the past five decades geared toward characterizing the structural and mechanical behaviors of the native ACL tissue under various external load applications. While these efforts have afforded important insights, both in terms of understanding treating and rehabilitating ACL injuries; injury rates, their well-established sex-based disparity, and long-term sequelae have endured. In reviewing the expanse of literature conducted to date in this area, this paper identifies important knowledge gaps that contribute directly to this long-standing clinical dilemma. In particular, the following limitations remain. First, minimal data exist that accurately describe native ACL mechanics under the extreme loading rates synonymous with actual injury. Second, current ACL mechanical data are typically derived from isolated and oversimplified strain estimates that fail to adequately capture the true 3D mechanical response of this anatomically complex structure. Third, graft tissues commonly chosen to reconstruct the ruptured ACL are mechanically suboptimal, being overdesigned for stiffness compared to the native tissue. The net result is an increased risk of rerupture and a modified and potentially hazardous habitual joint contact profile. These major limitations appear to warrant explicit research attention moving forward in order to successfully maintain/restore optimal knee joint function and long-term life quality in a large number of otherwise healthy individuals.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020907-020907-7. doi:10.1115/1.4029255.

For patients suffering from severe coronary heart disease (CHD), the development of a cell-based tissue engineered blood vessel (TEBV) has great potential to overcome current issues with synthetic graft materials. While marrow stromal cells (MSCs) are a promising source of vascular smooth muscle cells (VSMCs) for TEBV construction, they have been shown to differentiate into both the VSMC and osteoblast lineages under different rates of dynamic strain. Determining the permanence of strain-induced MSC differentiation into VSMCs is therefore a significant step toward successful TEBV development. In this study, initial experiments where a cyclic 10% strain was imposed on MSCs for 24 h at 0.1 Hz, 0.5 Hz, and 1 Hz determined that cells stretched at 1 Hz expressed significantly higher levels of VSMC-specific genetic and protein markers compared to samples stretched at 0.1 Hz. Conversely, samples stretched at 0.1 Hz expressed higher levels of osteoblast-specific genetic and protein markers compared to the samples stretched at 1 Hz. More importantly, sequential application of 24–48 h periods of 0.1 Hz and 1 Hz strain-induced genetic and protein marker expression levels similar to the VSMC profile seen with 1 Hz alone. This effect was observed regardless of whether the cells were first strained at 0.1 Hz followed by strain at 1 Hz, or vice versa. Our results suggest that the strain-induced VSMC phenotype is a more terminally differentiated state than the strain-induced osteoblast phenotype, and as result, VSMC obtained from strain-induced differentiation would have potential uses in TEBV construction.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2015;137(2):020908-020908-8. doi:10.1115/1.4029210.

Cell adhesion to the extracellular matrix (ECM) involves integrin receptor–ligand binding and clustering to form focal adhesion (FA) complexes, which mechanically link the cell’s cytoskeleton to the ECM and regulate fundamental cell signaling pathways. Although elucidation of the biochemical events in cell-matrix adhesive interactions is rapidly advancing, recent studies show that the forces underlying cell-matrix adhesive interactions are also critical to cell responses. Therefore, multiple measurement systems have been developed to quantify the spatial and temporal dynamics of cell adhesive forces, and these systems have identified how mechanical events influence cell phenotype and FA structure–function relationships under physiological and pathological settings. This review focuses on the development, methodology, and applications of measurement systems for probing (a) cell adhesion strength and (b) 2D and 3D cell traction forces.

Commentary by Dr. Valentin Fuster

Expert View

J Biomech Eng. 2015;137(2):024701-024701-8. doi:10.1115/1.4029235.

Engineering virtual internships are a novel paradigm for providing authentic engineering experiences in the first-year curriculum. They are both individualized and accommodate large numbers of students. As we describe in this report, this approach can (a) enable students to solve complex engineering problems in a mentored, collaborative environment; (b) allow educators to assess engineering thinking; and (c) provide an introductory experience that students enjoy and find valuable. Furthermore, engineering virtual internships have been shown to increase students'—and especially women's—interest in and motivation to pursue engineering degrees. When implemented in first-year engineering curricula more broadly, the potential impact of engineering virtual internships on the size and diversity of the engineering workforce could be dramatic.

Commentary by Dr. Valentin Fuster

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