In the last half century the modern era of biomedical engineering has emerged, and with this there has been a technological revolution in health care. In parallel biology has undergone a revolution, and this biological revolution now is demanding an engineering revolution. With this there has been the emergence of a biology-based engineering, what this author calls bioengineering. With this we are seeing a revolution in engineering education, and today in the U.S. alone there are more than 70 departments. This revolution, however, is global in nature with exciting developments taking place in Europe and Asia as well. Other more traditional engineering fields also have recognized the importance of the bio world. The medical device and diagnostics in industry also is changing due to the convergence of the biological revolution with it, and there will be new biology-based industries, where in the future there being just as many applications outside of the medical field as within it. Thus, as we move further into the 21st century, the changes in bioengineering will be just as dramatic as those of the last 50 years.
Three-dimensional porous scaffolds play an important role for tissue engineering. The recent developments of porous scaffolds and their preparation methods, especially those developed by our group, are summarized in this review. A method for the preparation of biodegradable porous scaffolds has been developed by using pre-prepared ice particulates as porogen material. A kind of composite biodegradable porous scaffolds has been developed by forming collagen microsponges in the pores or interstices of a synthetic polymer sponge or mesh. A composite sponge of synthetic polymer, collagen and hydroxyapatite has been developed for hard tissue engineering. Bovine articular cartilage-like tissue has been engineered by culturing chondrocytes in the PLGA-collagen scaffolds.
This work is a review of recent advances in the understanding of strain adaptive bone remodeling. The phenomenological theories of surface bone strain adaptation and internal bone strain adaptation are summarized as well as the possible cellular mechanisms for mechanotransduction that occurs in bone tissue adaptation. The phenomenological bone strain adaptation theories are based on the postulate that there exists a causal relationship between the rate of deposition or resorption of the bone matrix and a stimulus; the stimuli considered are generally measures of the mechanical loading (strain, strain rate, strain energy, stress, fatigue microdamage) applied to the bone matrix of a whole living bone. The exact measure of the mechanical loading history at a point that is the biological stimulus, although much discussed and written about, is not precisely known. The focus of this review is to highlight our ignorance concerning the nature of precise biological stimulus and to suggest ways to deal with this ignorance.
Over the past few decades, a large number of novel numerical methods have been proposed to analyze blood flows and to understand the relationship between vascular diseases and hemodynamics. In this paper, we review recent computational fluid dynamics studies on macroscale hemodynamics such as blood flow in the heart and large arteries, microscale blood flows in small vessels in which blood is assumed to be a suspension of red blood cells in plasma, and single red blood cell motions in an induced flow field. The advantages and disadvantages of numerical methods are discussed, and current trends in these research fields are introduced.
In the past three decades, there has been great progress in the mathematical modeling and computational methods for fluid mechanics of suspensions of micron-scale particles. In medical or biological applications, the particles can be very deformable, self propelled or both. Research on mathematical and computational methods for the modelling of suspensions of such particles is currently very active. In this review paper, we introduce some of the concepts that are used to analyse suspensions of either passive deformable particles or active locomotive particles. To simplify matters, we consider simple model particles that are initially spherical. In one case, the particle is a liquid droplet enclosed by a thin deformable membrane (a ‘capsule’) and is deformed by hydrodynamic forces. In the other case, the particle remains spherical but propels itself by means of a velocity wave on its surface. Athough the basic equations for locomotive spherical cells and for capsules are similar, the resulting suspension characteristics are quite different owing to the different boundary conditions on the surface of the particles.
Tribology of hip joints is reviewed, covering a full spectrum from natural hip joints to total hip replacements, as well as tissue engineered articular cartilage. The importance of integrated tribological studies of contact mechanics, friction, wear and lubrication, as well as fully coupled with biological considerations, has been emphasized. The exact lubrication mechanism in natural hip joints is still not clear, although the unique biphasic characteristics of articular cartilage play an important role. Tribological studies of bearing surfaces for artificial hip joint replacements are important in developing and optimizing alternative material combinations to conventional polyethylene. Recently developed tissue engineered articular cartilage has been shown to be inadequate as far as the tribological property is concerned.
Living cells do possess structural and mechanical properties' and any deviation in these properties not only results in the breakdown of their physiological functions, but may also give rise to human diseases. One such example is that of malaria. Single cell mechanics study of malaria had been done to investigate the changes in the structure-property-function relationship of red blood cells (RBCs) arising from infection by the malaria parasite, Plasmodium falciparum. Here, biophysical experiments using micropipette aspiration, optical or laser tweezers and microfluidics are presented to highlight some research work done to quantitatively investigate the progressive stiffening and change in biorheological properties of RBCs at the different stages of infection. This stiffening is due to the cellular and molecular changes caused by the parasite within the infected RBCs and can result in the impairment of blood flow thus leading to organ failure, coma or even death. These single cell biomechanics studies demonstrate the relevance of biomechanics in the understanding of the pathophysiology of malaria. Also, the biophysical methodologies developed may provide a suitable testing strategy to quantitatively evaluate the effectiveness of certain agents and drugs being developed to prevent or inhibit stiffening of the Plasmodium falciparum infected RBCs.
The Circle of Willis (CoW) is a ring-like arterial structure located in the base of the brain, responsible for the distribution of oxygenated blood throughout the cerebral mass. Among the general population, approximately 50% have a complete CoW, and among a multitude of possible anatomical variations, vessels absent from the CoW are common. Certain conditions such as a build up of atherosclerotic plaque on the arterial wall can result in ischaemic damage and stroke-like symptoms. A 3D computer model has been developed based on the results of MRA scans of 3 patients' cerebral-vasculature incorporating a numerical algorithm to simulate the body's autoregulation mechanism. The intention of the present study was to investigate different anatomical states, including different vessels missing from the circle whilst occluding the main afferent arteries such as the Internal Carotid and Basilar Arteries.
Ultrahigh molecular weight polyethylene (UHMWPE) is the popular material of choice for use as a bearing surface in total joint replacement (TJR). Despite an extremely low friction coefficient of UHMWPE to metals with liquid lubrication, however, wear and fatigue fractures are major problems limiting the durability of implanted UHMWPE components. Although highly crosslinked UHMWPE has been intensively studied for decades, its use in orthopedic implants has been limited to relatively low stress and multidirectional load applications, such as acetabular cups in hip joint replacements (HJR). This is mainly because highly crosslinked UHMWPE requires thermal treatment process, indispensable for eliminating the residual free radicals, which leads to a decrease in crystallinity resulting in the reduction of fatigue performance of highly crosslinked UHMWPE. By contrast, recently α-tocopherol doped UHMWPE has been viewed seriously as a novel orthopedic UHMWPE. The α-tocopherol doped UHMWPE exhibits excellent wear and fatigue performance and can be applicable to high stress and linear motion applications, such as total knee replacements (TKR). This paper comprehensively reviews recent advances in the mechanical properties and oxidation stability of medical grade UHMWPE, particularly focusing on highly crosslinked UHMWPE and α-tocopherol doped UHMWPE.
Mechanical quantities at the microstructural level play important roles as stimuli of trabecular bone remodeling by which cancellous bone maintains and adapts its trabecular structure to the mechanical environment. In this study, distribution functions of mechanical quantities on trabecular surfaces were estimated using digital image-based finite element models of five specimens of rat vertebral bodies under physiological loading conditions. As the representative quantities that have been used as mechanical stimuli in the remodeling rate equation, strain energy density (SED) and von Mises equivalent stress were considered for the mechanical quantities at the local point (namely, local mechanical quantities), and SED integration and stress nonuniformity were considered for the quantities that are integrated in space (namely, integral mechanical quantities). As a result of finite element analysis, it was demonstrated that these mechanical quantities were nonuniformly distributed over the trabecular surface due to the three-dimensionally complicated trabecular structure, even though only simple external loading was applied to the vertebral body. The magnitude of the skewness of the distribution function was calculated in order to compare the distribution patterns of the four mechanical quantities. The skewness for SED and equivalent stress in all the loading cases were larger than those for SED integration and stress nonuniformity, respectively, except that in the loading of axial compression, the skewness for equivalent stress was smaller than that for stress nonuniformity. It was also revealed that the skewness varied with changes in the external loading conditions, where changes in the mean and the standard deviation of the skewness for SED integration and stress nonuniformity were smaller than those for SED and equivalent stress. The results support the understanding that the concept of the integral formulae proposed for the bone remodeling stimulus corresponds not only to the actual biological system but also to the observed phenomenon of trabecular structural adaptation to the mechanical environment.
Control of three-dimensional (3D) microvessel formation is critical for regenerative medicine and tissue engineering because vessels are essential for the formation and maintenance of organ function. In order to function, tissues need an internal network of vessels. To introduce a 3D vessel network deep into the tissue, it is necessary to introduce 3D microvessel control which makes it a critical factor in regenerative medicine and tissue engineering. This study focuses on the effect of the concentration gradient of growth factors used in seeding the endothelial cells (ECs) on the morphology of the network. First, ECs were seeded using two model environments: collagen gel containing bFGF and incubated without bFGF medium (gel-bFGF model), and collagen gel containing no bFGF and incubated with bFGF medium (medium-bFGF model). The networks were observed in 3D with confocal laser scanning microscopy. The migration of ECs on the collagen gel was analyzed to study the effect of the concentration gradient on the network formation process. We found that the ECs of the gel-bFGF model showed significantly longer migration distance and more sprouting points compared with those of the medium-bFGF model. The networks of the gel-bFGF model, expanded mainly in a depth of 20-30 μm, and many reached a depth of 50-60 μm, whereas many networks in the medium-bFGF model expanded in a depth of only 10-20 μm. These results revealed that the initial growth factor distribution affects (a) both EC migration of the network formation process and the number of sprouting points, and (b) network morphology.
In this study, a new noninvasive sensor system is developed to detect compliance of minute living cells and tissues by using dynamic response of a piezoelectric vibrator. The bending mode of vibration, excited impulsively by piezoelectric ceramics, is utilized in a small clamped-free beam type vibrator. A three-dimensional micro actuator, in which a doubly L-shaped clamped-free beam type vibrator is utilized, is also developed to enforce dynamic stimulations. The sensor and the three-dimensional actuator were united and integrally controlled by a micromanipulator system, while dimensions and morphologies of the cells were measured by an inverted phase contrast microscope system. Experimental studies have been carried out using fertilized egg cell of killifish. The studies have shown the sensor's capability to detect changes of mechanical properties of the minute living cells. Also, the method has shown that the reaction of living cells might have frequency dependence on vibrating stimulations by the actuator.
The effects of hematocrit (Hct) on blood flow in microcirculation were investigated by computer simulation using a particle method. Deformable red blood cells (RBCs) and blood plasma were modeled by assembly of discrete particles. It was assumed that an RBC consisted of an elastic membrane and inner viscous fluid, and that plasma was viscous fluid. The particles for the RBC membrane were connected with their neighboring membrane particles by stretch/compression and bending springs. The motion of all the particles that was subjected to incompressible viscous flow was solved by the moving particle semi-implicit (MPS) method based on Navier-Stokes (NS) equations. The forces induced by the springs to express the elastic RBC membrane were substituted into the NS equations as the external force, which enabled coupled analysis of elastic RBC motion and plasma fluid flow. Two-dimensional simulations of blood flow between parallel plates were carried out for various Hct values. As a result, it was shown that at higher Hct, RBCs were less deformed into a parachute shape during their downstream motion, indicating that mechanical interaction between RBCs restricted the RBC deformation. Mechanical interaction between RBCs had a significant influence on RBC deformation and the velocity profile of plasma flow when the Hct value was more than 0.20∼0.30. Apparent blood flow resistance increased with Hct, corresponding to previously reported in vitro experimental results compiled to an empirical formula.
Atherosclerotic renal artery stenosis (RAS), which accounts for approximately 7% of peripheral vascular diseases, is considered a major cause for secondary hypertension and other renal complications such as chronic renal failure and ischemic nephropathy. In this study, the fluid dynamic features of a human aortorenal bifurcation are investigated in detail with a computational fluid dynamics (CFD) solver to assess the localization of RAS in relation to the sites exposed to abnormal hemodynamic events. Specially, a normal renal artery is artificially rendered stenosed to examine the RAS-induced hemodynamic changes and their effect on the progression of RAS. The CFD solver is partially validated by a model experiment conducted for steady state flow. The computed results indicate that low oscillatory wall shear stress (WSS), which stands for the most prominent hemodynamic factor responsible for atherosclerosis, correlates intimately with flow separation; WSS distribution depends significantly on vascular geometric structure; and RAS may elicit pronounced flow disturbances that are likely to promote the spread of atherosclerotic lesions towards downstream region.
In order to analyze the pressure wave propagation in circulatory systems, we previously presented a one-dimensional numerical flow simulation model that describes wave propagation in silicone tubes well and shows that the viscoelasticity of the tube has an important role in the wave propagation. In the present study, by comparison with experimental results, we show that the one-dimensional numerical model describes well the propagation of small pressure waves in silicone tubes even when their deformation compliance and viscoelasticity change independently, provided that appropriate values of the viscoelastic parameter are used.
Over 7000 patients are suffering from osteonecrosis of the femoral head annually in Japan. The patients have to undergo surgical treatments if the femoral head collapsed. The mechanism of femoral head collapse is still unclear, although morphological and mechanical changes in the necrotic hard bones or the reparative soft tissues have been believed to cause this collapse. We analyzed three-dimensional morphological and mechanical changes in the metaphyseal cancellous bone during bone regeneration after traumatic osteonecrosis of young rat femoral head using a micro-CT. Morphological indices and apparent modulus were calculated based on parallel plate model and finite element model, respectively. Bone volume, trabecular thickness, and apparent modulus initially decreased on day 7 after osteonecrosis, and they gradually increased during regenerating process. These findings indicate that the structural rigidity of cancellous bone in the regenerative area transiently decreases after osteonecrosis. These changes possibly induce femoral head collapse. The reparative area should be a target to treat osteonecrosis of the femoral head.
In adherent cells, such as osteoblasts and endothelial cells, the actin stress fiber structure is dynamically reorganized under changes in the surrounding mechanical environment such as cyclic stretch deformation or extracellular fluid flow. Although many studies have been conducted to clarify the biochemical signaling pathways in the reorganization process, details of the reorganization mechanism are still not clearly understood. In addition, to known biochemical mediators, intracellular tension has been proposed as a candidate mechanical mediator for stress fiber reorganization. In previous studies, it was reported that the release of intracellular tension by contracting the cell body induced the disassembly of the stress fiber as an initial phase of the reorganization process. However, in these experimental systems, deformation or force was applied to the entire cell body, so that it was difficult to directly discuss the relationship between the individual mechanical condition of stress fibers and the disassembling phenomenon. In this study, we have designed a novel experimental system by which local contraction was applied to a single osteoblast-like cell and intracellular tension in the targeted stress fiber was selectively released. The dynamic change in stress fiber structure was observed in the EGFP-tagged actin expressed osteoblast-like cell MC3T3-E1. The results indicated that only tension-released stress fibers were selectively disassembled and disappeared in a single cell. This result suggests that the existence of intracellular tension is essential for the dynamical stability of the stress fibers in osteoblast-like cells.
The morbidity associated with idiopathic osteonecrosis of the femoral head (ION) is increasing. The primary goal of treatment for ION is to prevent collapse of the femoral head. With the exception of hip arthroplasties, current joint-preserving surgeries for ION require long-term reduction of the load placed on the hip joint. To allow these patients to return quickly to their daily and social activities, we have developed a novel extra-articular device that reduces the weight-bearing of the hip joint. In this study, we evaluated the load-bearing function and the range of motion of a hip joint equipped with the extra-articular device. To demonstrate load reduction on the hip joint with this device, we measured the contact pressure on the femoral head surface and the principal strain on the coxal bone during static loading conditions, which simulated the various phases of human gait. The range of motion of the hip joint with the device was measured using an electro-goniometer. The extra-articular device remarkably reduced the contact pressure on the hip joint, with some restriction in hip flexion. Our novel extra-articular device appears to be a promising tool to secure reductions in the weight-bearing function of the hip joint, and will be applicable to new bone regeneration therapies.
This study investigated nitric oxide (NO) production and phenotype changes of smooth muscle cells (SMC) in a cocultured model (CM) exposed to fluid shear stress. The CM was composed of human umbilical endothelial cells (EC) and SMC, a collagen layer, and a porous membrane. After exposing the CM to shear stress of 1.5 Pa for 24 hours, α-smooth muscle actin (α-SMA) expression of SMC and NO production in culture media were examined. Under static conditions, α-SMA expression in the CM was significantly lower than that of a SMC monocultured model (SMC model). After exposure to shear stress, NO production in the CM increased compared to that in the static CM, and there was no significant difference in α-SMA expression between the CM and SMC model. These results suggest that EC may regulate phenotype changes of cocultured SMC, and NO may be one of the factors which induce dedifferentiation of SMC.
A multi-block-and overset grid-based computational fluid dynamic (CFD) study is conducted for the unsteady flows about a realistic body-wing model and the force-generation in the flapping flight of hawkmoth hovering. Computations are performed with the geometric-and-kinematic model constructed based on the experimental data of a real hawkmoth. The computed results demonstrate the presence of interaction among the leading-edge vortex (LEV), the trailing-edge vortex (TEV) and the wing tip vortex (TV), and hence quantify the roles of the vortices in aerodynamic force-generation. Moreover, both inertial and aerodynamic torques and powers are evaluated for the flight maneuver and the cost in hovering flight. Our results indicate that relative roles played by the inertial and aerodynamic torques in the translational phase of the wing motion show distinguishable discrepancy compared with those in the rotational phase of the wing motion; and the aerodynamic power shows much higher magnitude rather than the inertial one, very likely owing to the unsteady mechanisms.
The vocal folds in the larynx experience a self-excited oscillation with a wavelike motion during speech owing to interaction with respiratory airflow. The mechanism of the onset of the oscillation remains elusive partly because of compound effects of laryngeal muscles, although its better understanding has clinical significance in determining the ease with which phonation can be achieved. Approaches to the mechanism using a mechanical vocal fold model are useful because it allows investigating the roles of interested parameters in isolation. Here, we designed a mechanical vocal fold model made of a pair of rubber sheets. A key feature of the experimental setup is that it enables observations of high-speed deformation of the oscillating vocal fold model, together with pressure evaluations while changing separately isolated parameters associated with the laryngeal muscle functions. The observations of the oscillation onset demonstrated a gradually developed wavelike oscillation that spreads out over the rubber sheets. The magnitude of the motion is restricted by either increase in rubber restoring force or reduction in flow path width, each of the effects mimics the actual laryngeal muscle functions and reduces, in the experimental results, the threshold upstream pressure that induces the onset of the self-excitation. Thus, the present study highlights close association between degrees of oscillation, flow-tissue interaction, and threshold pressure required for the onset.
We established a quasi-in situ tensile test to measure the tensile properties of smooth muscle cells (SMCs) cultured on substrate maintaining their shape and cytoskeletal integrity. SMCs were cultured on a substrate coated with thermoresponsive gelatin (PNIPAAm-gelatin) and were held with a pair of micropipettes coated with an adhesive. Cells were detached from the substrate by lowering ambient temperature to dissolve the PNIPAAm-gelatin. Tensile tests for fusiform SMCs up to ∼15% strain performed 3 times in normal and Ca2+-free Hank's balanced salt solution (HBSS(+) and HBSS(-), respectively) in order to investigate the effects of Ca2+ on the change in their tensile properties during loading/unloading cycles. The stiffness of the fusiform SMCs obtained by the first loading process in HBSS(-) and in HBSS(+) was 0.041±0.024 N/m (n=6, mean±SEM) and 0.031±0.008 N/m (n=6), respectively, and was significantly lower than that of spherical cells detached from the substrate by trypsinization (∼0.09 N/m), indicating that cell stiffness is overestimated when cells are trypsinized. Cell stiffness increased from the first cycle to the second and then stabilized in HBSS(-), while it increased continuously with the number of the cycles in HBSS(+). These results suggest that the mechanical properties of SMCs change with stretching and that extracellular Ca2+ has a significant effect on their response to stretch.
When macrophages are cultured under cyclic strain, they align parallel to the direction of strain, in contrast to the perpendicular alignment reported for other types of cells. However, the time at which their orientation starts and the influence of fluid shear stress acting on cells during cyclic stretching have not been identified. In the present study, murine peritoneal macrophages were attached to silicone membranes and cultured up to 8 hours under cyclic uniaxial stretch of 10% amplitude and 1 Hz frequency. Cell morphology was observed and the angle of orientation of spindle-shaped cells (spindle cells) was determined. Distributions of actins in macrophages were also examined after the application of cyclic strain. Percentage of spindle cells increased with culture period, and the cells were getting longer with time. After around 2 hours, spindle cells started to align parallel to the direction of strain. At 8 hours, 53% of spindle cells were aligned within the angle of 20 degrees to the direction of strain. Prior to the orientation of cell bodies, accumulation of actin filaments was observed in the peripheral area of cells in the direction parallel to the strain direction. When the silicone membranes were moved back-and-forth in culture medium without stretching for 8 hours, macrophages did not show preferential orientation. These results suggest that macrophages actively align parallel to the direction of strain and start to orient around 2 hours after the initiation of cyclic strain.
Since the propulsion mechanism using elastic fins, such as the caudal fin and pectoral fin of fish, is effective in fluid, many studies on bioinspired elastic fins for propulsion in water and on the development of fish-type robots with elastic fins have been carried out. The optimum elasticity of the fin is not constant and varies according to the movement task and environment, such as swimming speed and oscillating frequency. However, it is very difficult to exchange fins of different stiffnesses while moving. Thus, we aimed to develop a variable-stiffness fin of which stiffness can be changed dynamically. As the one such variable-stiffness fin, we have developed a fin with a variable-effective-length spring. The effective length of a plate spring is changed by adjusting the length of the rigid plate that supports the plate spring. Apparent stiffness is changed by varying the effective length. In this paper, we have described the structure of the propulsion mechanism in fluid using a fin with a variable-effective-length spring, and the thrust force characteristics in water. Furthermore, we have discussed the optimum effective length for providing the maximum thrust force and the effect of the dynamic change of effective length on thrust force.