The Penn State Safety Floor: Part I--Design parameters associated with walking deflections.

A new flooring system has been developed to reduce peak impact forces to the hips when humans fall. The new safety floor is designed to remain relatively rigid under normal walking conditions, but to deform elastically when impacted during a fall. Design objectives included minimizing peak force experienced by the femur during a fall-induced impact, while maintaining a maximum of 2 mm of floor deflection during walking. Finite Element Models (FEMs) were developed to capture the complex dynamics of impact response between two deformable bodies. Validation of the finite element models included analytical calculations of theoretical buckling column response, experimental quasi-static loading of full-scale flooring prototypes, and flooring response during walking trials. Finite Element Method results compared well with theoretical and experimental data. Both finite element and experimental data suggest that the proposed safety floor can effectively meet the design goal of 2 mm maximum deflection during walking, while effectively reducing impact forces during a fall.     

Prediction of femoral impact forces in falls on the hip.

A major determinant of the risk of hip fracture in a fall from standing height is the force applied to the femur at impact. This force is determined by the impact velocity of the hip and the effective mass, stiffness, and damping of the body at the moment of contact. We have developed a simple experiment (the pelvis release experiment) to measure the effective stiffness and damping of the body when a step change in force is applied to the lateral aspect of the hip. Results from pelvis release experiments with 14 human subjects suggest that both increased soft tissue thickness over the hip and impacting the ground in a relaxed state can decrease the effective stiffness of the body, and subsequently reduce peak impact forces. Comparison between our fall impact force predictions and in-vitro measures of femoral fracture strength suggest that any fall from standing height producing direct, lateral impact on the greater trochanter can fracture the elderly hip.     

Influence of muscle activity on the forces in the femur: An in vivo study

Experiments were performed on two patients with custom-made instrumented massive proximal femoral prostheses implanted after tumour resection. In vivo axial forces transmitted along the prostheses were telemetered during level walking, single- and double-leg stance, and isometric exercises of the hip muscles. These activities varied the lever arms available to the external loads: minimum for double-leg stance and maximum for hip isometric exercises. Kinematic, force plate, EMG and telemetered force data were recorded simultaneously. The force magnification ration (FMR; the ratio of the telemetered axial force to the external force) was calculated. The FMRs ranged from 1.3 (during double-leg stance) to 29.8 (during abductors test), indicating that a major part of the axial force in the long bones is a response to muscle activity, the strength of which depends on the lever arms available to the external loads. From these results, it was shown that the bulk of the bending moment along limbs is transmitted by a combination of tensile forces in muscles and compressive forces in bones, so moments transmitted by the bones are smaller than the limb moments. It was concluded that appropriate simulation of muscle forces is important in experimental or theoretical studies of load transmission along bones.     

Fracture prediction for the proximal femur using finite element models: Part II--Nonlinear analysis.

In Part I we reported the results of linear finite element models of the proximal femur generated using geometric and constitutive data collected with quantitative computed tomography. These models demonstrated excellent agreement with in vitro studies when used to predict ultimate failure loads. In Part II, we report our extension of those finite element models to include nonlinear behavior of the trabecular and cortical bone. A highly nonlinear material law, originally designed for representing concrete, was used for trabecular bone, while a bilinear material law was used for cortical bone. We found excellent agreement between the model predictions and in vitro fracture data for both the onset of bone yielding and bone fracture. For bone yielding, the model predictions were within 2 percent for a load which simulated one-legged stance and 1 percent for a load which simulated a fall. For bone fracture, the model predictions were within 1 percent and 17 percent, respectively. The models also demonstrated different fracture mechanisms for the two different loading configurations. For one-legged stance, failure within the primary compressive trabeculae at the subcapital region occurred first, leading to load transfer and, ultimately, failure of the surrounding cortical shell. However, for a fall, failure of the cortical and trabecular bone occurred simultaneously within the intertrochanteric region. These results support our previous findings that the strength of the subcapital region is primarily due to trabecular bone whereas the strength of the intertrochanteric region is primarily due to cortical bone.     

Fracture prediction for the proximal femur using finite element models: Part I--Linear analysis.

Over 90 percent of the more than 250,000 hip fractures that occur annually in the United States are the result of falls from standing height. Despite this, the stresses associated with femoral fracture from a fall have not been investigated previously. Our objectives were to use three-dimensional finite element models of the proximal femur (with geometries and material properties based directly on quantitative computed tomography) to compare predicted stress distributions for one-legged stance and for a fall to the lateral greater trochanter. We also wished to test the correspondence between model predictions and in vitro strain gage data and failure loads for cadaveric femora subjected to these loading conditions. An additional goal was to use the model predictions to compare the sensitivity of several imaging sites in the proximal femur which are used for the in vivo prediction of hip fracture risk. In this first of two parts, linear finite element models of two unpaired human cadaveric femora were generated. In Part II, the models were extended to include nonlinear material properties for the cortical and trabecular bone. While there was poor correspondence between strain gage data and model predictions, there was excellent agreement between the in vitro failure data and the linear model, especially using a von Mises effective strain failure criterion. Both the onset of structural yielding (within 22 and 4 percent) and the load at fracture (within 8 and 5 percent) were predicted accurately for the two femora tested. For the simulation of one-legged stance, the peak stresses occurred in the primary compressive trabeculae of the subcapital region.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 12 cc Penn State pulsatile pediatric ventricular assist device: fluid dynamics associated with valve selection

The mortality rate for infants awaiting a heart transplant is 40% because of the extremely limited number of donor organs. Ventricular assist devices (VADs), a common bridge-to-transplant solution in adults, are becoming a viable option for pediatric patients. A major obstacle faced by VAD designers is thromboembolism. Previous studies have shown that the interrelated flow characteristics necessary for the prevention of thrombosis in a pulsatile VAD are a strong inlet jet, a late diastolic recirculating flow, and a wall shear rate greater than 500 s(-1). Particle image velocimetry was used to compare the flow fields in the chamber of the 12 cc Penn State pediatric pulsatile VAD using two mechanical heart valves: Bjork-Shiley monostrut (BSM) tilting disk valves and CarboMedics (CM) bileaflet valves. In conjunction with the flow evaluation, wall shear data were calculated and analyzed to help quantify wall washing. The major orifice inlet jet of the device containing BSM valves was more intense, which led to better recirculation and wall washing than the three jets produced by the CM valves. Regurgitation through the CM valve served as a significant hindrance to the development of the rotational flow.     

Internal forces and moments in the femur of the rat during gait

The rat is of increasing importance for experimental studies on fracture healing. The healing outcome of long bone fractures is strongly influenced by mechanical factors, such as the interfragmentary movement. This movement depends on the stability of the fracture fixation and the musculoskeletal loads. However, little is known about these loads in rats.The musculoskeletal loads during gait were estimated using an inverse-dynamic musculoskeletal model of the right hindlimb of the rat. This model was based on a micro-CT scan of the lower extremities and an anatomical study using 15 rat cadavers. Kinematics were reconstructed from X-ray movies, taken simultaneously from two perpendicular directions during a gait cycle. The ground reaction forces were taken from the literature. The muscle forces were calculated using an optimization procedure.The internal forces and moments varied over the gait cycle and along the femoral axis. The greatest internal force (up to 7 times bodyweight) acted in the longitudinal direction. The greatest internal moment (up to 13.8 bodyweight times millimeter) acted in the sagittal plane of the femur. The validity of the model was corroborated by comparing the estimated strains caused by the calculated loads on the surface of the femoral mid-shaft with those from the literature.Knowledge of the internal loads in the femur of the rat allows adjustment of the biomechanical properties of fixation devices in fracture healing studies to the desired interfragmentary movement.     

The impact of the State Innovation Models Initiative on population health

In this paper, we examine the effects of the State Innovation Models Initiative (SIM) on population-level health status. SIM provided $250 million to six states in 2013 for broad delivery system reforms. We use data from the Behavioral Risk Factor Surveillance System for the years 2010–2016. Our sample is restricted to individuals ages 45 and older residing in 6 SIM and 15 control states. Treatment effects in a difference-in-difference design are estimated using a latent factor model for multiple indicators of health status. In addition to estimates for the primary sample, we obtain estimates for six subsamples based on strata of age, education, income, race and urban/rural status. We find that individuals in states that implemented SIM show significant improvements in health status. The effects of SIM are greater among older, Medicare eligible individuals, including those living in rural areas. The State Innovation Models Initiative, which provided financial incentives for states to implement health care delivery system reforms, led to population-level improvements in health status.     

Observations on the effects of static and impact loading on the human femur

The amount of energy required to fracture the shaft of the femur was shown to vary with the rate of application of the load. One member of each of 32 pairs of femora was fractured with a gradually applied bending load. The mean energy required to cause failure of the specimens was 20·50 ft-lb. Impact tests in which the same loading geometry was employed, were performed on the remaining member of each pair of specimens. The impact loading velocity was 32 ft/sec. The mean energy absorbed to the point of failure by the impact loaded specimens was 31·33 ft-lb.

Attention was drawn to the possible significance of these findings in the field of accident protection studies.     

Pelvis and femur geometry: Relationships with impact characteristics during sideways falls on the hip

While metrics of pelvis and femur geometry have been demonstrated to influence hip fracture risk, attempts at linking geometry to underlying mechanisms have focused on fracture strength. We investigated the potential effects of femur and pelvis geometry on applied loads during lateral falls on the hip. Fifteen female volunteers underwent DXA imaging to characterize two pelvis and six femur geometric features. Additionally, participants completed low-energy sideways falls on the hip; peak impact force and pressure, contact area, and moment of force applied to the proximal femur were extracted. No geometric feature was significantly associated with peak impact force. Peak moment of force was significantly associated with femur moment arm (p = 0.005). Peak pressure was positively correlated with pelvis width and femur moment arm (p < 0.05), while contact area was negatively correlated with metrics of pelvis width and femur neck length (p < 0.05). This is the first study to link experimental measures of impact loads during sideways falls with image-based skeletal geometry from human volunteers. The results suggest that while skeletal geometry has limited effects on overall peak impact force during sideways falls, it does influence how impact loads are distributed at the skin surface, in addition to the bending moment applied to the proximal femur. These findings have implications for the design of protective interventions (e.g. wearable hip protectors), and for models of fall-related lateral impacts that could incorporate the relationships between skeletal geometry, external load magnitude/distribution, and tissue-level femur loads.     

Immunogenicity of therapeutic proteins. Part 1: impact of product handling

The patents of first-generation biopharmaceutical proteins are expiring, creating opportunities for biosimilar products. Unlike conventional generic pharmaceuticals, the development of biosimilar products is far more complex and requires more than a simple demonstration of pharmacological bioequivalence to establish efficacy and safety. The main concern with biosimilar products, as for any therapeutic protein, is immunogenicity and with it the potential for serious clinical sequelae. In the absence of adequate predictors of immunogenicity outside the clinical trial setting, biosimilar products should be evaluated in the same way that any novel pharmaceutical is evaluated. Herein, the factors involved in breaking host tolerance following administration of a therapeutic protein are discussed. The impact of product handling on immunogenicity is considered in the context of some hard-fought lessons that have helped to shape the current era of biopharmaceutical manufacturing, packaging, distribution, storage, and quality assurance.     

Immunogenicity of therapeutic proteins. Part 2: impact of container closures

Immunogenicity as a potential consequence of therapeutic protein administration is increasingly being scrutinized in the biopharmaceuticals industry, particularly with the imminent introduction of biosimilar products. Immunogenicity is an important safety aspect requiring rigorous investigation to fully appreciate its impact. Factors involved in product handling, such as storage temperature, light exposure, and shaking, have been implicated in immunogenicity, while container closure systems are no less important. Intended to provide a stable environment for the dosage form, container closures may also interact with a product, affecting performance and potentially enhancing immunogenicity. Glass surfaces, air-liquid interfaces, and lubricants can mediate protein denaturation, while phthalates in plastics and latex rubber are sources of extractables and leachates that may contaminate a product, causing allergic reactions and increasing immunogenicity. The manufacture of therapeutic proteins therefore requires rigorous safety evaluations not just in the context of the product, but also product containment.     

Immunogenicity of therapeutic proteins. Part 3: impact of manufacturing changes

Immunogenicity of biopharmaceuticals relates to the intrinsic complexity of proteins as well as the complexities of the manufacturing process. The manufacture of biopharmaceuticals involves a number of complex processing steps designed to create a highly pure, stable, safe, and effective product. The process often lasts many months and can be divided into seven stages - host cell development, master cell bank establishment, protein production, purification, analysis, formulation, and storage and handling. Even minor variations at any of these stages can lead to clinically relevant changes in efficacy and/or safety of the end product. Due to the complexity of the process and the inherently unstable nature of proteins outside the body, compositional changes can occur, leading to decreased biological activity, alteration of molecular structure, and possible increased risk of host immune responses following administration. Examples are discussed whereby immunogenicity associated with some of these changes has occurred with potentially serious clinical consequences.