Improving Musculoskeletal Function

Improving Musculoskeletal Function - understanding skeletal development, adaptation and aging

Gary S. Beaupré, PhD; Dennis Carter, PhD; Virginia L. Giddings, MS; Tishya Leong, MS; Borjana Mikic, MS; Sheila S. Stevens, MS; Robert T. Whalen, PhD

Tendon, ligament, articular cartilage, and bone are living tissues that adapt throughout life to meet changing functional demands. While biological influences such as genetics, hormones, and growth factors play a critical role in growth and development, these tissues also respond to mechanical influences. For example, individuals who engage in high-impact activities develop denser and stronger bones and connective tissues than individuals who engage in minimal physical activity. Abnormal forces or activities for which the tissues are inadequately adapted can result in injury. The normal aging process can also adversely affect tissue properties leading to degenerative diseases such as arthritis and osteoporosis.

We are studying the effects of biological and mechanobiological factors in shaping the development, adaptation, and aging of skeletal tissues. By understanding how these tissues normally develop and how they respond to mechanical stimuli, we can better understand and predict tissue response in conditions of injury or disease. This understanding is important in developing new and improved methodologies for the prevention and treatment of musculoskeletal injuries and disorders.

Growth of Long Bones

Mikic, Carter

Growth and development of the long bones of the skeleton are influenced by numerous epigenetic factors, including both local and systemic growth factors and hormones, as well as mechanical stimuli. In the long bones, growth in bone length and girth occur via two distinct processes. Growth in girth or cross section is accomplished by direct bone apposition and resorption, whereas growth in bone length occurs via endochondral ossification whereby cartilage is replaced by bone. Numerous experimental investigations have demonstrated that appositional bone growth is largely driven by the changing mechanical stimulus that parallels the increase in body mass of a growing individual. In contrast, while mechanical loading plays a role in endochondral growth and ossification, experimental evidence suggest that longitudinal bone growth is largely controlled by local and systemic biochemical factors. Changes in mechanical stimuli associated with altered physical activity have a minimal effect on longitudinal bone growth unless those changes are extremely severe.

In the present study, we developed a mathematical model to simulate endochondral growth and ossification of the proximal humerus. Within a growing cartilaginous rudiment, a continuous distribution of tissue maturity can be observed, with the oldest tissue adjacent to the primary bone front, and the youngest proliferating tissue located farthest from this front. Based on experimental studies in the literature, we assume that the growth rate at any point within the cartilage tissue is a function of tissue maturity and age. In addition, tissue maturation rate is assumed to be proportional to the growth rate. When a critical maturity level is reached, the cartilage is assumed to turn into bone and no longer contributes towards growth in length. The dependence of growth rate on tissue maturity reflects observations that the greatest contribution to cartilage growth is from the older tissue that is actively synthesizing extracellular matrix molecules. With age, the growth response is modulated by a function which represents the time-dependent influence of epigenetic events associated with infancy, childhood, and puberty. The modulation of growth is largely reflective of the hormonal events associated with these three phases in the lifetime of an individual, but also reflects the net effect of a changing mechanical stimulus over time. However, the site-specific influence of mechanical stresses and strains on cartilage maturation and growth are not explicitly formulated in our model. The simulation commences at 8.5 weeks of development and is carried out to approximately 21 years of age.

Figure 1. (Top) Predicted growth in length of the proximal humerus. (Bottom) Predicted growth rate for the same bone.

The simulation results for predicted length of the proximal half of the humerus are in good agreement with data from the literature (Fig. 1). The increase in total growth rate associated with the onset of childhood and the increase in growth hormone sensitivity that occurs between 6 and 12 months postnatally can be seen, as well as the increased growth rate associated with the pubertal growth spurt at approximately 14 years of age. From these results we conclude that the age-dependent influence of epigenetic hormonal events must be incorporated in mathematical and computational models of bone development in order to capture the subtle characteristics of longitudinal bone growth.

Articular Cartilage and Osteoarthritis

Stevens, Carter, Beaupré

Articular cartilage is a remarkable tissue which allows near frictionless movement between bones yet transmits high loads across the joint. Osteoarthritis is a disease characterized by articular cartilage thinning, subchondral bone density changes, and mechanical property degradation within the cartilage. Osteoarthritis occurs naturally with age, however, its severity and associated pain can vary greatly among individuals. The disease can have multiple causes. Dramatic loading changes within a particular joint (overloading, immobilization, or joint instability) and genetic predisposition may accelerate the natural progression of osteoarthritis.

This study explores a mechanism not previously modeled in the context of osteoarthritis. In this study, osteoarthritis is considered to be the result of endochondral ossification reinitiated late in life due to mechanical and genetic factors. Endochondral ossification, or the process of bone replacing cartilage, is the mechanism by which all long bones increase in length during development. In utero, ossification begins in the center of a cartilaginous model of the future bone and gradually extends toward the bone ends. In healthy cartilage, ossification of the articular cartilage surface is prevent by a complex mechanical and biochemical environment. An adult bone end (Fig. 2, a) consists of a very dense cortical bone shaft, a less dense cancellous region, a thin layer of subchondral bone, and a layer of articular cartilage. The cartilage thickness will remain constant in normal cartilage, but will decrease under conditions of osteoarthritis. Similarly, changes in the subchondral bone density just below the articular cartilage will affect the ability of cartilage to transmit loads effectively. Through the use of finite element techniques, we are modeling the influence of loading conditions and bone geometry on the progression of this disease.

Figure 2. a) Features of an adult long bone end; b) Finite element model used to predict the progression of osteoarthritis.

In this model (Fig. 2, b), each element represents a region of cartilage or bone. In our computer simulations, we predict changes in cartilage thickness and bone density as the bone develops and ages. The simulations begin very early in development, when the bone end is chiefly cartilaginous. Within the model, cartilage is assumed to mature based on a combination of mechanical and genetic factors. Mature cartilage is subsequently replaced by bone. Bone density is increased in areas of high stress and decreased in areas of low stress. These computer models are run repeatedly to simulate the passage of time and aging. Our preliminary models predict early development and endochondral ossification of long bones very well. These models are now being applied over longer time periods to predict the influence of bone geometry and loading conditions on the progression of osteoarthritis.

Tendons and Ligaments

Leong, Carter

Tendons and ligaments are susceptible to a variety of traumatic and overuse injuries. In severe cases, these injuries can impair the musculoskeletal function and mobility of a patient. Tendons transmit forces from muscles to bones, while ligaments stabilize joints by connecting bone to bone. To carry out these functions successfully without sustaining damage, tendons and ligaments must maintain mechanical properties that allow them to withstand the tensile forces imposed on them.

The mechanical properties of tendons and ligaments depend on the tissue composition and microstructure. Tendons and ligaments contain collagen fibers that make these tissues stiff and strong. The volume fraction, alignment, and material properties of these fibers largely determine the tissue stiffness and strength. We have developed a model that predicts the mechanical response of tissues such as tendons and ligaments to tensile loading based on tissue composition and microstructure. The tendon or ligament initially stiffens as crimped fibers straighten, stretches linearly as the fibers stretch, and finally fails as fibers rupture. The stress-strain behavior predicted by our model is illustrated in Fig. 3.

Figure 3. Mechanical response of tendons and ligaments to tensile loading.

We are using this model to study time-dependent changes in the mechanical properties of tendons and ligaments. We are currently investigating how the composition and microstructure, and consequently the mechanical properties, of tendons and ligaments change with age and mechanical loading. These studies will improve our understanding of how tendons and ligaments develop and age and how they adapt to their biomechanical environment. This understanding should provide insight into methods for better preventing and treating tendon and ligament injuries.

Computer Predictions of Calcaneal Bone Density

Giddings, Whalen, Beaupré, Carter

Like muscles that increase in size and strength with increased physical activity and decrease in size and strength with inactivity, bones adapt to the mechanical demands imposed on them. Combined with genetic and other biological factors, mechanics play an important role in bone development and maintenance. Experimental studies have shown that a reduction in mechanical loading, e.g., after cast immobilization or spinal cord injury, results in a more porous and weaker bone (osteoporosis) . When bone is subjected to higher than normal loading conditions it adapts by increasing bone mass. Our research group has developed a mathematical theory to better understand the response of bone to mechanical loading. We have used this theory to examine bone adaptation in a variety of skeletal locations including the femur, tibia and acetabulum.

The purpose of the present study was to evaluate the contribution of mechanics to the distribution of density and the architecture of the cancellous bone in the calcaneus, or the heel bone. The calcaneus is of special interest since clinicians have recently begun using it as a site to assess bone quality in vivo. Dual-energy absorptiometry (DXA) and ultrasound measurements of the calcaneus have been used as predictors of bone quality and fracture risk. Unfortunately, ultrasound and DXA do not measure the regional density variations within a bone such as the calcaneus, nor do they provide an understanding of the relationship between loading history and bone structure. The present study examined how loads applied to the calcaneus influence the bony architecture.

The geometry of the calcaneus was taken from a computed tomography (CT) scan slice (Fig. 4) through the center of the calcaneus (mid-sagittal section). Based upon the external geometry in the CT slice, we performed a bone adaptation simulation to examine the influence of different loading histories on the resulting density distribution within the calcaneus. The loads were representative of walking. The density predictions from the computer simulation are shown in Fig. 5. The predicted density distribution has similar features to the CT measurements, although some architectural details are different. This study suggests that there is a strong relationship between bone structure and loading history in the calcaneus. Our next goal is to use this model to predict the effects of disuse or altered loading conditions on calcaneal bone density in patients.

Figure 4. Computed Tomograpic (CT) section taken through the center of the calcaneus. This section shows the distribution of different density bone through the calcaneus.

Figure 5. The density distribution predicted by the bone adaptation simulation.

Republished from the 1996 Rehabilitation R&D Center Progress Report. For current information about this project, contact: Gary S. Beaupré.