A 3D bone marrow analog reveals the role of trabecular volume in MSC mechanoresponse and bone loss during aging and microgravity

A group led by Professors Gunes Uzer from Mechanical and Biomedical Engineering Department, Boise State University developed a versatile 3D platform to study how mechanical signals affect multicellular processes and discovered that age-related reductions in mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse.

Aged individuals and astronauts experience bone loss despite rigorous physical activity, underscoring the importance of bone mechanoresponse regulated by mesenchymal stem cells (MSCs). Low-intensity vibration (LIV) has been shown to restore MSC proliferation in aging and simulated microgravity models, suggesting that age-related declines in mechanical signaling within bone marrow contribute to reduced bone mechanoresponse. MSCs, found in adult musculoskeletal tissues, are essential for tissue turnover and repair, serving as progenitors for osteoblasts, osteocytes, and adipocytes. During habitual loading, MSCs provide osteoblast populations necessary for bone modeling. However, aging and chronic unloading under microgravity reduce exercise-induced bone formation, linked to decreased MSC proliferative and osteogenic capacity. Mechanically active environments, such as treadmill activity or ladder climbing, improve MSC function, indicating that trabecular volume may play a role in declining bone mechanoresponse during aging and unloading.

To address these challenges, the authors developed a 3D bone marrow analog to study the effects of trabecular bone volume on MSC mechanoresponse under mechanical stimulation. The cell-laden bone marrow analog with a 3D printed PLA trabeculae and hyaluronic acid-based bone marrow can be used to quantify the effects of trabecular-like scaffold volume on MSC response during LIV. The hydrogel strains created during 1 ​g, 100 ​Hz vibrations in both 13 ​% and 25 ​% scaffold bone volumes – representing bone volumes of 64 week old (aged) and 8 week old (young) adult male C57BL/6 ​J mouse – were compared. Both validated finite element (FE) simulations and in vitro experiments were used to determine whether trabecular-like scaffold volume affects the scaffold mechanical environment and MSC response. Finite element (FE) simulations and in vitro experiments revealed that advanced-age trabecular densities resulted in higher hydrogel strains, while young densities produced smaller strains. Despite lower strain magnitudes, hydrogels mimicking young bone marrow supported higher F-actin and collagen production, suggesting additional factors beyond strain influence cell behavior.

These findings highlight the model's potential to study interactions between scaffold-lining and hydrogel-encapsulated cells, mimicking bone marrow mechanobiology. The 3D bone marrow analog provides a versatile platform to investigate how mechanical signals affect multicellular processes in contexts such as aging, inactivity, microgravity, and radiation, offering a robust and repeatable system for studying bone mechanobiology.