Increased deformations are dispensable for cell mechanoresponse in engineered bone analogs mimicking aging bone marrow

Abstract

Aged individuals and astronauts experience bone loss despite rigorous physical activity. Bone mechanoresponse is in-part regulated by mesenchymal stem cells (MSCs) that respond to mechanical challenge. Direct delivery of low intensity vibration (LIV) recovers MSC proliferation in senescence and simulated microgravity models, suggesting that reduced mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse in aging. To answer this question, we have developed a 3D bone marrow analog that controls trabecular geometry, marrow mechanics and external stimuli. Validated finite element (FE) models were developed to quantify strain environment within hydrogels during LIV. Bone marrow analogs with gyroid-based trabeculae of bone volume fractions (BV/TV) corresponding to adult (25%) and aged (13%) mice were printed using polylactic acid (PLA). MSCs encapsulated in migration-permissive hydrogels within printed trabeculae showed robust cell populations on both PLA surface and hydrogel within a week. Following 14 days of LIV treatment (1g, 100 Hz, 1 hour/day), type-I Collagen and F-actin were quantified for the cells in the hydrogel fraction. While LIV increased all measured outcomes, FE models predicted higher von Mises strains for the 13% BV/TV groups (0.2%) when compared to the 25% BV/TV group (0.1%). Despite increased strains, Collagen-I and F-actin measures remained lower in the 13% BV/TV groups when compared to 25% BV/TV counterparts, indicating that LIV response is does not depend on hydrogel strains and that age-related changes in bone fraction directly affects cell behavior in the hydrogel phase independent of the external stimuli. Overall, bone marrow analogs offer a robust and repeatable platform to study bone mechanobiology.

Development and Characterization of a low intensity vibrational system for microgravity studies

“…In a precursor study within our laboratory, we developed a 3D bone analog scaffold utilizing gyroid shapes to mimic the complex architecture of bone tissue 32 . For the current bioreactor design, these scaffolds are integral to our assessment, serving as a platform to implement and evaluate the bioreactor's capacity to support biological studies.…”