# Advanced Biomaterial-Based In Vitro Osteoarthritis Models: Integrating Sex as a Biological Variable in Hormonal, Subchondral Bone, and Mechanobiological Pathways

## TL;DR

This paper discusses how current osteoarthritis models fail to consider sex differences, and proposes advanced biomaterial systems that integrate hormonal and mechanical factors to better understand and treat the disease in men and women.

## Contribution

The paper introduces next-generation in vitro osteoarthritis models that integrate sex-specific hormonal and mechanobiological variables.

## Key findings

- Current in vitro models of osteoarthritis lack sex-specific variables, limiting their biological relevance.
- Hormonal changes, like estrogen decline in women, significantly influence OA progression and subchondral bone alterations.
- Advanced biomaterials with tunable properties could improve drug screening and sex-specific therapy development.

## Abstract

Osteoarthritis (OA) is the most common form of arthritis and represents a major clinical and socioeconomic burden. Epidemiological data consistently show that OA affects women more frequently and, in several joints, more severely than men. Nevertheless, current in vitro models rarely consider sex-specific variables, limiting their ability to capture the biological mechanisms that shape the pathogenesis and progression of OA. Increasing evidence indicates that age-related hormonal fluctuations and subchondral bone remodeling strongly influence OA evolution, and that these processes differ between the sexes. For instance, the decline in estrogen levels during menopause has been associated with accelerated cartilage degeneration, increased osteoclastic activity, and a higher susceptibility to subchondral bone alterations, which may contribute to more aggressive clinical manifestations in women. These mechanisms are only partially reproduced in widely used experimental systems, including traditional biomaterial scaffolds and simplified osteochondral constructs, leaving important sex-dependent pathways unresolved. While advanced biomaterials enable precise control of stiffness, porosity, and biochemical cues, most current in vitro OA models still rely on sex-neutral design assumptions, limiting their ability to reproduce the divergent disease trajectories observed in men and women. By integrating material properties with dynamic loading and tunable hormonal conditions, next-generation in vitro systems could improve mechanistic understanding, increase the reliability of drug screening, and better support the development of sex-specific therapies through the combined efforts of bioengineering, materials science, cell biology, and translational medicine.