# Biophysical signal-driven scaffold design for stem cell-guided osteochondral regeneration

## TL;DR

This paper reviews how biophysical signals in engineered scaffolds can guide stem cells to regenerate both cartilage and bone in a structured way.

## Contribution

The paper introduces a biophysical signal-driven framework for scaffold design to achieve spatially organized osteochondral regeneration.

## Key findings

- Biophysical cues in scaffolds can direct stem cell differentiation into cartilage and bone.
- Mechanobiology-based scaffolds offer more targeted and stable regulation than pharmacological methods.
- Layered osteochondral regeneration requires precise spatial guidance of stem cells.

## Abstract

Osteochondral tissue comprises two structurally and functionally distinct regions: An avascular, low-cellularity cartilage layer with poor self-healing capacity, and a vascularized, mineralized subchondral bone. This pronounced heterogeneity complicates the repair of defects that span both regions. Conventional clinical treatments, such as microfracture and autologous chondrocyte implantation, often fail to restore the native biphasic architecture, leading to disorganized fibrocartilage and poor tissue integration. Tissue engineering has emerged as a promising strategy by integrating mesenchymal stem cells (MSCs) with engineered biomaterial scaffolds. However, spatially directing MSCs toward chondrogenic and osteogenic lineages remains challenging. Beyond biochemical cues, biophysical cues play pivotal roles in modulating MSC fate via integrin-mediated mechanotransduction, cytoskeletal remodeling, and mechanosignaling pathways, including TRPV4, Piezo1, and YAP/TAZ. When appropriately encoded within scaffolds, these biophysical cues provide sustained, spatially defined guidance to MSCs. This review summarizes recent advances in scaffold design that leverage mechanobiology to construct biomimetic microenvironments, thereby manipulating lineage-specific MSC differentiation and facilitating layered, stratified osteochondral regeneration.

•Stem cell-loaded scaffolds are essential and durable platforms for osteochondral repair.•Layered osteochondral architecture requires precise guidance of stem cells toward cartilage and bone formation.•Structural scaffold design encodes biophysical cues that direct orderly stem cell differentiation.•Biophysical signals provide targeted and stable regulation with fewer side effects than pharmacological approaches.•A biophysical signal-driven framework is proposed to engineer scaffolds for spatially organized osteochondral regeneration.

Stem cell-loaded scaffolds are essential and durable platforms for osteochondral repair.

Layered osteochondral architecture requires precise guidance of stem cells toward cartilage and bone formation.

Structural scaffold design encodes biophysical cues that direct orderly stem cell differentiation.

Biophysical signals provide targeted and stable regulation with fewer side effects than pharmacological approaches.

A biophysical signal-driven framework is proposed to engineer scaffolds for spatially organized osteochondral regeneration.