# Mechanical regulation of endochondral bone regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $349,658

## Abstract

Abstract
Large bone defects caused by traumatic injury or tumor resection pose a significant clinical challenge as they
cannot not heal without intervention, and current bone grafting therapies are limited. Tissue engineering is a
promising alternative. Many bone tissue engineering strategies use scaffolds designed to match the structure
and properties of mature bone. However, natural fracture healing is most efficient (90-95% success rate) when
it recapitulates bone development through endochondral ossification. A tissue engineering therapy that
enabled large defects to heal with the same fidelity as natural fracture healing would be transformative.
Here, we apply these developmental and endogenous repair mechanisms to the regeneration of challenging
defects, which, unlike simple fractures, do not form a callus and cannot heal on their own. In both development
and repair, endochondral ossification requires mechanical cues. Recently, developed a scaffold-free approach
that recapitulates the cellular organization of the developing limb bud to induce endochondral ossification in
large bone defects. We found that in vivo mechanical loading significantly enhanced endochondral
regeneration, with functional regeneration induced by load initiation at the time of chondrocyte hypertrophy-to-
ossification transition. However, it remains unclear how the cellular differentiation state or the composition and
properties of the extracellular matrix influence this mechanotransductive endochondral response.
The goal of this project is to understand the mechanisms by which cellular lineage and extracellular matrix
influence mechanical regulation of endochondral bone defect regeneration. Our governing hypothesis is that
mechanical stimulation of endochondral bone defect regeneration depends on chondrogenic cell lineage
maturation and extracellular matrix composition through YAP/TAZ mechanosensation. We will determine the
influence of endochondral differentiation state, matrix composition and properties, and YAP/TAZ signaling on
mechanical regulation of endochondral ossification using a combination of bioreactor and large bone defect
models. These results will identify when and how mechanical stimuli induce endochondral regeneration and
may provide insights for development-inspired tissue engineering strategies in other tissues.

## Key facts

- **NIH application ID:** 9895627
- **Project number:** 5R01AR074948-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joel D Boerckel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,658
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895627

## Citation

> US National Institutes of Health, RePORTER application 9895627, Mechanical regulation of endochondral bone regeneration (5R01AR074948-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9895627. Licensed CC0.

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