# Improving tendon-to-bone repair with hedgehog signaling therapeutics

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2021 · $168,738

## Abstract

SUMMARY
 Approximately 30% of U.S. adults suffer from tendon and ligament injuries. These injuries often require repair
(e.g., rotator cuff) or reconstruction (e.g., anterior cruciate ligament (ACL)) to re-integrate the midsubstance with
the adjacent bone. Recreating the zonal tendon-to-bone insertion site (i.e., enthesis) is critical to restoring normal
function. Zonal enthesis formation involves anchoring collagen fibers, synthesizing proteoglycan-rich
fibrocartilage, and mineralizing this fibrocartilage. The hedgehog (Hh) signaling pathway is critical to the
formation of a zonal insertion during development by promoting the formation of unmineralized and mineralized
fibrocartilage zones of the enthesis. Unfortunately, studying this pathway in traditional tendon-to-bone repair has
been a challenge since these repair models do not sufficiently anchor collagen fibers to bone, much less produce
zones of fibrocartilage. Conversely, ligament reconstructions, where a tendon graft is placed through bone
tunnels, can produce zonal attachments. Therefore, we utilize innovative transgenic murine ACL reconstruction
models to elucidate the mechanisms of zonal tendon-to-bone repair in order to develop novel therapies to
improve the repair outcome. Our preliminary data demonstrate that Hh signaling promotes zonal tendon-to-bone
integration following ACL reconstruction. The objective of this proposal is to locally stimulate hedgehog signaling
via scaffold delivery of Hh agonist to increase the formation of zonal tendon-to-bone attachments. Our hypothesis
is that delivery of the agonist will stimulate the local progenitor cells to proliferate and then differentiate into
fibrochondrocytes in the attachments, leading to improved tunnel integration. We will use multiplexed,
mineralized cryohistology to monitor the zonal attachments and novel mechanical testing to assess tunnel
integration strength. If the Hh pathway could be harnessed therapeutically, it would result in a paradigm shift in
the treatment of these debilitating injuries.

## Key facts

- **NIH application ID:** 10301318
- **Project number:** 1R21AR078429-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathaniel A. Dyment
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $168,738
- **Award type:** 1
- **Project period:** 2021-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301318

## Citation

> US National Institutes of Health, RePORTER application 10301318, Improving tendon-to-bone repair with hedgehog signaling therapeutics (1R21AR078429-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10301318. Licensed CC0.

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