# Localized small molecule delivery to improve tendon-to-bone integration following anterior cruciate ligament reconstruction

> **NIH NIH R03** · UNIVERSITY OF DELAWARE · 2023 · $92,080

## Abstract

Bone fractures are common injuries that impact millions of people each year, and poorly healed fractures
cause impaired mobility, long-term nursing care, or even premature death. It is known that controlled
mechanical loading can improve the quality and speed of fracture repair, but our understanding of mechano-
therapeutics is still underdeveloped. Recent research has indicated that zinc may play a fundamental role in
the evolution of fracture repair. Zinc is known to stimulate new bone formation, preserve bone mass, and
regulate apoptosis. Importantly, intracellular zinc homeostasis must be carefully coordinated to regulate
uptake, excretion, and intracellular storage/trafficking. It is believed that zinc may be mechanosensitive;
however, the relationships between mechanical loading, zinc homeostasis, and fracture healing remain
unclear. This project will generate preliminary data regarding the relationships between mechanotransduction
in regenerative cells and establish links between mechanical load transfer and intracellular Zinc homeostasis in
bone fractures. Our global hypothesis is that the combination of zinc with mechanical loading will lead to
synergistic bone healing responses. In Aim 1, we will extend our existing K25 study with an in vivo rat femoral
osteotomy model and determine changes in bone healing caused by zinc delivery and load transfer. Sprague
Dawley rats will undergo femoral osteotomy and reconstruction. Mechanical loads across the callus will be
controlled with either rigid locking plates (0-3% strain, low load across fracture) or more compliant locking
plates (10-15% strain, high load across fracture). Zinc levels in animals will be manipulated locally by
implantation of a non-loadbearing intramedullary nail. We hypothesize that the combinatory application of
mechanical loads and localized zinc delivery will lead to synergistic improvements in bone healing that are
demonstrated by faster and more robust development of callus. Changes in bone healing will be quantified
with micro-CT imaging, biomechanical testing, histology, and qPCR. In Aim 2, we will define the causal
relationships between zinc delivery, load transfer, zinc storage/trafficking, and osteoblast formation in an in
vitro cell culture model. Here, we will use cell culture techniques to examine the fate of human mesenchymal
stem cells. We hypothesize that zinc-rich cells plated on stiff, smooth surfaces will elicit improved osteoblastic
proliferation and superior calcium matrix formation. These experiments will yield fundamental new
understanding into the mechanisms by which cells receive and respond to mechanical stimuli and provide
foundational data for long-term development of Zinc-augmented mechano-therapeutics. Characterizing these
relationships may have immense implications for cellular mechanobiology and development of mechano-
therapeutic approaches for bone regeneration and repair.

## Key facts

- **NIH application ID:** 11250194
- **Project number:** 7R03AR082449-02
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Michael William Hast
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $92,080
- **Award type:** 7
- **Project period:** 2023-09-18 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11250194

## Citation

> US National Institutes of Health, RePORTER application 11250194, Localized small molecule delivery to improve tendon-to-bone integration following anterior cruciate ligament reconstruction (7R03AR082449-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11250194. Licensed CC0.

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