# The Development and Rescue of an Atrophic Nonunion Model

> **NIH NIH F32** · WASHINGTON UNIVERSITY · 2021 · $22,960

## Abstract

PROJECT SUMMARY/ABSTRACT
 Nonunion is defined as the permanent failure of a bone to heal, where surgical intervention is required
to achieve healing [1]. There are two types of nonunion, hypertrophic and atrophic, and at the 2018 Intl.
Society of Fracture Repair (ISFR), a need for new models of atrophic nonunion was identified. Animal models
of atrophic nonunion have been around as early as 1999, providing an in vivo representation of the bone's
inability to heal, resulting in nonunion [1, 2]. However, the majority of the animal models used to replicate
nonunion involve osteotomy, periosteal stripping, bone marrow removal, devascularization, or the creation of a
critical-sized defect. While all approaches result in nonunion, such invasive methods are not representative of
many clinical nonunions where osseous regeneration has been arrested by a disturbance of metabolic
pathways [3, 4]. The “failure of biology” seen in atrophic nonunion should, instead, be modeled closely to those
seen clinically with a reduced/absent callus. Thus, there remains a need for the development of a more
relevant, pre-clinical nonunion model to test therapeutic interventions.
 In a previous study by Jilka et al. [5], 3.6Col1a1-tk (Col1-tk) mice were developed in which proliferating
osteoblast lineage cells can be ablated through exposure to the nucleoside analog ganciclovir (GCV). In
preliminary studies in our lab, we have observed that ablation of proliferating osteoblasts in the Col1-tk mice
causes a failure to form a callus. We posit that a more comprehensive assessment of the impaired healing in
the Col1-tk mice may lead to its establishment as a useful atrophic nonunion model. Further, in atrophic
nonunion, the bone healing has become stagnant and the addition of a biological agent, such as a bone graft,
is often necessary to induce regeneration. We propose that a tissue-engineered scaffold-mediated gene
delivery of a bone marrow mesenchymal stem cell (MSC) population overexpressing the osteogenic transgene
bone morphogenetic protein-2 (BMP-2) will induce osteogenesis at the site of nonunion [6-10]. This research is
significant to not only establish a clinically relevant model of atrophic nonunion, but also explore a novel rescue
technique to restore healing, following the NIAMS mission of treating musculoskeletal injury and disease.

## Key facts

- **NIH application ID:** 10242918
- **Project number:** 5F32AR076191-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Katherine Hixon
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $22,960
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242918

## Citation

> US National Institutes of Health, RePORTER application 10242918, The Development and Rescue of an Atrophic Nonunion Model (5F32AR076191-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242918. Licensed CC0.

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