# Bone-targeted polymer therapeutics for non-union fracture healing

> **NIH NIH R21** · UNIVERSITY OF OREGON · 2022 · $184,375

## Abstract

Of the more than 15 million Americans suffer from fractures each year, 5% result in nonunions. Standard
nonunion management is revision surgery: debridement, followed by autograft, and/or additional fixation.
However, revision surgery carries risks inherent to any surgery and fails in up to 60% of cases due to
underlying comorbidities. Therefore, novel therapeutics for treating nonunions are critical and should obviate
surgery through noninvasive delivery or increase revision surgery success. Mesenchymal stem cell (MSC)
deficiencies underpin poor healing. Despite the promise of several drug candidates for augmenting MSC
function for nonunion healing, side effects due to poor fracture biodistribution have hampered development.
Thus, a critical technological gap exists in delivery of potent, regenerative drugs to fracture sites while
limiting biodistribution to off-target tissues to improve safety and clinical translatability. To address these
hurdles, we have developed a fracture-targeted nanoparticle (NP)-based delivery system for the GSK-3β
inhibitor AR28 to upregulate the regenerative Wnt/β-catenin pathway. Targeting is achieved by incorporation of
a peptide that binds specifically to tartrate resistant acid phosphatase (TRAP5b), a matrix-bound protein
deposited by osteoclasts throughout healing and at nonunions. TRAP5b-binding peptide (TBP) targeted NP
exhibit preferential accumulation at conventional femur fractures. Fracture localized activation of β-catenin is
greatly increased compared with untreated, free drug, untargeted NP, and scrambled peptide NP controls.
Expedited callus formation was observed in fractures treated with TBP-NPAR28 versus controls with more rapid
ossification of cartilage callus. Finally, the maximum torque to failure of treated fractures was ~3-4-fold greater
than controls 4 weeks after treatments. While promising to expedite healing in conventional fractures that will
regenerate without intervention, the efficacy of this technology must be tested in more clinically rigorous and
relevant preclinical models. We hypothesize that TBP-NPAR28 will enable drug delivery to fracture nonunions in
aged and adult mice. With a long-term goal of treating fracture nonunions using this approach, we propose the
following aims:
Aim 1: Assess the therapeutic effect of a TBP-NPAR28 for the prevention of nonunion in adult and aged
murine models.
Aim 2: Assess the therapeutic effect of TBP-NPAR28 in fully established nonunions in adult and aged
mice.
Successful completion of these Aims will significantly advance our ability to target drugs to prevent or enable
healing of adult and aged nonunion fractures.

## Key facts

- **NIH application ID:** 10733942
- **Project number:** 7R21AG072692-02
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Danielle S. Benoit
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $184,375
- **Award type:** 7
- **Project period:** 2022-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10733942

## Citation

> US National Institutes of Health, RePORTER application 10733942, Bone-targeted polymer therapeutics for non-union fracture healing (7R21AG072692-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10733942. Licensed CC0.

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