# Bone-targeted polymer therapeutics for nonunion fracture healing

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $1

## 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. There is a reduction in overall
number and regenerative capacity of MSCs within a critical sized defect. Deficient MSCs reduces cartilage and
bone formation, soft callus remodeling, mineralization, and expression of critical osteogenic growth factors
within the callus. Additionally, prolonged inflammation contributes to aging-related changes that underlie
nonunion development. 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 callus
ossification. Finally, the maximum torque to failure of treated fractures was ~3-4-fold greater than controls 4
weeks after treatments. However, the potential of this technology within more clinically relevant situations (e.g.,
acute and established fracture nonunions in adult and aged models) is critical for further development, setting
up this high-risk/high-reward proposal. With the hypothesis that TBP-NPAR28 will enable drug delivery to
promote healing in fracture nonunions in aged and adult mice, the following aims are proposed:
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:** 10371267
- **Project number:** 1R21AG072692-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Danielle S. Benoit
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 1
- **Project period:** 2022-08-15 → 2022-08-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371267

## Citation

> US National Institutes of Health, RePORTER application 10371267, Bone-targeted polymer therapeutics for nonunion fracture healing (1R21AG072692-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371267. Licensed CC0.

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