# Validation of pre-clinical models of musculoskeletal healing following trauma

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

With aging, there is a precipitous loss in activities of daily living (ADLs), and a decline in the function and repair
of musculoskeletal (MSK) tissues is a significant contributor to this loss. Veterans are particularly vulnerable to
a reduction in ADLs because the likelihood of experiencing severe trauma that injuries multiple MSK tissues is
higher in military service than in civilian life. While these severe traumatic injuries are less life-threatening now
than in the past, complications of MSK regeneration arise and lead to the requirement of assisted living later in
life. Thus, there is a strong need for preclinical models of polytrauma injury that facilitate studies into the
mechanisms connecting poor MSK repair to fewer ADLs. Several such models exist in the literature, but none
have been validated with respect to the key clinical problems associated with impaired MSK regeneration,
namely delayed fracture healing, muscle fibrosis or soft tissue calcification, osteoporosis, cognitive impairment,
pain sensitivity, and hyper-inflammation. Therefore, the goal of this project is to validate a murine model of
combined injuries – skin burn, muscle injury to the lower hindlimb, and fracture of the femur mid-shaft – for its
ability to recapitulate many of the problems that reduce ADLs. In Aim 1, we will compare the healing response
of adult, transgenic mice among 3 injury groups: i) single femur fracture or single muscle injury in the lower
hindlimb, ii) femur fracture plus single muscle injury, and iii) combined femur fracture, muscle injury, and skin
burn. These transgenic mice express luciferase when the NFκB regulatory element is active, thereby allowing
us to image tissue inflammation by bioluminescence. To validate the model, we will determine if fracture healing
is delayed at 28-days post injury (DPI) and muscle fibrosis persists at 42-DPI in the polytrauma mice compared
to the single injury mice. In Aim 2, using the same mice in Aim 1 but adding sham littermates (no injury), we will
compare the effect of injury on degeneration among 5 groups: i) sham control, ii) single femur fracture, iii) single
muscle injury in the lower hindlimb, iv) dual injury to bone and muscle, and v) combined polytrauma injury with
skin burn. Starting at baseline (before injury) and at post-injury intervals, areal bone mineral density (dual-energy
X-ray absorptiometry) of the uninjured femur, whole-body weight (mass), cognitive function (novel object
recognition test), pain sensitivity (allodynia and hyperalgesia to mechanical stimuli), duration of sleep (cage
activity), and mobility (voluntary wheel running plus gait analysis) will be assessed until 42-DPI. Additionally, the
contralateral, uninjured femur and the lumbar vertebral body will be imaged ex vivo by μCT and subjected to
load-to-failure tests in three-point bending (femurs) or in compression (vertebra) to determine whether the cortical
structure, trabecular micro-architecture, volumetric bone mineral den...

## Key facts

- **NIH application ID:** 10871803
- **Project number:** 5I01BX005062-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jeffry Stephen Nyman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871803

## Citation

> US National Institutes of Health, RePORTER application 10871803, Validation of pre-clinical models of musculoskeletal healing following trauma (5I01BX005062-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871803. Licensed CC0.

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