# Customized MSCs to Enhance Healing of Bone Defects

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $347,266

## Abstract

Healing of large residual long bone defects associated with trauma, infection, irradiation, wear particle disease
and other conditions is still an unsolved clinical challenge. These bone defects often will not heal due to their
size, injury to the periosteum and endosteum, and insufficient numbers of osteoprogenitor and vascular
progenitor cells. Autologous bone grafting is the gold standard for treatment, however this source can be
limited in quantity or quality, and accompanied by morbidity at the harvest site. Another approach is to
combine autologous harvested and concentrated progenitor cells with an appropriate scaffold to provide the
elements for bone healing. We recently showed that preconditioning of MSCs with lipopolysaccharide (LPS)
and tumor necrosis factor-α (TNF-α) to induce acute transient activation of NF-κB enhances osteogenesis, and
improves MSCs' ability to polarize macrophages from a pro-inflammatory (TNF-α+, iNOS+) to a more
favorable anti-inflammatory pro-tissue healing (Arginase 1+, CD206+, IL1Ra high) phenotype. We have also
genetically modified MSCs (hereafter termed GM MSCs) to over express the anti-inflammatory, pro-tissue
healing molecule Interleukin-4 (IL-4), and furthermore created a construct to first sense NF-κB activation and
then increase production of IL-4 (NF-κB sensing and IL-4 secreting GM MSCs). These GM MSC would be
very beneficial for bone defects in which low-grade subacute/chronic inflammation is also present, a scenario
frequently seen clinically. The purpose of this grant is to accelerate the healing of long bone defects via
immune modulation using preconditioned MSCs and GM MSCs, in a unique injectable macroporous
scaffold, transplanted directly to the bone defect site.
Specific Aim #1: To determine whether transplanted preconditioned MSCs, GM MSCs, and preconditioned
GM MSCs delivered via a novel injectable macroporous hydrogel scaffold are better than autograft bone with
respect to in vivo healing of: SA1a: an acute critical size murine long bone defect; SA1b: a chronic critical size
murine long bone defect
Specific Aim #2: To demonstrate that the above principles of enhancing the healing of acute and chronic long
bone defects are valid for: SA2a: male and female mice; SA2b: younger and more elderly mice
Specific Aim #3: To compare the most promising of the MSC treatments with autograft bone in a more
challenging chronic critical size defect in larger and older animals: male and female elderly NZ white rabbits.
We expect that addition of preconditioned or GM MSCs in a novel scaffold will lead to similar bone healing at
sacrifice, compared to addition of autograft bone, but superior to addition of unaltered MSCs. Treatment with
primed preconditioned or GM MSCs is highly innovative, mechanistic and directly translational to traumatic and
acquired acute and chronic long bone defects in humans, and may be an effective, less invasive alternative to
conventional bone graft techniques.

## Key facts

- **NIH application ID:** 9897409
- **Project number:** 5R01AR073145-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** STUART B GOODMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,266
- **Award type:** 5
- **Project period:** 2018-05-09 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897409

## Citation

> US National Institutes of Health, RePORTER application 9897409, Customized MSCs to Enhance Healing of Bone Defects (5R01AR073145-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897409. Licensed CC0.

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