# Micrococcal nuclease-triggered antibiotics release: a prophylactic implant coating against S. aureus infections

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $489,447

## Abstract

PROJECT SUMMARY/ABSTRACT
Periprosthetic infections is one of the most serious complications in orthopedic surgeries, occurring in 1-4% of
primary total joint replacement and up to 30% of revisions. Infections caused by Staphylococcus aureus (S.
aureus), the most prevalent microbial culprit in orthopedic infections, are particularly hard to treat due to their
tendency to form biofilms on implant and notorious ability to invade the canalicular network of surrounding
bone. Existing prophylactic antibiotic deliveries involve high drug doses that are unsafe yet ineffective and
could lead to the development of drug resistance. Utilizing an oligonucleotide linker labile to S. aureus
micrococcal nuclease (MN) cleavage, we recently developed a hydrogel capable of on-demand release of
covalently tethered vancomycin. When applied as a hydrogel coating to Ti6Al4V intramedullary (IM) pin and
inserted to mouse femoral canal inoculated with S. aureus, the MN-triggered release of vancomycin timely
killed the bacterial on implant surface and within IM space before they had a chance to colonize or invade
surrounding bone, thereby preventing biofilm formation and osteomyelitis development in the 3 weeks
examined. The covalent tethering dose of vancomycin in this coating was orders of magnitude lower than the
typical prophylactic antibiotic content used clinically. The goal of the proposed study is to further engineer this
exciting on-demand drug release system to enhance its serum stability and rigorously examine its efficacy in
providing sustained protection against periprosthetic infections using two clinically relevant implant infection
models. In Aim 1, the oligonucleotide linker is chemically modified by selective 2'-O-methylation and
phosphorothioate modifications to achieved enhanced mammalian serum nuclease stability while maintaining
necessary sensitivity to MN cleavage. In Aim 2, the in vitro optimized nucleotide linker will be implemented in
MN-sensitive hydrogel coating and applied to Ti6Al4V IM pins for on-demand delivery of vancomycin. The
efficacy and safety of this prophylactic coating in providing timely and sustained protection against S. aureus
periprosthetic infections will be rigorously evaluated over 6 months using a rat femoral canal infection model. In
Aim 3, the efficacy of this on-demand antibiotic release strategy in reducing the high periprosthetic infection
rates following surgical debridement of previously infected rat femoral canal will be examined using a rat IM
implant revision surgery model. The degree of infections as a function of pin coating and bioluminescent S.
aureus inoculation are longitudinally monitored by bioluminescent imaging and µCT quantification of cortical
bone thickening at 2 weeks, 1, 2, 3 and 6 months, and by end-point quantification of bacteria on the retrieved
pin, torsion test of explanted femur and femoral histology at 1, 3 and 6 months. Long-term safety of the coating
is examined by systemic organ pathology...

## Key facts

- **NIH application ID:** 10072811
- **Project number:** 1R01AR078044-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jie Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,447
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072811

## Citation

> US National Institutes of Health, RePORTER application 10072811, Micrococcal nuclease-triggered antibiotics release: a prophylactic implant coating against S. aureus infections (1R01AR078044-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10072811. Licensed CC0.

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