NIH grant: Immune reprogramming with bioengineered scaffolds for the treatment of biofilm infection (1R01AI192682-01A1)

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NIH grant 1R01AI192682-01A1: Immune reprogramming with bioengineered scaffolds for the treatment of biofilm infection
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Bin  Duan. Award: $762758.
Start: 2026-06-24T00:00:00.
A craniotomy is a common neurosurgery where a portion of the skull is removed (bone flap) to access the brain
for procedures that include tumor resection, resection of epileptogenic foci, and aneurysm clipping, where the
bone flap is replaced intraoperatively. Nearly 1 million craniotomies are performed in the US annually, which
increases to ~14 million worldwide. Despite prophylaxis, infectious complications after craniotomy average from
1-3%, with upwards of 15% depending on the institution. Over 75% of infections are due to gram-positive
Staphylococci, with approximately 50% attributed to Staphylococcus aureus (S. aureus), which forms a biofilm
on the bone flap. Therefore, considering the volume of craniotomy procedures, the incidence of craniotomy
infection is significant. Currently, there are no existing methods to treat craniotomy infections without surgical
interventions because the biofilm elicits aberrant immune responses. Systemic antibiotics require weeks to
months for therapeutic levels to accumulate in the brain, which is inefficient and may promote antibiotic
resistance, microbiome dysbiosis, and other adverse side effects. Therefore, there is a critical need to develop
more effective treatment strategies for combating post-surgical infection. This project will leverage our novel
mouse model of S. aureus craniotomy infection and 3D bioprinted antibiotic scaffold technology to develop and
implement new engineered systems. Our 3D bioprinted scaffolds are based on two strategies- (1) targeted and
refillable antibiotic administration; and (2) controlled delivery of immune mediators to promote macrophage
recruitment and activation. The bioengineered scaffolds will be used to treat craniotomy infections and serve as
a controlled system to explore how S. aureus adapts to immune and antibiotic pressure in vivo using bacterial
scRNA-seq. In addition, the efficiency of persister cell eradication will be assessed using a comprehensive set
of validated assays. This proposal will explore the hypothesis that both immune-targeted and antibiotic
formularies will provide benefit to clear chronic S. aureus craniotomy infection and that biofilm differentially reacts
on a transcriptomic level to immune-mediated and antibiotic pressures. This will be examined in the following
Specific Aims: 1) Determine the functional activity of refillable antibiotic scaffolds to clear S. aureus craniotomy
infection; 2) Explore the efficacy of immune-mediated therapy for the treatment of craniotomy infection; and 3)
Identify the genetic mechanisms of how biofilm adapts to select pressures in vivo. The broader applicability of
our scaffold formulary will also be tested against other craniotomy pathogens including E. coli and P. aeruginosa.
Several variables of the scaffold system are tunable, including loading materials and conditions as well as dosing
amounts and times, and the plug-and-play nature of our click chemistry system allows for integration with a panel
of various antibiotics and immune activators as a path towards personalized medicine. Our bioengineered
antimicrobial scaffolds will advance the field with the features of sustained antibiotic and inflammatory mediator
release directed to the site of infection, which concentrates therapeutic efficacy and minimizes off-target effects.

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