Journal club: Using micro-needle to deliver gene therapy via the round window.

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Today's journal article

Hammer DR, Voruz F, Aksit A, Breil E, Rousset F, Senn P, Ilmjärv S, Olson ES, Lalwani AK, Kysar JW. Novel dual-lumen microneedle delivers adeno-associated viral vectors in the guinea pig inner ear via the round window membrane. 

Why I picked this article

Inner-ear gene therapies often need relatively large volumes to be injected into the inner ear. This is currently done by surgical direct administration of the therapy into the inner ear. The challenge is the pressure spikes and fluid imbalance created during the injection of the volume, and the risk of any injury from the process. 

This research team had built a two-channel (inject + aspirate) microneedle to cross the round window membrane RWM. Using the guinea pig as the animal model, researchers have tested whether simultaneous aspiration can stabilise pressure while delivering adeno-associated virus (AAV).

Some of the research findings

Microneedle: 
  • Dual-lumen microneedle:
    • Design - drawn in SolidWorks (Dassault systemes, USA) computer aided design (CAD) software. 
    • Printing preparation - DeScribe (Nanoscribe GmbH, Germany)
    • Fabrication - 2PP, Nanoscribe Photonic Professional GT+ (Nanoscribe GmbH, Germany)
  • Dual-lumen microneedle was mounted on a blunt 30-gauge steinles-steel needle and connected to a micropump. 
Animal model testing: 
  • Guinea pig, < 1- month old (jugenile) 
  • What to deliver: AAV-PHP.eB vector or AAV-PHP.eB-cmv-GFP packed into AAV9. 
  • Under anaesthesia, auditory bulla was exposed and opened to access the round window. 
  • Injection: simultaneous 5 µL AAV-GFP injection and 5 µL perilymph aspiration across the round window membrane. 
  • Hearing assessment: auditory brainstem response (ABR) before and 1 week post-procedure.
  • Distribution assay: confocal imaging of the cochlea, utricle, and contralateral ear to check for the successful delivery of the viral vector. 
Outcomes: 
  • The device functioned in the operating setting. 
  • ABR threshold shifts were limited to high frequencies. +13 dB SPL at 24 kHz (p = 0.03) and +23 dB SPL at 28 kHz (p < 0.01) at 1 week post-surgery. 
  • Transduction pattern: 
    • AAV-GFP transduced cochlear hair cells with a stereotyped base-to-apex gradient in all animals (n = 5)
    • On average, ~80% in base, ~40% in mid- and 20% apex along the cochlea. 
    • Vestibular (utricle) labelling was documented. 
    • The contralateral ear was also evaluated and no transduction was observed. 

Part of visual abstract. Microneedle - Hammar et al. 2025

Haruna's takeaway

The design is an interesting idea. I wonder what would happen with transduction if you didn't have the second "aspiration channel" in place. The subtle shift in the ABR thresholds for all animals 1 week after the operation is a concern. I wonder if this will be considered a major risk. It might be very hard to mitigate this depending on the cause. 

3D design tool and printing/fabrication tool sounds powerful. I would love to be able to use those tools myself! 

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This is Haruna's 81/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.