In the battle against herpes simplex virus (HSV), 3D printing technology is offering a new approach to drug development by creating models of human skin. Current antiviral drugs often fall short because they cannot replicate the complexity of human tissue. To address this, Dr. Jia Zhu from the Fred Hutch Vaccine and Infectious Disease Division, alongside biofabrication experts Dr. Ian Hayman and Dr. Tori Ellison, is using 3D printing to develop these models, enhancing the precision of virus studies.
Herpes Simplex Virus (HSV) and Current Treatments
Herpes Simplex Virus (HSV) affects about two-thirds of the global population. While many individuals remain asymptomatic, others experience painful flare-ups that can significantly impact their quality of life. Antiviral medications like acyclovir, famciclovir, and valacyclovir help manage these outbreaks by reducing their frequency and severity. However, these treatments do not cure the virus, which can remain dormant in sensory neurons, evading both medications and the immune system. Their effectiveness may also diminish over time, particularly in patients with resistant HSV strains.
Dr. Zhu explained that current antivirals were developed using simplified cell cultures, which often fail to replicate the complexity of human tissues. As a result, these treatments underperform in real-world infections and struggle to fully address the virus’s behavior in the body. “The antivirals we use to treat HSV today were developed using in vitro culture of Vero cells and fibroblasts. It’s perhaps not surprising that these antivirals show sub-optimal performance in HSV infections in patients,” said Zhu.
Dr. Jia Zhu Research and the Future of HSV Treatment
To address the challenge of limited accuracy in traditional models, the team developed ‘3D-bioprinted human skin equivalents’ by depositing fibroblasts into culture vessels, layering keratinocytes on top, and incubating the cells in various media formulations. This technique produced organoids that replicate human skin, including both dermal and epidermal tissues.
To gain a deeper understanding, the Zhu research team developed two organoid models to replicate different stages of HSV infection: a submerged model, simulating an initial infection through a break in the skin, and an air-liquid interface (ALI) model, which mimics flare-ups from latent reservoirs in the body. These models were used to screen 738 medicinal compounds, including both novel and FDA-approved drugs.
Using a recombinant HSV that expressed a green fluorescent protein alongside fibroblasts labeled with a red fluorescent protein, the team employed high-content fluorescent microscopy to examine the drugs’ direct effects on the virus. They assessed how effectively the treatments reduced the green HSV signal, while also evaluating potential off-target effects on host cells.
Among the tested drugs was acyclovir, the current standard of care for HSV. Researchers found that acyclovir was less effective in the submerged model, where HSV primarily infects keratinocytes, compared to the ALI model. This suggests that acyclovir may not be potent enough to control HSV in keratinocytes, potentially explaining its inconsistent effectiveness in treating flare-ups in patients.
Beyond the results with acyclovir, the researchers identified nearly 20 other antiviral compounds that showed promise in suppressing HSV infection with minimal toxicity to surrounding cells.
Moving forward, the focus will shift to further analyzing the top antiviral candidates and advancing the development of their organoid models. “We are particularly excited at the prospect of using patient-derived cells to 3D-print the next generation of these skin organoids because this would allow us to incorporate patient-specific biology into the drug discovery pipeline, and ensure that the drugs we are spending time and money to test are actually showing effectiveness in the cellular environments they will eventually be used in,” said Hayman and Zhu.
Breakthroughs in Health Technology with 3D Printing
For years, companies have turned to 3D printing to gain deeper insights into viruses, diseases, and medical conditions. In 2020, researchers from the USA and Germany introduced a new approach to studying glioblastoma (GBM), an aggressive brain tumor, with 3D printing. By combining a 3D bioprinted model with advanced imaging techniques, this approach aims to enhance our understanding of tumor growth and accelerate the development of potential treatments. The integration of 3D imaging offers a non-invasive way to assess tissue structures, improving the research process.
In another advancement, the NOVOPLASM consortium developed cold plasma technology for treating infected burns and promoting skin graft healing. By using their 3D bioprinted CTISkin model, NOVOPLASM has been able to implement clinical strategies for skin healing and burn patient care. Once finalized and approved, this advanced medical device will be available for use in hospitals and specialized burn treatment centers, offering a cutting-edge solution to improve patient outcomes.
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