Hi there,

We reached out to the manufacturer, Dr. Peter Pham at Zocular, and here is what he had to say.

"Thank you for reaching out to us about your concern after reading the study (https://pubmed.ncbi.nlm.nih.gov/32387382/). The is also a similar study on tea tree oil (https://pubmed.ncbi.nlm.nih.gov/32947397/), which has caused quite a bit discomfort among those who use tea tree oil .

It is indeed scary and worrisome for anyone who struggles with dry eye to read studies that use cells similar to those found in our own eyes. But I hope with some context and clarification, it'll be easier to understand how to accurately interpret cell culture studies.

There are two important issues that need to be addressed with regards to the meibomian gland cell culture studies. The first is the use of cell cultures and the second is the study design. As we know, cell cultures are a very poor approximation of complex biologic systems and is generally used to study cell signaling and cascades. Mammalian cell cultures require a constant and intricate mix of growth media as well as temperature and humidity control in order to survive. Vary any of these important parameters, and the cell culture will die even before any experiment begins. In contrast, most bacterial and fungal, especially the common ones like Staph aureus or Candida albicans, are much less susceptible to environmental changes, which helps to explain their pathogenic potential.

With regards to the study design, the meibomian gland cell culture study is actually a variation of a well known study that's used on a daily basis in laboratories throughout the world to assess for the effectiveness of preservatives. This test is called the "Preservative Efficacy Test", or PET. A PET is used to answer a very simple question - is a preservative able to extinguish the growth of common bacterial and fungal organisms? If a preservative is unable to stop microbial growth, then its obviously unsafe to use since no one would want a product contaminated with fungi and/or bacteria. This means that all preservative are toxic in nature when tested in vitro using cell cultures. And there is no such thing as "safe" preservatives. The "safe" preservatives that allow continued growth of microbial or mammalian cell cultures are actually the most unsafe preservatives, since they would fail the PET.

Knowing that mammalian cell cultures much more fragile than microbial ones and knowing that the cell culture study is actually a Preservative Efficacy Test, the correct interpretation of the preservative and tea tree oil studies using meibomian gland cells is that both tea tree oil and phenoxyethanol are effective preservatives, which has been well known for decades. The meibomian gland cell culture study also used serial dilution of the preservatives to show that the meibomian gland cells were able to survive at lower preservative concentration, suggesting that this may be the safe or safer concentration. A PET will often employ serial dilution to ascertain the preservative concentration at which the microbes grow, since the would be the UNSAFE concentration to use. One cannot conclude from the study that any of the tested ingredients (methylparaben, ethylparaben, phenoxyethanol, chlorphenesin) is toxic to human tissue since PET cannot answer this important question. A PET can only tell us if a preservative is effective, and the meibomian gland cell culture studies are really just preservative efficacy tests that used the wrong cell culture, resulting in an emotional rather than a clinical interpretation of the results. If the study had the headline "Phenoxyethanol eradicates the growth of Staph aureaus", we would thrilled and reassured. But change the headline to "Phenoxyethanol eradicates the growth of meibomian gland cells", our emotions hold sway.

We chose phenoxyethanol because its effectiveness and safety have been demonstrated over decades (see attachment). There's a lot of confusion and misunderstanding regarding preservatives, even among medical professionals, because we all want products that work but have little to no side effects. While this is true for some products for some people, it is not true for all products for everyone. And if a product is working well for you, there's no need to make changes unless things change."

So sorry to hear that! I wonder if it could possibly be the preservative? (It's Phenoxyethanol.)