03-02 girl brushing teeth

[Image above] Credit: Diana Polekhina, Unsplash

Bioactive glass took quite the journey to incorporate itself into your morning routine—that is, if you live in the United States. If you do, you may be excited to know that U.K.-based company BioMin recently received FDA premarket clearance for its bioactive glass-containing toothpaste, opening the door for this product to finally be offered on the U.S. market.

Of course, if you live outside the U.S., you might already be quite familiar with bioactive glass toothpastes, which have been available in other countries for at least a decade now.

If you’re not familiar, bioactive glass—in addition to the material’s countless other biomedical applications—is a beneficial additive in toothpaste, both anecdotally and in reported scientific research. After brushing with toothpaste that contains bioactive glass, the bioactive material reacts with saliva in the mouth and forms a protective mineral layer on the surface of your teeth. This layer is reported to help strengthen the enamel (although not necessarily repair any damage), protect against acid erosion, and, perhaps most notably, effectively treat tooth sensitivity.

Tooth sensitivity is an incredibly common condition caused by weakening or wearing down of the protective outer enamel coating on your teeth. That loss of protection exposes the layer underneath the enamel—called the dentin—where openings called tubules provide a direct pathway to nerves within the tooth’s pulp chamber. When exposed to hot or cold substances such as coffee or ice cream, fluid flow in those tubules triggers the sensation of pain that is the absolute annoyance we call tooth sensitivity.

Bioactive glass toothpastes, along with other treatments for sensitive teeth, work by blocking those dentin tubules, preventing access to the nerve. The advantage of bioactive glass in particular is that it offers much longer-lasting, robust, and effective blockage.

Yet despite this knowledge, regulatory approval has hampered the availability of bioactive glass toothpaste in the U.S. market.

Why? The story stretches back to 2009, when pharmaceutical giant GlaxoSmithKline (GSK) acquired bioactive glass startup NovaMin for some $135 million. Despite the acquisition, in the years following, GSK proceeded to offer its Sensodyne Repair and Protect toothpaste product in markets beyond the U.S. with NovaMin bioactive glass included, yet puzzlingly omitted the bioactive glass from such products sold in the U.S.—a decision that caused former ACerS editor Peter Wray to scratch his head and write this popular CTT post from 2013.

There have been a lot of speculations and even conspiracy theories as to the omission, but it seems to come down to a lack of U.S. FDA clearance and the company deciding against investing to further pursue that clearance. Other countries outside the U.S. categorize toothpastes as a different type of product (cosmetics rather than drugs), so less prohibitive regulatory processes allowed bioactive glass to be more easily incorporated into toothpaste products abroad.

According to an article on Medium from someone with reported knowledge on the topic: “If GSK were to make therapeutic claims about NovaMin in their toothpaste, GSK would need FDA-approved evidence to back up those claims. Running the required studies is expensive. The projected increase in revenue could not justify the costs.” (There is much speculation here, which I won’t get into.)

So U.S. markets have been mostly denied access to the benefits of bioactive glass toothpaste. While some in the U.S. privy to those benefits have taken to purchasing the product abroad, BioMin’s new announcement and regulatory clearance indicate that soon may no longer be necessary.

BioMin Restore Plus is set to be available in the U.S. in spring 2021. Credit: BioMin

BioMin is bringing bioactive glass back

I first wrote about BioMin on CTT back in 2016, when the company was first releasing its bioactive glass toothpaste in the U.K., with hopes to eventually gain FDA approval so that it could expand to toothbrushes across the U.S.

Now, nearly five years later, that is finally happening. BioMin will offer its Restore Plus toothpaste under the Dr.Collins brand as the “first fluoride-containing bioactive glass toothpaste to be approved by the FDA for sale in the United States,” according to a BioMin press release. The toothpaste will be available with a prescription in the U.S. starting spring 2021.

BioMin Restore Plus contains just 5% of its BioMin F bioactive glass formulation, but that small amount of bioactive material confers a disproportionately large benefit with its ability to form a long-lasting, acid-resistant, protective barrier on the tooth’s surface. BioMin F is not the same as NovaMin bioactive glass, however, as BioMin F contains fluoride as well.

This point is an important one because it means brushing with BioMin F results in release of fluoride, calcium, and phosphate ions to form a protective layer of fluorapatite on the tooth’s surface, in contrast to the hydroxyapatite layer that forms from calcium and phosphate ions with NovaMin.

“Fluorapatite is about a unit of pH more stable than hydroxyapatite. So hydroxyapatite will start to dissolve at about pH 5, whereas fluorapatite will start to dissolve at about pH 4. So once you form fluorapatite, it’s less likely to be dissolved away. And that gives us an advantage,” says Robert Hill, materials engineer and chief scientific officer for BioMin, in a video conference call.

While many other kinds of toothpastes contain fluoride in a soluble form, BioMin F is different in that it incorporates the fluoride into the glass structure. This strategy allows fluoride ions, as well as calcium and phosphate ions, to slowly dissolve from the bioactive glass over time, achieving a sustained release effect after brushing—at neutral pH, up to 8–12 hours.

Those ions are what react in the mouth to form the protective fluorapatite layer on the tooth, so the process extends long after you put your toothbrush down.

“The uniqueness is for the first time we’ve got this controlled delivery of fluoride, which is what’s always been wanted in dentistry, but nobody has really been able to get a low-level fluoride for long term delivery,” says Richard Whatley, CEO of BioMin, in the call.

This unique feature offered a unique challenge in terms of designing the bioactive glass, Hill says, because simply mixing the ions together would result in formation of fluorapatite in the toothpaste rather than on the tooth’s surface. So BioMin designed the fluoride into the glass amorphous matrix so that it can be slowly released as the bioactive glass dissolves.

“We’re really using the glass as a slow release vehicle,” Hill says.

BioMin F bioactive glass incorporates fluoride into the glass structure to achieve slow release over time, whereas toothpastes that incorporate soluble fluoride generate high initial fluoride levels that decrease quickly after brushing. Credit: BioMin

“One of the big issues is you need quite a disruptive glass network,” Hill says. Instead of being heavily crosslinked, as some other types of glass might be, the structure of the bioactive glass needs to be much more open, he explains. “And that means that they can rearrange and crystallize very easily when you’re making them. So the trick is to be able to make a low network connectivity glass without it crystalizing. That’s the challenge.”

The resulting fluoride-containing bioactive glass that BioMin developed, called BioMin F, has higher phosphate content—about three times as much—as NovaMin, along with a lower silica content. BioMin’s bioactive glass also has smaller particle sizes, which allow them to fit better within the tubules to block access to the tooth nerve.

Micrographs showing open dentine tubules that cause tooth sensitivity (left) are blocked after brushing with bioactive glass toothpaste (middle), and the protection remains after an acid challenge to simulate what happens in the mouth (right). Credit: BioMin

The smaller size of BioMin’s particles also mean that the toothpaste itself is less abrasive. “The problems we have today with everybody using abrasive whitening toothpaste is the high abrasion causes a lot of damage to the tooth surface,” says Colin Suzman, a dentist and owner of Dr.Collins, in the call. “But BioMin has a low relative dentin abrasion value, below the level that would cause abrasion of the tooth surface. So it’s not only a chemical advantage but a mechanical advantage as well.”

While the effects of the fluorapatite layer that forms on the tooth’s surfaces are not permanent, continued use of a bioactive glass toothpaste can help maintain the protection long-term. According to BioMin’s website, “When BioMin F is used regularly, a coating of acid-resistant fluorapatite is continuously produced, building and maintaining an enhanced natural defence for teeth and occluding exposed tubules to counter dentine hypersensitivity.”

FDA clearance

BioMin received 510K premarket clearance from the FDA, a certification that clears the way for a product to be offered on the market. An accepted 510K demonstrates that a product is similar to an existing product on the market, so this clearance process can bypass the lengthy and expensive clinical trials that would be required to bring a completely new product to market.

“I think the biggest hurdle was, generally speaking, we didn’t really have a solid predicate device that was actually on the market,” says Suzman, who was closely involved with the BioMin Restore Plus FDA clearance process. “So finding the right device and using that sort of as a bridge between our product and the discontinued NovaMin product was probably a challenge. There was a lot of back and forth with the FDA.”

One of the factors that the team says helped them gain clearance was that, because the fluoride is incorporated into the glass structure, the product was not considered by the FDA as a combination product. If the toothpaste contained bioactive glass and, separately, fluoride, the FDA would consider that two active ingredients. BioMin has only active ingredient, BioMin F, which likely helped gain the FDA clearance.

Although BioMin Restore Plus will soon be available in the U.S. market, it will require a prescription. Yet Whatley says that taking a prescription route is a common trajectory to initially get a product onto the market because it provides time to accumulate additional safety data, making it easier to eventually make a product more widely available, say as an over-the-counter product. “Many other products that had FDA approvals, they start off as a Rx products. And they morph over time as they can show more data that there’s no risk. And risk is very low in this product,” he says.

FDA clearance is a big deal for other products as well, whether from BioMin/Dr.Collins or their competitors. Now that one product is on the market, it could provide an established precedent that makes it much easier for similar types of products to come to market. Having a similar product on the market, what the FDA calls “substantial equivalence,” was one of the main hurdles that BioMin Restore Plus faced. But with that hurdle now cleared, future 510K applications for similar types of products may be easier to get accepted.

While that’s encouraging in terms of the availability of other oral care products that leverage the potential of bioactive glass, expansion could also be problematic if companies make false claims about the materials they incorporate into their products.

“There are some dental companies producing so-called bioactive materials that are actually not doing what they supposed to do, and they are promoting these products,” Suzman says. “Dentists are buying into it, and these are leading to restorative failures and secondary decay underneath existing so-called bioactive materials. Robert has done some research on some of these materials and found out that they’re not doing what they claim.”

Those false claims threaten to tarnish the reputation of bioactive glass and bioactive glass-containing products, a legitimate concern not only in terms of ineffective devices but also public perception and market acceptance. 

Expanding horizons

If you read the feature article of the December 2020 ACerS Bulletin, you know that bioactive glass is a hot topic in many areas of biomedical research and development, and tooth applications and oral care are certainly no exception.

So it is no surprise that BioMin’s 510K clearance is set to open a door for the company. The $10.7 billion value of the dental industry in the U.S. alone means there is rich potential residing within our mouths. “So there will be a suite of products all around the oral hygiene side,” Whatley says.

For instance, BioMin is currently working on developing self-healing tooth fillings containing bioactive glass. Hill explains, “Rather than using inert glass in a resin matrix, we use some of the slightly different fluoride glasses from the ones used in the toothpaste. These ones we’re designing so that if you’ve got any decay left by the dentist, providing it’s not decay of the protein component, you can actually put back the mineral into the decay and dentine. And it will also deposit mineral in any gaps caused by polymerization shrinkage.”

Hill says a paper describing this research was recently accepted and will be published soon, providing some of the scientific evidence needed to back such new developments.

And there are likely to be many more. “I think bioactive glasses have got a huge potential in oral care. We’re looking at the next, say, 20 years,” Whatley says. “We obviously believe this and hope this, but I think bioactive glasses have a huge opportunity to change and to improve the quality of materials used in dentistry.”

Correction (3/5/2021): An earlier version of this story indicated that BioMin Restore Plus received FDA approval, rather than FDA clearance.