Barry Lazarus, owner and managing director of Austramedex, shares his experience of researching and deciphering the various exosome products on the market:
Exosome therapy has burst onto the market, but with such a new technology, and a growing number of companies offering exosome products, how can you ensure which exosome brand is the best fit for you?
We conducted an extensive amount of market research to choose the right exosome product, and as Austramedex was the first Australian company to work with the technology, we had the choice of every brand on the global market. We started with one brand and as we learned more about the technology and other brands we then learnt why that brand wasn’t the best fit for us. We want to share the key points and findings that we used, in a hope that it can help you to select the best exosome product for your clinic.
Our three major points include:
- Stability
- Purity
- Source
Many would claim that “price” should have made the list, but for us this was not a deciding factor.
Stability
Exosomes come in 2 forms:
- Lyophilised (freeze-dried) needing reconstitution
- Pre-suspended
The vast majority of the brands on the international market are lyophilised. Lyophilising is a complicated and costly endeavour, so why do they do it?
It has been shown that suspended exosomes have a limited timeframe before they begin to denature. In fact, most of the brands suggest that after reconstitution the mixed solution may be stored in the fridge for up to 2 weeks, or frozen for up to 2 months. However, the pre-suspended products (which we started with) are shipped to you with a 12-24 month shelf life, shipped via standard shipping, with instructions to store in an ambient temperature. If other brands recommend refrigeration for 2 weeks, how can the pre-suspended brands claim that their product will be okay in 1-2 years at ambient temperature?
A basic search on PubMed will result in many results of clinical papers referring to lyophilising as the “Gold Standard” when it comes to preservation of the exosomes. Furthermore, to use other products/technologies as an example, botulin toxin comes lyophilised to ensure product stability. Also, clinical biologists rely on lyophilisation as a way to preserve cells or viruses when studying them. If the lyophilisation process was damaging to the cells/viruses, it would render all of their research as useless.
Our conclusion: select a brand that is lyophilised. This gives the best chance of a stabilised product. A stable product means more chance of the exosomes being effective, rather than just relying on the suspension solution of hyaluronic acid and various peptides to deliver results.
There is also an add-on to this point. Interestingly, not all lyophilisation techniques are the same. Most lyophilised exosomes on the market utilise mannitol or sucrose in the lyophilisation process, however E50 (the brand we ultimately selected) has pioneered the use of hyaluronic acid to essentially encapsulate the exosomes which adds a further layer of exosome preservation.
Purity
What is in the ampoule? We all assume that it is simply billions of exosomes in a hyaluronic suspension. Usually we are told by the supplier that the ampoule contains 5 billion, 6 billion or even 10 billion exosomes. But take a closer look at the brand’s literature – it will usually say in writing “contains 5 billion particles”.
Why? Basically speaking, the companies do not specifically count the exosomes; they count particles that fall into the size range that an exosome should be. Unfortunately, this means that in this count are exosomes, cellular debris plus a wide array of apoptotic bodies and non-exosome micro vesicles. This is normal, but impurities such as apoptotic bodies can be detrimental to surrounding exosomes and can also illicit a cytokine storm when exposed to the recipient’s cells.
Why are there apoptotic bodies in the mix?
All cells have an exosome, but the original concept of exosome therapy was to harvest an exosome (essentially the hard drive of the cell) from a stem cell. The logic being that the stem cell “hard drive” contains every possible file the body could need.
This is a great concept, but unfortunately, as these cell lines need to be expanded into cell counts in the billions-trillions (rather than being used fresh), a cellular expansion/ cellular culturing process must take place in a laboratory. For mesenchymal stem cells (MSCs), this process can take 1-3 months. Due to such a long time, there is a degree of cellular death that takes place, and this cellular death (apoptosis) leads to the creation of apoptotic bodies and cellular debris.
So how can we reduce the risk of apoptotic bodies, cellular debris and non-exosome micro vesicles?
There are 2 ways to do this:
- Use freshly sourced with no (or minimal) expansion.
- Use a cell type and/or technique that proliferates faster than cultured MSCs.
Fresh clearly isn’t as convenient, and is limited to who can perform and will almost always contain the exosomes still attached to their original cell. Minimally expanded is also possible but with massive cost due to limited access to the technology.
Alternate cell types and/or technique is a definite possibility. A great example is the use of skin fibroblast cells and, more recently, cells derived from salmon testis. Both of these cell lines, when combined with a specific ultrasound treatment, can massively reduce this expansion rate from months down to 12-48 hours. This massive reduction in time significantly reduces the risk of impurities.
Does this present a downside?
Let’s use the analogy of the hard drive again. If the MSC exosome has a hard drive that has all of the files to essentially create a human being, what files of benefit to your patient are in the fibroblast exosome or the exosome harvested from salmon testis?
This is where things really start to get more fascinating.
PrimaCure, the manufacturers of E50, have pioneered (and patented) a technique where they can choose the files that they want, then by using ultrasound can cavitate (or bounce) these files into the exosome prior to expansion. This means they are offering a “customised” or “engineered” exosome solution to treat specific concerns.
Furthermore, the exposure to ultrasound causes the cells to feel like they are under threat, significantly increasing the production of exosomes as the cells attempt to send out their signals and pass on their information before they die. This process not only enhances the quantity but also the quality of the exosomes produced.
We chose to move towards the “engineered” exosomes, but whatever you choose, try to ensure that the product contains as few impurities as possible. This will help keep your real exosome count higher and will also help reduce the risk of complications such as a cytokines storm.
What “files” to choose?
As all exosome products have globally been classified as topical cosmetics, we are bound to be treating concerns of the skin and hair. Considering this, we don’t really need the cardiothoracic “files”, the kidney files, gastrointestinal files, ocular files, etc. We only need the files that relate to skin or, in the case of a hair product, the files/proteins that relate to hair health and growth.
Exosome source
Most of the original leading exosome brands contain a mix of different MSC sources, including:
- Amniotic fluid
- Umbilical cord
- Fat
- Skin fibroblast (non MSC).
However, in recent times regulatory authorities in countries such as the UK, Singapore and we estimate soon to be Australia, have called for a stop on the use of human-derived exosome products. The regulatory concerns stem from a mix of ethical and safety. The primary perceived safety concern is around theoretical disease transmission.
In response to these concerns, there are more alternate products becoming available. As all cells contain an exosome, sourcing from alternate cells should be an easy step.
To guide through this point, we ought to refer back to a combination of basic medical/ disease history and high school biology.
Source → recipient
Human → Human. We know this works but there are regulatory concerns, including disease transmission.
Mammal → Human. This makes sense; we are mammals. However, medical/disease history has taught us that IF there is a concern of disease transmission from Human Human then the same could be the case for Mammal Human (Covid, AIDS, vCJD aka Mad Cow disease, etc)
Fish → Human. Historically this has a safe track record, plus we share an outstanding 85-90% DNA similarity to salmonoid species.
Plant → Human. Also has a good track record.
So, for alternate source options for exosomes, we can conclude that salmon derived and plant derived are logical options.
However, we should return to the hard drive analogy. Are there benefits in using plant or salmon derived exosomes if they don’t carry the “files” that are of benefit to the patient’s concerns? Fortunately, largely due to the DNA similarities between salmon and human, there are certain proteins that will be of benefit to human skin, probably not as much for hair, and as we all know, certain plants have been used in medicine (especially Eastern Medicine) for centuries but usually for inflammation reduction, etc.
Regardless of what “files” are in the harvested exosome, PrimaCure E50 have the patented technique for uploading the files into the target exosome, be it for skin or hair.
The final sub-topic of the exosome source category we need to cover is what we will call “connect-ability”.
All animal cells (including human cells) have an external structure called a dual lipid membrane. Thanks to this dual lipid membrane, the exosome can actually attach to the cell, not dissimilar to how bubbles connect to each other.
However, plant cells have a different structure, a cell wall. The dual lipid layer and the cell wall are not actually compatible. For this analogy I like to reference Lego.
Let’s say human cells are yellow Lego, salmon cells are pink Lego and cow cells are brown Lego. We can easily connect all of these parts, yellow to pink, pink to brown, etc. But plant cells aren’t Lego. Let’s think of them as green Duplo. Similar concept, a bit more basic, but definitely won’t attach. If they can’t effectively attach, they can’t transfer information.
Another way to think about this is trying to plug your iPhone charger into a Samsung device, as convenient as is would be to connect and work, it doesn’t.
Our opinion on this point is that human derived will phase out due to regulatory pressures, so stay with animal derived, but also be mindful of what “files” are in your selected exosome and how they may benefit your patient.
There is one more thing to be really careful about. We are now finding, due to these regulatory constraints demanding no more human sources, that several brands are claiming to be animal or plant sourced. Unfortunately, just recently 2 brands were banned in Singapore and in the UK for “claiming” to be plant sourced but were proven to still be human sourced.
Even though there is a tonne of, quite honestly, very confusing science and marketing information surrounding exosomes, I think that if you follow these 3 points you’ll be able to select the best possible product for your clinic.
Barry Lazarus is the owner and managing director of Austramedex, an established Australian manufacturer and distributor of high-quality medical devices. For more information visit austramedex.com/
