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What Is PRGF?

Published on Oct 13, 2021

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A new treatment called PRGF seems to have become popular this past year with physicians using orthobiologics. What is it? What’s it used for? What’s the evidence behind it? Why should you care? Let’s dig in?

What’s the Buzz About?

I was recently listening to a number of physicians who use orthobiologics discuss PRGF. There seemed to be an unusual buzz around it, so in my job as Chief Medical Officer for Regenexx, I have to investigate and learn what’s up. Since I do that by blogging, you’re coming along for the ride this morning as I perform a deep dive.

As I began this review yesterday, I really didn’t know much about the product. Hence, you’ll learn right along with me as I go deep into this topic.

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What Is PRGF?

PRGF stands for Plasma Rich in Growth Factors. There is a specific company called Endoret out of Spain that has a trademark on PRGF and that holds patents on the kits that doctors use to create the product. That company is also associated with both BTI (Biotechnology Institute) and the Eduardo Anitua Institute. The product has historically been used in dentistry and dental implants.

PRGF is made very similarly to PRP in that blood is placed in a blood collection tube containing anti-coagulant (ACD). That blood is then spun in a centrifuge to push the red and white blood cells toward the bottom half of the tube and keeping the plasma and platelets just above that layer. The platelet-rich layer just above the red cells is then collected. When used for injection this can be injected as a leukocyte-poor PRP (LP-PRP) and when used in surgery, it can be activated with calcium chloride and turned into a clot creating platelet-rich fibrin (PRF).

Not knowing much about how PRGF was made, I was a bit surprised that nothing about it seemed at all different than a commonly used method for making for either LP-PRP or PRF. Hence, my review so far doesn’t explain the hype. Hence, time to dig deeper.

What’s In PRGF?

A paper by Nishiyama analyzed PRGF (1). What’s in it? It’s basically a 3X LP-PRP. What does that mean? Platelet-rich plasma concentrates blood platelets. Your blood begins with 1X platelets, so a 3X PRP has three times as many platelets as was in the whole blood. That’s a pretty weak PRP. Meaning most bedside kit systems that many doctors use can concentrate platelets to 5-7X over baseline. We routinely concentrate them to 7-20X in the lab. Why does this matter? Let’s look at our recent paper on how concentration impacted how well tendon cells were able to grow and heal a defect (2):

Note that when you’re in your 20s and 30s (under 50 yrs here to the left) increasing the concentration of PRP beyond 3.5X doesn’t help much. In this graph, the higher the bar the better PRP helped the tendon cells heal. However, when you get older (the graph to the right), the higher the concentration, the more healing you get, here shown up to 14X. In fact, we have shown the same thing all the up to 20X. Given that most people getting PRP in the US are older as that’s when various parts and pieces really start going bad, concentration is key.

So why all the hype about PGRF? Maybe it’s something else? Let’s dig even deeper.

Does PGRF Stimulate Cells Better than PRP?

The Nishiyama paper above suggests that PRGF stimulates periodontal cells (very similar to the tenocytes above) better than PRP. However, there are all sorts of problems with that claim. Let’s dig in.

First, the authors made their own periodontal cells from the teeth of volunteers, but don’t tell us their age. Why is that critical to know? Look at the graph above. If the patients were younger (which is likely since this study was performed at a dental school and students are often the volunteers for lab studies), then the 3X PRGF would be expected to perform well and the almost 9X PRP they prepared would be expected to underperform (graph on the left). However, increase the age of the volunteers and you would get the opposite result (graph on the right).

Second, the PRP made by the authors was red and white blood cell rich, which we have seen decreases proliferation of cells in culture. We’ve often theorized that the extra red cells and their breakdown products could be toxic in the closed system of cell culture. Hence, we have no idea what would have happened if the authors made 9X LP-PRP which would have been an apples-to-apples comparison since PRGF is a LP-PRP.

What Else Is Published On the Basic Science Behind PRGF?

The company that makes the PRGF has published a paper on the proteins in the resulting platelet-rich fibrin clot that’s used in surgery (4). Other papers have also been published. This one extols the virtues of leaving out the white blood cells (leukocytes) from PRGF (58). However, given that more than half of all of the PRP used these days is leukocyte poor (LP-PRP), that’s not so unique in the 2020s.

How Much Clinical Data Is there Supporting the Use of PRGF?

One of the mysteries of why there is such hype around PRGF are the dozens of randomized controlled trials showing that PRP works (5-54). Meaning, as I recently listened to one physician extoll his opinion of the magical properties of PRGF, my mind went to one thought-why switch horses from tried, true, and extensively tested PRP to PRGF?

So are there dozens of randomized control trials on PRGF compared to the four dozen-plus on PRP? I found two RCTs where the company compared PRGF to hyaluronic acid injections to treat knee osteoarthritis (56,57). At 6-months, PRGF was better, which is what would have been expected for a 3X LP-PRP, as 18 studies have compared PRP to HA for knee OA and have shown the superiority of PRP over HA. I also found a small case series and opinion piece extolling the virtues of PRGF in a surgical bone healing application (55).

After that literature search, I continued to be stupefied about the hype around PRGF.

PRGF Gets Called Out by Scientists

What I had never seen before was a 2014 editorial I came across when researching PRGF for this blog. The founder of the company that makes the PRGF kits (Anitua who founded the company Endoret), was called out by scientists who were tired of his claims about the fantastic properties of PRGF (3). I had never seen anything quite like this in the medical literature:

“These authors rarely disclosed all their conflicts of interest since the beginning of the PRGF^® story5. In most articles from this group, no disclosure of interest was clearly spelled, even though, in this case, the conflicts of interest cannot be bigger. After a few conflicts that highlighted this reality5, these authors were also using the affiliation “Eduardo Anitua Foundation for Biomedical Research”, while it is obvious that this entity is heavily conflicted by commercial interests like BTI. We will voluntarily not cite any references from this group for the reason explained further in this letter, but they are easy to find on Pubmed and in other electronic databases.”

The accusation was that in papers published by the company, there was often inadequate disclosure that the research was performed by the company making the PRGF kit. This editorial was apparently prompted by the authors writing a paper on classifying PRP preparations that Dr. Anitua felt didn’t reference enough of the company’s published work.

My PRGF Conclusions?

PRGF is nothing more than a low-concentration 3X LP-PRP that can be made into a platelet-rich fibrin clot just like any PRP can be by adding calcium chloride. I can find no evidence of magical healing properties. In fact, while this would be a good product to use in a young patient with a tendon or other issue, in older patients, the platelet concentration, based on the existing in-vitro data is far too low.

The upshot? Whenever I hear a product is magical, I dig deep to find out what’s up. Why? Because while orthobiologics in many ways are a game-changer, none of them are magic. When the right orthobiologic product is used in the right way, by a doctor with the right training, and in the right patient, we can help patients avoid invasive orthopedic surgery. However, claims of fantastic properties do more to set the field back than advance it.

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References:

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