Latest / Deep Dive Ortho — Orthopaedic Surgery, AI & Digital Health Podcast. / Orthobiologics

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Orthobiologics · Deep Dive Ortho — Orthopaedic Surgery, AI & Digital Health Podcast.

0:00
Welcome back to The Deep Dive. Today we're taking
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a really close look at her, a fascinating area
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in musculoskeletal medicine, orthobiologics.
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It seems to be everywhere now. It really does.
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It's a field that's certainly captured a lot
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of attention. And at its heart, orthobiologics
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is about using biological materials, often ones
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naturally found in your body, to try and, well...
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boost healing and regeneration in tissues like
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bone, cartilage, tendons. Right, the musculoskeletal
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system. And these materials, they can be from
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the patient themselves. Autologous, is that the
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term? That's one, yes. Autologous means from
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you. Or they can be allogeneic, meaning they
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come from another human donor. Okay. And our
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aim today, really, is to unpack this whole area.
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We've got some great sources, recent reviews,
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even a curriculum outline for professionals.
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Yes. And what these sources really highlight
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is this sort of tension. On one hand, you have
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this increasing popularity, this huge interest.
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But on the other, establishing really solid evidence
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-based guidelines is proving, well, quite difficult.
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Why is that? Is it because the treatments themselves
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are so different? That's a huge part of it. The
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term orthobiologics covers such a diverse range
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of materials and preparation methods. It's not
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like a single pill with a defined dose. So comparing
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studies, standardizing treatment, it's complex.
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It feels like the underlying idea is incredibly
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appealing though, moving beyond just managing
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symptoms to actually trying to heal the damaged
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tissue itself. That's absolutely the goal. Targeting
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the root cause, stimulating repair rather than
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just masking pain. But as you said, translating
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that promise into reliably effective, predictable
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treatments, well, that journey is proving quite
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intricate. So let's start with the basics. What
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exactly falls under this umbrella term orthobiologics?
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What are the main types we should know about?
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OK, good place to start. We can broadly divide
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them into two main categories, really based on
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the source material. First, you have the blood
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-based therapies. Like PRP. That's the one most
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people have probably heard of. Precisely. Platelet
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-rich plasma, or PRP, is the best known. And
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then you have some variations, sometimes called
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PRP -like products. Things like autologous condition
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serum ACS, or autologous protein solution APS.
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They all start with the patient's blood. OK,
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blood -based. What's the other main group? The
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second major category involves tissues or cells.
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So this includes things like bone marrow, aspirate
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concentrate, or BMAC. Right, from bone marrow.
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Yes. And then microfragmented adipose tissue,
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emahete. which is derived from fat tissue. And
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then you get into more specific cell populations,
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perhaps the most talked about being mesenchymal
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stromal cells or MSCs. And getting hold of these
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materials, how is that done? Does it involve
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complicated procedures? It varies quite a bit
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depending on the product. For PRP, the concept
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is fairly simple. You draw some blood from the
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patient, much like a standard blood test, and
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then you use a centrifuge. To spin it down. Exactly.
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to separate the components and concentrate the
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platelets. Platelets are packed with growth factors,
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which are key to the proposed mechanism. Okay,
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and for the others, BMAC and MFAT. BMAC requires
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aspirating bone marrow, usually from the iliac
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crest, the hip bone. That aspirate is then typically
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centrifuged as well to concentrate the nucleated
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cells. Right. Which include those MSCs amongst
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other cell types. An MFAT from fat. Yes. That
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usually involves a small liposuction procedure
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to harvest some fat tissue. This fat is then
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processed essentially minced or washed to create
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this micro fragmented tissue that can be injected.
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It retains cells within their natural matrix
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to some extent. So you're taking something the
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body already has, concentrating or processing
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it minimally and putting it back where it's needed.
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What are they actually doing then, once injected?
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How are they supposed to help healing? The mechanism
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of action. That's perhaps the most debated and
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researched area. The central idea is that these
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preparations are loaded with bioactive molecules,
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growth factors, cytokines, signaling molecules.
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Biological messengers, essentially. That's a
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good way to put it. Platelets in PRP, for instance,
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release a whole cocktail of potent growth factors
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when activated at the injury site. Things like
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PDGF, TGF -beta, VEGF, the list goes on. And
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these factors trigger something. They're thought
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to orchestrate a complex biological response.
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This includes potentially dampening down excessive
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inflammation, which can actually hinder repair
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if it goes on too long. Okay, reducing that inflammation.
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Yes, but also promoting the good stuff. Yeah.
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stimulating local cells to multiply, proliferate,
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and perhaps change into the cell types needed
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for repair, like cartilage cells or tendon cells,
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that's differentiation. Right. They also encourage
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the growth of new blood vessels, angiogenesis,
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which is vital for bringing oxygen and nutrients
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to the healing tissue. Some components might
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even provide a temporary scaffold or directly
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interact with cell signaling pathways to guide
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the repair process. So it's not just one thing,
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it's a whole local conversation stimulating repair.
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Precisely. A complex interplay. And it's important
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to realize different orthobiologics contribute
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differently. PRP's main contribution is considered
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to be that burst of growth factors from the platelets.
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Whereas BMS or MFAT contain a mixture of cells,
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including MSCs, which can also release factors,
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modulate the immune response, and potentially
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contribute more directly to tissue building.
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Although the extent to which they truly differentiate
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in vivo is still debated. And you mentioned PRP
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isn't technically cell therapy in the same way?
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That's a key distinction made in the sources,
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yes. While platelets are cell fragments, PRP's
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action is primarily through the factors within
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those fragments. It's not usually classified
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alongside therapies, where the intent is to deliver
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a concentrated dose of viable cells like MSCs
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from bone marrow or fat. That makes sense. And
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although using these for, say, arthritis or tendon
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injuries feels quite cutting edge, this idea
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of using the body's own materials isn't brand
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new, is it? Not at all. The concept has roots
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going back decades. One of the reviews mentions
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the first documented clinical use of autologous
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PRP blood taken and given back to the same patient
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was actually in cardiac surgery, way back in
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1987. Really? Cardiac surgery? Yes. So while
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the focus on joints and tendons has boomed more
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recently, the underlying principle isn't entirely
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novel. It's been evolving for quite some time.
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Given that history and these really interesting
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potential mechanisms, you'd think the evidence
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base would be rock solid by now. But you said
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earlier establishing guidelines is tough. What's
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the reality of the research? Ah, yes. Moving
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from the theory to the clinical evidence. This
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is where things get, well, complicated. The single
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biggest challenge echoed across all the sources
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is the heterogeneity. Meaning the variability.
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Exactly. Orthobiologics aren't standardized drugs.
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Take PRP. Its exact composition can vary massively
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depending on the patient's own biology, their
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age, health status, even recent activity levels.
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Right. Then add in variations in how the blood
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is collected, which commercial kit is used for
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processing, the centrifuge settings, the final
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volume, whether an activator is used. You end
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up with potentially very different products,
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all being called PRP. So comparing study results
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is like comparing apples and, well, sometimes
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very different apples or maybe even pears. That's
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a fair analogy. And this lack of standardization
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extends beyond just the product. Dosing isn't
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standardized, injection techniques vary, post
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-injection rehab protocols differ. It makes pooling
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data and drawing firm conclusions incredibly
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difficult. And you mentioned even practitioners
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might lack standardized training. Yes. The curriculum
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outline we looked at specifically points to a
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need for more comprehensive standardized education.
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There's a knowledge gap, which can further contribute
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to inconsistent application and outcomes. All
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this variability inevitably impacts research
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quality. Okay. So bearing that major caveat in
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mind, let's try to pick apart what the evidence
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does show. Starting with PRP again, as it's the
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most studied, where does it seem to stand? Right.
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PRP certainly has the largest volume of research,
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especially for common things like knee osteoarthritis
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or KOA. Several meta -analysis studies that pool
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data from multiple trials do report positive
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findings for KOA. Improvements in patient -reported
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outcomes, things like pain scores and functional
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ability. For example, a well -known meta -analysis
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by Shen and colleagues looked at 14 randomized
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controlled trials, or RCTs, involving over 1
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,400 patients. They found that PRP injections
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led to statistically significant improvements
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in WAC, scores a standard measure for OA pain,
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stiffness, and function compared to control groups.
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At 3, six, and even 12 months follow -up. That
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sounds pretty positive, doesn't it? Significant
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improvements lasting up to a year. On the surface,
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yes, it does sound encouraging. However... And
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this is a crucial, however, the same meta -analysis
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performed a risk of bias assessment on those
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14 trials. Assessing the quality of the studies
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themselves. Exactly. And they found that 10 out
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of the 14 RCTs were judged to have a high risk
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of bias. The other four were at moderate risk.
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High risk of bias in most of the studies. What
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does that mean practically? It means we have
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to be cautious about how much we trust the results.
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High -risk bias could stem from issues like inadequate
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blinding patients or assessors, knowing who got
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which treatment, unclear methods for selecting
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patients, or inconsistent follow -up. These flaws
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can skew the results, potentially exaggerating
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the benefit. So, the overall signal might point
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towards a benefit for NEOA, but the foundations
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of that evidence aren't as solid as we'd ideally
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like, partly due to study quality and that variability
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in PRP itself. That sums it up well. There's
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potential benefits suggested, but the evidence
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quality is a significant concern. What about
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other common problems, like, say, tennis elbow
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lateral epicondylitis. Yes, that's another area
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where PRP has been studied quite a bit. A systematic
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review and meta -analysis by Nemec did report
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improvements in patient outcome scores that were
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considered clinically meaningful, meaning the
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average improvement was large enough for patients
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to actually notice a difference. Okay, so potentially
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helpful there, too. Potentially. But again, caveats
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apply. That particular review highlighted major
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inconsistencies in the studies it included. things
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like missing data on patient age or sex, or crucially,
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not specifying the exact PRP preparation used.
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Ah, that standardization issue again. Precisely.
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And importantly, that NEMEAC review didn't include
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a formal risk of bias assessment using standard
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tools. So while the results seem positive, it's
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harder to gauge the reliability without knowing
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the quality of the underlying studies. It's a
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recurring pattern, isn't it? Promising signals,
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but hampered by inconsistency in questions about
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research quality? What about plantar fasciitis,
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that heel pain condition? Indeed. A fairly recent
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meta -analysis from 2024 by Herber looked at
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21 RCTs with over 1 ,300 patients. They found
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the PRP injections seemed more effective at reducing
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pain compared to several other common treatments,
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corticosteroids, shockwave therapy, and even
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placebo injections. Better pain relief, that's
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significant. It is. They also found better scores
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on a specific foot and ankle function scale,
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the AOFAS Ankle Heimfoot score, when comparing
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PRP to steroid injections and placebo. So improvements
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in pain and function there? Well, better scores
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on that specific functional scale, yes. But interestingly,
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the same analysis found no significant difference
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between PRP and the other groups when looking
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at objective measures, like the actual thickness
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of the plantar fascia measured on ultrasound,
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or when using a different functional score called
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the foot function index. Hmm, so pain relief
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seems better, but maybe not changing the underlying
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tissue thickness or overall foot function consistently.
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That seems to be the implication. And echoing
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the findings in other areas, the authors explicitly
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noted significant variability in the PRP methods
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used across the trials and concluded that the
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overall quality of the included RCTs was low.
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low -quality evidence again. It really underlines
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the challenge, doesn't it? Even where results
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look positive, like pain relief for plantar fasciitis,
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the confidence in that finding is weakened by
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the study quality. Absolutely. It's a constant
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refrain in the literature. What about less common
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applications? We hear about PRP being used for
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ligament tears, other tendon problems, even spine
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issues, or during meniscus surgery. Yes. Clinical
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practice has certainly expanded into these areas,
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but the sources suggest that strong evidence
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-based consensus statements or clear guidelines
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are generally lacking here. Meta -analyses looking
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into these applications often find, well, a similar
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picture. Promising hints, but not definitive.
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Exactly. Some studies might suggest a benefit,
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for instance, lower failure rates after meniscus
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repair surgery when PRP is added, but then maybe
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no significant difference in functional outcome
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scores. Or for low back pain or spinal fusion,
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some studies report pain reduction or maybe faster
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signs of bone healing on scans, but don't necessarily
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show that PRP improves the overall success rate
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of the fusion compared to standard methods. The
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evidence tends to be quite mixed, often based
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on smaller studies and hampered by that same
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issue of heterogeneity. So, really, outside of
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maybe neo -A, where there's a larger volume of
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research, albeit flawed, the evidence for PRP
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across the board is quite patchy and often low
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quality. That's a fair summary of the current
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state, according to these reviews. And what about
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those PRP -like products you mentioned earlier,
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ACS and APS? Right. These are variations where
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the blood undergoes extra processing steps, aiming
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to perhaps enhance certain components, like anti
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-inflammatory factors in ACS or concentrating
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a broader range of proteins in APS. Is the evidence
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any clearer for them? Actually, it's much less
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developed. The key finding from the sources is
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stark. There are currently no randomized controlled
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trials published specifically evaluating these
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PRP -like products. The studies that do exist
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are generally preliminary, small pilot studies
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with limited statistical power to draw firm conclusions.
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So even less evidence to go on there compared
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to standard PRP? Considerably less, yes. Okay.
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That paints a rather complex picture for the
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blood -based therapies. Let's switch focus now
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to the other main category. The tissue and cell
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-based options like BMA, MFA, and MSC therapies.
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How does the evidence stack up for those? Well,
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generally speaking, the development pathway for
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these therapies tends to be longer and more expensive
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than for blood products like PRP. Makes sense.
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Dealing with tissues and cells seems more involved.
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It is. And while safety data from initial studies
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often looks acceptable for several of these products,
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the overall volume of high -quality research,
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especially large RCTs and meta -analyses, is
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significantly lower than what we see for PRP.
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And is a research focus similar, mainly knee
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OA? Yes. Much of the existing clinical trial
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evidence for BMH, MST and MSCs in orthopedics
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has also concentrated on knee osteoarthritis.
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Are they plagued by the same issues of study
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quality and potential bias that affect the PRP
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literature? Unfortunately, yes. The sources explicitly
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state that a high risk of bias is frequently
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identified in trials of cell and tissue based
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therapies. This can sometimes be linked to factors
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like industry funding, influencing study design
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or reporting, or simply due to poor methodological
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execution. It makes interpreting the results
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reliably quite challenging. So similar problems,
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just with less data overall. Can you give us
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some examples of the findings or lack thereof?
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Let's stick with KOA, as it's the most researched
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area. One of the reviews cited a meta -analysis
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that specifically searched for large randomized
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controlled trials. They defined large as having
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over 100 participants in each treatment group
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published between the years 2000 and 2023. OK,
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looking for the most robust evidence, what did
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they find? Quite strikingly, they found only
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one trial focused on a cell -based therapy for
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OA that met their size criteria. Just one in
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over two decades of research. Wow, only one large
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RCT. Which therapy was that? It was a trial investigating
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autologous adipose -derived MSC stem cells taken
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from the patient's own fat tissue, which were
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then expanded in culture, meaning grown to larger
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numbers in the lab, before being injected. That
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really highlights the scarcity of large -scale
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evidence for these therapies compared to PRP,
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doesn't it? It certainly does. And, adding another
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layer of complexity, even that single large trial
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was assessed in the meta -analysis as having
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a high risk of bias. Oh dear. Why was that? Issues
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were raised regarding how patients were allocated
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to the treatment groups and how the study handled
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missing data, which can introduce bias. When
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the meta -analysis pulled the data, Primarily
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from this one large high -bias study, it concluded
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there was no superior effect on pain relief at
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12 weeks compared to other interventions. So
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the big picture from that analysis wasn't overwhelmingly
16:35
positive? Not from the pooled analysis, no. However,
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there's an important nuance mentioned in the
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source. The original publication of that specific
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large trial did report that significantly more
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patients treated with the expanded MSCs achieved
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what's called the minimal clinically important
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difference. or MCID, for both pain and function
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scores at the six -month mark. Meaning enough
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patients experienced a meaningful improvement
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at six months, even if the average difference
17:02
wasn't significant at 12 weeks in the meta -analysis.
17:05
Exactly. It shows how different analysis approaches
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or time points can sometimes lead to different
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headline conclusions, which adds to the confusion.
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That's a critical point. Was there any significant
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research published after that meta -analysis
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cutoff? Yes. A very important one. A large multi
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-center RCT with 480 patients was published in
17:26
late 2023 by Motner and colleagues after the
17:29
time frame cover by the previously mentioned
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meta -analysis. OK, what did that one look at?
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It directly compared intra -articular injections
17:35
of BMAC and SVF stromal vascular fraction, which
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is another preparation derived from fat containing
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MSCs and other cells, but typically not culture
17:45
expanded against the saline placebo injection
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for patients with knee OA. A head -to -head comparison
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with placebo in a large trial? That sounds like
17:52
exactly the kind of study needed. What were the
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results? The primary outcome was knee pain at
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12 months, and the finding was quite clear. The
17:59
study reported no superiority of either BMAC
18:01
or SVF compared to the placebo injection. No
18:05
statistically significant difference in pain
18:07
improvement. No difference compared to placebo
18:09
in a large, well -conducted trial. That's quite
18:11
significant, isn't it? It seems to temper some
18:13
of the enthusiasm. It certainly does. It represents
18:16
a high -quality piece of evidence that challenges
18:18
some of the positive findings reported in smaller,
18:21
potentially less rigorous studies. It suggests
18:24
that for knee -away pain, at least at 12 months,
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These specific preparations might not offer a
18:30
benefit beyond a placebo effect. So while smaller
18:33
studies might hint at benefits, the bigger, better
18:35
trials aren't consistently backing that up for
18:38
cell or tissue therapies in KOA. That seems to
18:41
be the trend emerging from the high -level evidence
18:43
landscape right now. Now, it's fair to say there
18:46
are other smaller meta -analyses often looking
18:48
at trials with fewer than 30 patients per group.
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Right. Some of these have reported positive findings
18:53
regarding safety and efficacy for therapies like
18:56
ADMS. MSCs, adipose -derived MSCs, or SVF. However,
19:00
the sources caution that the criteria used to
19:02
assess bias in these smaller reviews might be
19:05
less strict, or many of the included studies
19:07
themselves don't meet the criteria for low risk
19:09
of bias across all important domains. So again,
19:12
the quality of the underlying evidence is a concern.
19:15
Yes, a recent 2024 meta -analysis pooled 15 RCTs
19:19
on various cell therapies for OA, mostly small
19:22
studies using VMSC -BME, ADMSE, or even umbilical
19:27
cord MSCs. While its overall conclusion leaned
19:30
towards safety and efficacy, it also noted that
19:32
only about a third of the included studies were
19:34
judged to have a low risk of bias. So if you
19:36
had to summarize the evidence for these cell
19:38
and tissue therapies? Based on the sources, the
19:40
most studied are bone marrow -derived, BMSC -BMA,
19:43
and adipose -derived ADMS CSVF products, mainly
19:47
for an EOA. They appear generally safe in the
19:50
context of these trials. However, the current
19:52
high -level evidence from large, low -bias RCTs
19:55
cannot definitively support clear mechanisms
19:57
of action, leading to superior clinical outcomes
20:00
compared to placebo or other treatments for many
20:02
indications. Right. Therefore, the sources strongly
20:04
emphasize the need for absolute transparency
20:07
with patients about this limited high -level
20:09
evidence when discussing these therapies as potential
20:11
options. That makes perfect sense. So we have
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this complex picture of variable evidence, further
20:18
complicated by issues of standardization and
20:21
study quality, and then layered on top of that
20:23
is the regulatory situation, which sounds like
20:26
another minefield altogether. It absolutely is,
20:29
particularly in the U .S., where the FDA, the
20:32
Food and Drug Administration, is the main player.
20:34
But it's not just them. Who else is involved?
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You've got the Federal Trade Commission, the
20:38
FTC, which looks at advertising claims, making
20:40
sure they aren't false or misleading. You have
20:43
state medical boards overseeing how doctors practice.
20:46
And then a whole host of professional societies
20:48
and international groups issue guidelines or
20:51
position statements, organizations like the APM
20:54
&R, AMSSM, the ISSCR. A lot of cooks in the kitchen,
20:57
potentially. How does the FDA actually categorize
21:00
these orthobiologics? Is there a specific system?
21:03
Yes, they have a framework specifically for what
21:05
a term human cells, tissues, and cellular and
21:07
tissue -based products, or HCTPs for short. It's
21:11
outlined in Title 21 of the Code of Federal Regulations,
21:14
Part 1271. Within that, There's essentially a
21:17
tiered risk based system. Tier one is the lowest
21:19
risk, focused mainly on preventing disease transmission
21:22
through good tissue practices. Tier two falls
21:25
under section 361 of the Public Health Service
21:27
Act. These HCTPs need to meet specific criteria
21:30
and require FDA registration and adherence to
21:33
good tissue practices, but don't need pre -market
21:35
approval. In tier three. Tier three is for higher
21:38
risk products, regulated under section 351. These
21:41
are treated much more like drugs or traditional
21:43
biologics. They require an investigational new
21:46
drug application, or IND, to even conduct clinical
21:49
trials in humans. And before they can be marketed,
21:52
they need a full biologics license application,
21:54
or BLA, demonstrating safety and effectiveness.
21:57
That's a very high bar. A huge difference between
21:59
Tier 2 and Tier 3, then. Where do common orthobiologics
22:02
like PRP, BMAC, and mFAT2 typically fit? This
22:06
is where it gets particularly nuanced. PRP and
22:09
PPP platelet -poor plasma derived solely from
22:12
a patient's blood are generally not regulated
22:14
by the FDA under the HCTP framework as Section
22:17
361 products. They tend to fall under different
22:20
less stringent regulatory oversight focused on
22:23
blood product safety and device clearance for
22:25
the preparation kits. So PRP has a relatively
22:28
simpler regulatory path within this specific
22:31
HCTP structure. Compared to cell and tissue products,
22:34
generally yes, regarding the HTTP rules specifically.
22:38
Now products like MFT and BMAC can potentially
22:40
qualify as section 361 HTTPS, avoiding the stringent
22:44
361 pathway, but only if they meet four key criteria.
22:48
Four criteria, what are they? Okay, they are.
22:50
One, the product must be minimally manipulated,
22:52
meaning processing doesn't alter its relevant
22:54
biological characteristics. Two, it must be intended
22:56
for homologous use only, meaning it performs
22:59
the same basic function in the recipient as it
23:01
did in the donor. Right, like using bone graft
23:03
for bone healing. Exactly. Three, the product
23:06
isn't combined with other articles, apart from
23:08
water, crystalloids, or certain sterilizing agents.
23:11
And four, it either has no systemic effect and
23:14
is independent on the metabolic activity of living
23:16
cells for its primary function, or it's for autologous
23:20
use, used in a first or second degree relative
23:22
or reproductive use. That sounds quite specific
23:25
and potentially open to interpretation. Very
23:28
much so. The interpretation of minimal manipulation
23:31
and homologous use is precisely where a lot of
23:34
the regulatory debate and enforcement actions
23:36
have focused, especially concerning fat -derived
23:39
products like MF fat or SVF. Does the processing
23:42
significantly alter the tissue? Is injecting
23:45
it into a joint for cartilage repair truly homologous
23:48
to the fat's original function? I see. And if
23:50
a product doesn't meet all four criteria? Then,
23:53
according to the FDA guidance outlined in the
23:55
sources, it generally defaults to being regulated
23:57
as a Section 351 product, a drug or biologic,
24:00
requiring that full IND and BLA approval process
24:03
before marketing. Which is a much longer and
24:05
more expensive road. Is there any way around
24:07
that, perhaps for treatments prepared and used
24:09
immediately? Yes. There's a critical exception
24:12
known as the same surgical procedure exception,
24:15
detailed in Section 1 .71 .15b. of the regulations.
24:19
Same surgical procedure? What does that cover?
24:22
It applies when an HTTP like bone marrow or fat
24:25
tissue is removed from a patient and implanted
24:27
back into the same patient within the same single
24:29
surgical procedure. The tissue must also remain
24:32
in its original form and only be minimally manipulated
24:35
as defined by the FDA. Okay, so if a surgeon
24:38
takes some bone marrow during a knee operation,
24:41
spins it down minimally, and injects it back
24:43
into the knee during that same operation, that
24:45
might fall under this exception. Precisely. If
24:48
the criteria are met, This exception essentially
24:50
supersedes the need to meet those four criteria
24:52
for being a 361 product. It provides a regulatory
24:55
pathway for many common autologous procedures.
24:58
But the definition of minimal manipulation is
25:00
still key here, too. Absolutely. And the FDA
25:03
has issued guidance clarifying its interpretation.
25:06
For example, using enzymes to digest fat tissue
25:08
to isolate the stromal vascular fraction, SVF,
25:11
is generally considered by the FDA to be more
25:13
than minimal manipulation. Ah, so that would
25:16
likely push SBF outside of this exception and
25:18
potentially into the 351 category, needing full
25:21
drug approval. That's the current FDA stance,
25:24
yes. It's a really significant point of contention
25:26
and regulatory focus. The source has also mentioned
25:29
some products being advertised that aren't actually
25:31
legal for widespread use. Yes, this is a major
25:34
point of concern highlighted in the curriculum
25:36
material. It warns practitioners and patients
25:39
about products like many amniotic fluid or umbilical
25:42
cord tissue products, culture expanded stem cells
25:45
where cells are grown in a lab to multiply in
25:47
exosomes? What's the issue with them? While these
25:49
are areas of active research, they are frequently
25:52
marketed directly to patients for various orthopedic
25:55
conditions. However, according to the sources
25:58
and current FDA enforcement, these products generally
26:01
do not meet the criteria for Section 361 regulation
26:04
and have not obtained the required BLA approval
26:06
under Section 351 for these uses. Therefore,
26:09
their marketing and use outside of an FDA -approved
26:12
clinical trial under an IND is considered illegal.
26:15
So things people might see advertised online
26:17
or in clinics might not actually be compliant
26:19
with FDA regulations. That's the stark warning.
26:22
The FDA has particularly increased its enforcement
26:26
actions against unapproved birth tissue products
26:28
since 2021, making it clear they view most of
26:31
these as 351 biologics requiring full approval.
26:35
That's a huge disconnect. It also brings up the
26:37
terminology FDA cleared versus FDA approved.
26:41
They aren't the same, are they? Absolutely not.
26:42
And it's a critical distinction. FDA cleared
26:45
usually applies to medical devices, often through
26:47
the 510K pathway. This means the device like
26:50
a centrifuge or a kit used to prepare PRP or
26:53
BMAC is deemed substantially equivalent to a
26:56
device already legally on the market. It does
26:59
not mean the FDA has evaluated the orthobiologic
27:01
product itself for safety and effectiveness for
27:04
specific clinical use. OK, so the kit might be
27:06
cleared, but not the PRP itself for treating
27:08
arthritis. Exactly. FDA approved is the standard
27:12
for drugs and biologics. like Section 351 -HCTPs.
27:16
This requires rigorous clinical trial data demonstrating
27:19
safety and efficacy for a specific intended use
27:23
or indication. And the sources are unequivocal
27:25
on this point. Currently, no orthobiologic products
27:28
or devices have received FDA approval specifically
27:31
for treating osteoarthritis or tendinopathy.
27:34
That is such a crucial piece of information for
27:36
patients and clinicians. So... Technically, using
27:40
PRP for knee arthritis is considered off -label
27:43
use? Correct. Since PRP hasn't gone through the
27:45
BLA process and received FDA approval specifically
27:48
for the indication of knee osteoarthritis, using
27:51
it for that purpose is off -label. But off -label
27:54
doesn't necessarily mean bad or experimental,
27:56
does it? Doctors use medications off -label quite
27:58
often. That's true. The sources clarify that
28:01
off -label use doesn't automatically imply a
28:03
lack of supporting evidence, as we discussed.
28:05
There is research on PRP for KOA, even with its
28:07
limitations. However, it absolutely does mean
28:10
the product hasn't met the FDA's highest bar
28:12
for approval for that specific condition. It's
28:14
about the regulatory status, not necessarily
28:16
the scientific underpinning, although the two
28:18
are related. Precisely. And this is where the
28:21
FTC, the Federal Trade Commission, steps in regarding
28:23
advertising. Clinics can't legally make claims
28:26
that imply FDA approval for unapproved use, nor
28:30
can they make unsubstantiated claims about curing
28:32
diseases. Like broadly advertising stem cell
28:35
cures. Exactly. Using misleading terms like stem
28:39
cells for products that aren't primarily stem
28:41
cells or overstating the evidence can attract
28:44
FTC attention. Violating FDA or FTC regulations
28:48
can have serious consequences, including warning
28:51
letters, injunctions, and penalties. It really
28:53
underscores why staying informed about the evolving
28:56
regulatory landscape is so vital for practitioners.
28:59
This complex web of evidence and regulation inevitably
29:02
leads to significant ethical considerations,
29:05
doesn't it? Absolutely. Ethics and transparency
29:07
are arguably even more critical in orthobiologics
29:10
than in areas with well -established approved
29:12
treatments, precisely because of the variability
29:15
in regulatory nuances. What are some of the key
29:17
ethical challenges highlighted? A major one revolves
29:20
around nomenclature, particularly the pervasive
29:23
misuse of the term stem cells. Patients hear
29:26
stem cells, and often equate it with powerful
29:28
regenerative potential, maybe thinking of embryonic
29:31
stem cells. But in orthobiologics, it's often
29:34
used loosely to describe PRP, which contains
29:37
no cells capable of differentiation, or BMSI
29:40
and MIT. Which do contain some mesenchymal stromal
29:43
cells, or MSCs. They do, yes. MSCs are a type
29:46
of adult multipotent stromal cell, sometimes
29:49
referred to as medicinal signaling cells now.
29:52
But BMSC and MFA contain a whole mixture of cell
29:55
types. And the MSCs present are typically in
29:58
very low concentrations compared to culture expanded
30:01
products. And they aren't being administered
30:02
as a purified stem cell therapy in the way the
30:04
term might imply. So using that stem cell label
30:07
broadly can create unrealistic expectations.
30:10
Definitely. It can significantly inflate patient
30:12
hopes and misunderstandings about what's actually
30:14
be administered and what it can realistically
30:17
achieve based on current evidence. This relates
30:19
to the broader problem of misleading public representations.
30:22
Given the regulatory status, no FDA approval
30:25
for common uses and the variable evidence, some
30:28
marketing practices can cross ethical lines.
30:31
The curriculum source actually lists several
30:33
tactics that might be used to give their be an
30:35
unearned air of legitimacy. What sort of tactics
30:38
should people be aware of? They mentioned things
30:40
like registering clinical trials, but then failing
30:43
to publish the results, especially if they're
30:46
negative. That creates a publication bias. Right.
30:49
You only see the positive studies. Exactly. Also,
30:52
publishing in predatory or low -impact journals
30:54
that lack rigorous peer review, offering significant
30:58
financial incentives for patients to pay cash
31:00
upfront, bypassing insurance scrutiny. using
31:03
carefully selected patient testimonials or celebrity
31:06
endorsements that aren't representative of typical
31:09
outcomes. And the misleading terminology we discussed.
31:11
Yes, using terms like stem cells inaccurately.
31:15
Even things like forming seemingly official sounding
31:18
organizations that are essentially self -regulatory
31:20
bodies without real oversight, or joining reputable
31:24
academic societies, mainly for the implied credibility
31:27
rather than active scientific contribution. These
31:31
are always the appearance of legitimacy can be
31:33
potentially manipulated. It paints a picture
31:35
where patients really need robust, honest guidance.
31:39
Absolutely. The cornerstone of ethical practice
31:41
here is patient autonomy, which requires truly
31:44
informed consent. That means having a detailed,
31:47
transparent conversation covering everything.
31:49
What needs to be included in that conversation?
31:51
The practitioner must clearly explain. the specific
31:54
indication based on the best available evidence
31:56
or lack thereof, the potential benefits and limitations
31:59
as shown in research, the known risks of the
32:02
procedure and the product, all reasonable alternative
32:05
treatments including standard non -surgical and
32:07
surgical options, the costs involved, making
32:10
it clear what is and isn't covered by insurance,
32:12
and crucially, the FDA regulatory status explicitly
32:16
stating that the product is not FDA approved
32:18
for the condition being treated. That's comprehensive.
32:21
The cost aspect also raises questions about access,
32:24
doesn't it? It certainly does. Because these
32:26
treatments are often not reimbursed by insurance,
32:29
they are primarily accessible to those who can
32:31
afford substantial out -of -pocket payments.
32:34
This creates a significant potential for social
32:36
inequity where access is dictated more by wealth
32:39
than by clinical need or evidence of potential
32:42
benefit. And conflicts of interest for the doctors
32:45
themselves. That's another potential ethical
32:47
pitfall. Physicians or clinics might have financial
32:50
ties to the companies making the orthobiologic
32:53
kits, or their business model might rely heavily
32:56
on these cash -based procedures. Such conflicts
33:00
need to be transparently disclosed and carefully
33:02
managed to ensure treatment recommendations are
33:04
driven by patient best interests, not financial
33:07
gain. For a patient trying to cut through the
33:09
hype and make a good decision, where can they
33:11
turn for reliable information? It is challenging,
33:14
but good resources exist. The FDA website has
33:17
information on regulated products and warnings
33:19
about unapproved therapies, though it can be
33:22
technical. The International Society for Stem
33:24
Cell Research, ISSCR, has excellent patient -focused
33:28
resources, particularly regarding what constitutes
33:31
legitimate stem cell therapy. The National Institutes
33:34
of Health, NIH, in the US also provides reliable
33:38
health information. Reputable patient advocacy
33:40
groups for specific conditions might also offer
33:42
guidance. Clinicians have an ethical duty to
33:45
guide patients toward these credible sources.
33:47
So if we pull all these threads together, the
33:49
variable evidence, the regulatory maze, the ethical
33:51
considerations, they all point towards significant
33:53
limitations and challenges still facing orthobiologics.
33:56
What are the biggest hurdles summarized across
33:58
the sources? I think the first one has to be
34:00
the inherent biological variability of the products
34:03
themselves. As we've discussed, even using a
34:06
patient's own blood or tissue doesn't guarantee
34:08
a consistent product. Their age, health, genetics,
34:12
even their immune profile. One source specifically
34:15
mentions how immune cell counts influence PRP
34:17
composition all play a role. It makes achieving
34:20
a standardized dose incredibly difficult. The
34:23
patient is the variable, in a way. In a significant
34:26
way, yes. And then layered on top of that is
34:29
the lack of standardization in everything else.
34:32
Collection methods, processing protocols using
34:34
different commercial kits, final preparation,
34:37
dosing, administration techniques. It seems like
34:39
this lack of standardization is the root of so
34:42
many other problems, particularly with comparing
34:44
research. It's absolutely fundamental. It directly
34:46
contributes to inconsistent clinical outcomes
34:48
and makes generating high quality, comparable
34:51
evidence incredibly challenging, which leads
34:53
to the next major limitation. the relative scarcity
34:56
of large -scale, high -quality, long -term clinical
34:59
trials. We need more big RCTs with low bias.
35:03
Precisely. Trials that use standardized, clearly
35:06
reported protocols and follow patients long enough
35:08
to truly assess effectiveness and safety. Without
35:11
that robust evidence base, it's hard to gain
35:14
widespread acceptance from the medical community,
35:17
difficult for regulators to grant specific approvals,
35:20
and almost impossible to secure consistent insurance
35:23
coverage. Which feeds directly into the cost
35:25
issue. Exactly. The high out -of -pocket cost
35:28
is a major limitation for patient access, and
35:31
the high cost of conducting the necessary large
35:33
trials is a barrier for researchers and companies.
35:37
Are there other unresolved questions limiting
35:39
progress? Yes, quite a few scientific unknowns
35:42
remain. What's the optimal dose of platelets,
35:45
cells, or growth factors for different conditions?
35:47
What's the best way to deliver them simple injection
35:49
combined with a scaffold, slow -release formulation?
35:53
Are combination therapies better? We don't have
35:55
definitive answers yet. And the underlying mechanisms
35:58
aren't always fully mapped out either. That's
36:00
another key area. While we have good hypotheses
36:03
about growth factors and cell signaling, the
36:06
precise biological pathways, how these therapies
36:09
interact with the complex environment of an injured
36:11
or degenerating joint, and crucially why some
36:14
patients respond well and others don't. That's
36:17
still not fully understood for many applications.
36:20
Better mechanistic understanding could lead to
36:22
much more targeted therapies. And are there lingering
36:25
safety concerns or potential downsides? While
36:28
the sources generally suggest serious adverse
36:30
events are rare, with commonly used preparations
36:32
like PRP and BMACM fat in clinical trials and
36:36
practice, theoretical concerns exist. These include
36:39
the potential for excessive scar tissue, fibrosis,
36:42
unpredictable inflammatory reactions, or a concern
36:44
primarily with cell -based therapies that might
36:46
involve proliferation or differentiation, the
36:49
theoretical risk of unwanted cell behavior, or
36:52
even tumorigenicity if not properly controlled.
36:55
These highlight the need for ongoing vigilance
36:57
and long -term safety monitoring. Okay, so there
37:00
are clearly significant hurdles still to overcome,
37:03
but the field isn't stagnant. Where is Orthobiologics
37:05
heading? What are the exciting future directions?
37:08
Despite the challenges, it's a very dynamic field.
37:11
Several innovative approaches are being actively
37:13
pursued. One area gaining a lot of traction is
37:17
exosome -based therapies. Exosomes. Tell us more.
37:20
Exosomes are tiny nanoparticles naturally released
37:23
by cells. They act like little delivery packages,
37:26
carrying proteins, lipids, and RNA from one cell
37:28
to another, basically mediating intercellular
37:30
communication. The idea is to harness these natural
37:34
messengers, potentially loaded with regenerative
37:36
cargo, to deliver therapeutic signals without
37:38
needing to inject whole cells. So cell -free
37:41
therapy, using the message rather than the messenger.
37:44
That's the concept. They might offer advantages
37:46
like lower immunogenicity, less chance of triggering
37:49
an immune reaction, and perhaps reduce concerns
37:52
about cells surviving or behaving unpredictably
37:54
after injection. It's still early days, needing
37:57
large trials, but it's a very promising cell
37:59
-free approach. Fascinating. What else is on
38:01
the horizon? Gene -based and mRNA -based strategies
38:04
are also being explored. The aim here is to actually
38:07
instruct the patient's own cells at the injury
38:09
site to produce specific healing factors or to
38:12
modify their behavior in beneficial ways. Using
38:14
things like CRISPR? Potentially, yes. Technologies
38:17
like CRISPR -Cas9 offer the possibility of precise
38:20
gene editing related to cartilage or bone biology.
38:24
Or... using mRNA, similar to some vaccines, to
38:27
temporarily make cells produce therapeutic proteins.
38:30
These are definitely more futuristic, facing
38:32
big challenges in terms of safe and effective
38:34
delivery and ensuring the effects are controlled
38:36
and durable. But the potential for programming
38:39
tissue repair is immense. It sounds like science
38:42
fiction becoming science fact. Beyond these novel
38:45
therapies, are there efforts to refine existing
38:47
approaches? Absolutely. A huge focus is on patient
38:51
stratification, figuring out which patients are
38:53
most likely to respond to which specific orthobiologic
38:56
treatment. Moving away from a one -size -fits
38:58
-all approach. Exactly. Researchers are hunting
39:00
for biomarkers, maybe genetic markers, specific
39:03
proteins or metabolites in blood or joint fluid,
39:06
or particular patterns of immune cells that can
39:08
predict treatment success. If we can identify
39:10
responders beforehand, we can personalize treatment
39:13
and improve overall success rates. That work
39:15
on immune profiles influencing PRP is a step
39:19
in this correction. Personalized regenerative
39:21
medicine, that seems key. It does, and alongside
39:24
that is the continued essential push for standardization.
39:27
Developing and adopting clear, consistent, widely
39:30
accepted protocols for how orthobiologics are
39:33
prepared, characterized, and administered is
39:36
seen as absolutely crucial for improving outcomes,
39:39
enabling meaningful research comparisons, and
39:41
ultimately achieving regulatory approvals and
39:44
broader clinical adoption. It seems like that
39:46
has to happen for the field to truly mature.
39:49
It really does. We're also seeing more large
39:51
-scale collaborative research efforts. The sources
39:54
mention the European Propo Consortium, for example,
39:57
which is bringing together multiple centers to
39:59
rigorously investigate a specific placenta -derived
40:02
cell therapy for knee OA. These kinds of structured
40:06
multi -center collaborations are vital for generating
40:08
high -quality evidence. What about improvements
40:10
in actually delivering the therapies to the target
40:13
tissue? Yes, that's another active area. Developing
40:16
advanced delivery systems, like embedding the
40:19
orthobiologic factors or cells within smart biomaterials,
40:23
perhaps injectable hydrogels that solidify in
40:25
place, or using nanoparticles to allow for slow,
40:29
sustained release over time directly where needed.
40:31
This could enhance efficacy and potentially reduce
40:35
the number of treatments required. And combining
40:37
therapies? Combination approaches are definitely
40:39
being explored using multiple orthobiologics
40:41
together, or combining them with physical scaffolds,
40:44
specific growth factors, or even traditional
40:46
rehabilitation therapies to achieve a synergistic
40:49
effect greater than any single component alone.
40:51
And technology like 3D printing fitting in? Yes.
40:55
3D bioprinting holds promise for creating patient
40:58
-specific scaffolds that mimic the structure
41:00
of the tissue being repaired. These scaffolds
41:03
could potentially be seeded with the patient's
41:05
own cells or infused with growth factors before
41:08
implantation, offering both structural support
41:10
and biological stimulation. And overarching all
41:14
of this is the potential role of artificial intelligence
41:17
and machine learning to analyze large data sets,
41:20
identify patterns, predict outcomes, and help
41:22
tailor these increasingly complex treatments
41:24
to individual patients. So the future looks towards
41:28
much more targeted, predictable, and personalized
41:30
treatments, leveraging biology and technology
41:33
together. That's certainly the long -term vision.
41:35
But, and it's a consistent message from the sources,
41:38
getting there depends entirely on continued rigorous
41:40
science, robust clinical trials, a commitment
41:43
to standardization, and unwavering ethical practice.
41:46
The potential is enormous, but there's still
41:48
a lot of work to do to fully realize it. Well,
41:51
as we wrap up this deep dive, it's clear orthobiologics
41:53
represent a really exciting frontier in musculoskeletal
41:56
medicine aiming to harness the body's own healing
41:59
power. Absolutely. But as we've explored, understanding
42:02
this field means grappling with the different
42:04
therapy types. The often complex and variable
42:07
evidence base, the intricate regulatory landscape,
42:10
and the very real limitations we currently face
42:13
regarding standardization and predicting outcomes.
42:16
There's definitely a gap, isn't there, between
42:19
the growing clinical use and enthusiasm and the
42:23
still developing high -level evidence and clear
42:25
guidelines, particularly once you move beyond
42:28
the most studied areas like PRP for NEOA. That
42:31
gap is undeniable. The future looks bright with
42:34
emerging technologies like exosomes in gene therapy
42:37
and the push towards personalized medicine. But
42:40
progress hinges on continued high quality research,
42:43
agreed upon standards, and complete transparency
42:45
with patients. If you found this deep dive valuable,
42:48
please do consider rating the show or sharing
42:50
it with a colleague who might find it interesting.
42:52
And perhaps the final thought to leave you with
42:54
is, could that convergence better patient stratification?
42:58
standardized combination therapies, advanced
43:01
delivery systems, could that finally be the key
43:04
to unlocking the full potential of orthobiologics,
43:07
moving them from promising but variable options
43:09
to truly predictable personalized regenerative
43:12
solutions? A fascinating question, and one we'll
43:15
surely be revisiting. Thank you for joining us
43:16
on the Deep Dive.