WEBVTT 00:00:00.000 --> 00:00:02.319 Welcome back to The Deep Dive. Today we're taking 00:00:02.319 --> 00:00:06.040 a really close look at her, a fascinating area 00:00:06.040 --> 00:00:09.800 in musculoskeletal medicine, orthobiologics. 00:00:10.060 --> 00:00:12.080 It seems to be everywhere now. It really does. 00:00:12.160 --> 00:00:13.939 It's a field that's certainly captured a lot 00:00:13.939 --> 00:00:17.160 of attention. And at its heart, orthobiologics 00:00:17.160 --> 00:00:20.199 is about using biological materials, often ones 00:00:20.199 --> 00:00:22.980 naturally found in your body, to try and, well... 00:00:22.969 --> 00:00:25.850 boost healing and regeneration in tissues like 00:00:25.850 --> 00:00:28.690 bone, cartilage, tendons. Right, the musculoskeletal 00:00:28.690 --> 00:00:30.789 system. And these materials, they can be from 00:00:30.789 --> 00:00:32.689 the patient themselves. Autologous, is that the 00:00:32.689 --> 00:00:34.649 term? That's one, yes. Autologous means from 00:00:34.649 --> 00:00:36.929 you. Or they can be allogeneic, meaning they 00:00:36.929 --> 00:00:39.880 come from another human donor. Okay. And our 00:00:39.880 --> 00:00:42.579 aim today, really, is to unpack this whole area. 00:00:42.679 --> 00:00:44.840 We've got some great sources, recent reviews, 00:00:45.119 --> 00:00:47.039 even a curriculum outline for professionals. 00:00:47.259 --> 00:00:49.359 Yes. And what these sources really highlight 00:00:49.359 --> 00:00:51.659 is this sort of tension. On one hand, you have 00:00:51.659 --> 00:00:53.820 this increasing popularity, this huge interest. 00:00:54.299 --> 00:00:57.579 But on the other, establishing really solid evidence 00:00:57.579 --> 00:01:00.719 -based guidelines is proving, well, quite difficult. 00:01:00.960 --> 00:01:02.979 Why is that? Is it because the treatments themselves 00:01:02.979 --> 00:01:05.870 are so different? That's a huge part of it. The 00:01:05.870 --> 00:01:08.689 term orthobiologics covers such a diverse range 00:01:08.689 --> 00:01:11.129 of materials and preparation methods. It's not 00:01:11.129 --> 00:01:14.189 like a single pill with a defined dose. So comparing 00:01:14.189 --> 00:01:17.709 studies, standardizing treatment, it's complex. 00:01:17.909 --> 00:01:20.049 It feels like the underlying idea is incredibly 00:01:20.049 --> 00:01:22.909 appealing though, moving beyond just managing 00:01:22.909 --> 00:01:25.409 symptoms to actually trying to heal the damaged 00:01:25.409 --> 00:01:28.790 tissue itself. That's absolutely the goal. Targeting 00:01:28.790 --> 00:01:31.930 the root cause, stimulating repair rather than 00:01:31.930 --> 00:01:35.159 just masking pain. But as you said, translating 00:01:35.159 --> 00:01:38.219 that promise into reliably effective, predictable 00:01:38.219 --> 00:01:40.500 treatments, well, that journey is proving quite 00:01:40.500 --> 00:01:42.959 intricate. So let's start with the basics. What 00:01:42.959 --> 00:01:46.120 exactly falls under this umbrella term orthobiologics? 00:01:46.319 --> 00:01:47.939 What are the main types we should know about? 00:01:48.140 --> 00:01:50.159 OK, good place to start. We can broadly divide 00:01:50.159 --> 00:01:52.200 them into two main categories, really based on 00:01:52.200 --> 00:01:54.200 the source material. First, you have the blood 00:01:54.200 --> 00:01:56.840 -based therapies. Like PRP. That's the one most 00:01:56.840 --> 00:01:59.480 people have probably heard of. Precisely. Platelet 00:01:59.480 --> 00:02:02.920 -rich plasma, or PRP, is the best known. And 00:02:02.920 --> 00:02:04.680 then you have some variations, sometimes called 00:02:04.680 --> 00:02:07.640 PRP -like products. Things like autologous condition 00:02:07.640 --> 00:02:10.680 serum ACS, or autologous protein solution APS. 00:02:10.879 --> 00:02:12.699 They all start with the patient's blood. OK, 00:02:12.780 --> 00:02:15.280 blood -based. What's the other main group? The 00:02:15.280 --> 00:02:18.199 second major category involves tissues or cells. 00:02:18.639 --> 00:02:20.840 So this includes things like bone marrow, aspirate 00:02:20.840 --> 00:02:23.960 concentrate, or BMAC. Right, from bone marrow. 00:02:24.080 --> 00:02:27.259 Yes. And then microfragmented adipose tissue, 00:02:27.460 --> 00:02:30.379 emahete. which is derived from fat tissue. And 00:02:30.379 --> 00:02:32.659 then you get into more specific cell populations, 00:02:33.060 --> 00:02:35.060 perhaps the most talked about being mesenchymal 00:02:35.060 --> 00:02:38.080 stromal cells or MSCs. And getting hold of these 00:02:38.080 --> 00:02:41.240 materials, how is that done? Does it involve 00:02:41.240 --> 00:02:44.240 complicated procedures? It varies quite a bit 00:02:44.240 --> 00:02:46.979 depending on the product. For PRP, the concept 00:02:46.979 --> 00:02:49.060 is fairly simple. You draw some blood from the 00:02:49.060 --> 00:02:51.319 patient, much like a standard blood test, and 00:02:51.319 --> 00:02:54.099 then you use a centrifuge. To spin it down. Exactly. 00:02:54.240 --> 00:02:56.159 to separate the components and concentrate the 00:02:56.159 --> 00:02:58.419 platelets. Platelets are packed with growth factors, 00:02:58.800 --> 00:03:00.500 which are key to the proposed mechanism. Okay, 00:03:00.539 --> 00:03:04.419 and for the others, BMAC and MFAT. BMAC requires 00:03:04.419 --> 00:03:06.580 aspirating bone marrow, usually from the iliac 00:03:06.580 --> 00:03:09.849 crest, the hip bone. That aspirate is then typically 00:03:09.849 --> 00:03:12.289 centrifuged as well to concentrate the nucleated 00:03:12.289 --> 00:03:14.870 cells. Right. Which include those MSCs amongst 00:03:14.870 --> 00:03:18.310 other cell types. An MFAT from fat. Yes. That 00:03:18.310 --> 00:03:20.409 usually involves a small liposuction procedure 00:03:20.409 --> 00:03:23.250 to harvest some fat tissue. This fat is then 00:03:23.250 --> 00:03:26.469 processed essentially minced or washed to create 00:03:26.469 --> 00:03:28.569 this micro fragmented tissue that can be injected. 00:03:28.969 --> 00:03:30.930 It retains cells within their natural matrix 00:03:30.930 --> 00:03:33.259 to some extent. So you're taking something the 00:03:33.259 --> 00:03:35.680 body already has, concentrating or processing 00:03:35.680 --> 00:03:37.500 it minimally and putting it back where it's needed. 00:03:37.979 --> 00:03:40.199 What are they actually doing then, once injected? 00:03:40.280 --> 00:03:42.860 How are they supposed to help healing? The mechanism 00:03:42.860 --> 00:03:46.180 of action. That's perhaps the most debated and 00:03:46.180 --> 00:03:48.280 researched area. The central idea is that these 00:03:48.280 --> 00:03:50.520 preparations are loaded with bioactive molecules, 00:03:51.080 --> 00:03:53.159 growth factors, cytokines, signaling molecules. 00:03:53.439 --> 00:03:55.219 Biological messengers, essentially. That's a 00:03:55.219 --> 00:03:58.000 good way to put it. Platelets in PRP, for instance, 00:03:58.219 --> 00:04:00.659 release a whole cocktail of potent growth factors 00:04:00.659 --> 00:04:03.000 when activated at the injury site. Things like 00:04:03.000 --> 00:04:07.300 PDGF, TGF -beta, VEGF, the list goes on. And 00:04:07.300 --> 00:04:10.159 these factors trigger something. They're thought 00:04:10.159 --> 00:04:13.000 to orchestrate a complex biological response. 00:04:13.620 --> 00:04:16.079 This includes potentially dampening down excessive 00:04:16.079 --> 00:04:18.699 inflammation, which can actually hinder repair 00:04:18.699 --> 00:04:21.740 if it goes on too long. Okay, reducing that inflammation. 00:04:21.920 --> 00:04:24.120 Yes, but also promoting the good stuff. Yeah. 00:04:24.279 --> 00:04:28.279 stimulating local cells to multiply, proliferate, 00:04:28.740 --> 00:04:30.959 and perhaps change into the cell types needed 00:04:30.959 --> 00:04:33.839 for repair, like cartilage cells or tendon cells, 00:04:33.879 --> 00:04:36.600 that's differentiation. Right. They also encourage 00:04:36.600 --> 00:04:39.459 the growth of new blood vessels, angiogenesis, 00:04:39.819 --> 00:04:42.339 which is vital for bringing oxygen and nutrients 00:04:42.339 --> 00:04:45.420 to the healing tissue. Some components might 00:04:45.420 --> 00:04:48.019 even provide a temporary scaffold or directly 00:04:48.019 --> 00:04:50.480 interact with cell signaling pathways to guide 00:04:50.480 --> 00:04:52.759 the repair process. So it's not just one thing, 00:04:52.759 --> 00:04:56.870 it's a whole local conversation stimulating repair. 00:04:57.269 --> 00:04:59.470 Precisely. A complex interplay. And it's important 00:04:59.470 --> 00:05:01.750 to realize different orthobiologics contribute 00:05:01.750 --> 00:05:04.930 differently. PRP's main contribution is considered 00:05:04.930 --> 00:05:07.269 to be that burst of growth factors from the platelets. 00:05:07.649 --> 00:05:10.810 Whereas BMS or MFAT contain a mixture of cells, 00:05:11.029 --> 00:05:13.470 including MSCs, which can also release factors, 00:05:13.649 --> 00:05:15.750 modulate the immune response, and potentially 00:05:15.750 --> 00:05:17.610 contribute more directly to tissue building. 00:05:17.769 --> 00:05:20.110 Although the extent to which they truly differentiate 00:05:20.110 --> 00:05:23.029 in vivo is still debated. And you mentioned PRP 00:05:23.029 --> 00:05:25.310 isn't technically cell therapy in the same way? 00:05:25.509 --> 00:05:27.250 That's a key distinction made in the sources, 00:05:27.589 --> 00:05:30.850 yes. While platelets are cell fragments, PRP's 00:05:30.850 --> 00:05:32.889 action is primarily through the factors within 00:05:32.889 --> 00:05:35.430 those fragments. It's not usually classified 00:05:35.430 --> 00:05:38.470 alongside therapies, where the intent is to deliver 00:05:38.470 --> 00:05:41.250 a concentrated dose of viable cells like MSCs 00:05:41.250 --> 00:05:43.649 from bone marrow or fat. That makes sense. And 00:05:43.649 --> 00:05:46.750 although using these for, say, arthritis or tendon 00:05:46.750 --> 00:05:49.569 injuries feels quite cutting edge, this idea 00:05:49.569 --> 00:05:51.829 of using the body's own materials isn't brand 00:05:51.829 --> 00:05:54.509 new, is it? Not at all. The concept has roots 00:05:54.509 --> 00:05:57.029 going back decades. One of the reviews mentions 00:05:57.029 --> 00:05:59.449 the first documented clinical use of autologous 00:05:59.449 --> 00:06:01.910 PRP blood taken and given back to the same patient 00:06:01.910 --> 00:06:04.350 was actually in cardiac surgery, way back in 00:06:04.350 --> 00:06:09.089 1987. Really? Cardiac surgery? Yes. So while 00:06:09.089 --> 00:06:11.610 the focus on joints and tendons has boomed more 00:06:11.610 --> 00:06:14.529 recently, the underlying principle isn't entirely 00:06:14.529 --> 00:06:16.790 novel. It's been evolving for quite some time. 00:06:17.129 --> 00:06:19.829 Given that history and these really interesting 00:06:19.829 --> 00:06:21.870 potential mechanisms, you'd think the evidence 00:06:21.870 --> 00:06:24.649 base would be rock solid by now. But you said 00:06:24.649 --> 00:06:27.370 earlier establishing guidelines is tough. What's 00:06:27.370 --> 00:06:29.990 the reality of the research? Ah, yes. Moving 00:06:29.990 --> 00:06:32.769 from the theory to the clinical evidence. This 00:06:32.769 --> 00:06:36.449 is where things get, well, complicated. The single 00:06:36.449 --> 00:06:38.629 biggest challenge echoed across all the sources 00:06:38.629 --> 00:06:41.009 is the heterogeneity. Meaning the variability. 00:06:41.310 --> 00:06:44.189 Exactly. Orthobiologics aren't standardized drugs. 00:06:44.649 --> 00:06:47.800 Take PRP. Its exact composition can vary massively 00:06:47.800 --> 00:06:49.860 depending on the patient's own biology, their 00:06:49.860 --> 00:06:52.199 age, health status, even recent activity levels. 00:06:52.240 --> 00:06:54.600 Right. Then add in variations in how the blood 00:06:54.600 --> 00:06:56.959 is collected, which commercial kit is used for 00:06:56.959 --> 00:06:59.500 processing, the centrifuge settings, the final 00:06:59.500 --> 00:07:02.519 volume, whether an activator is used. You end 00:07:02.519 --> 00:07:04.480 up with potentially very different products, 00:07:04.620 --> 00:07:06.980 all being called PRP. So comparing study results 00:07:06.980 --> 00:07:09.939 is like comparing apples and, well, sometimes 00:07:09.939 --> 00:07:12.230 very different apples or maybe even pears. That's 00:07:12.230 --> 00:07:14.889 a fair analogy. And this lack of standardization 00:07:14.889 --> 00:07:18.029 extends beyond just the product. Dosing isn't 00:07:18.029 --> 00:07:20.629 standardized, injection techniques vary, post 00:07:20.629 --> 00:07:23.709 -injection rehab protocols differ. It makes pooling 00:07:23.709 --> 00:07:26.290 data and drawing firm conclusions incredibly 00:07:26.290 --> 00:07:28.670 difficult. And you mentioned even practitioners 00:07:28.670 --> 00:07:32.110 might lack standardized training. Yes. The curriculum 00:07:32.110 --> 00:07:34.709 outline we looked at specifically points to a 00:07:34.709 --> 00:07:37.470 need for more comprehensive standardized education. 00:07:37.629 --> 00:07:40.490 There's a knowledge gap, which can further contribute 00:07:40.490 --> 00:07:43.410 to inconsistent application and outcomes. All 00:07:43.410 --> 00:07:45.790 this variability inevitably impacts research 00:07:45.790 --> 00:07:48.810 quality. Okay. So bearing that major caveat in 00:07:48.810 --> 00:07:50.709 mind, let's try to pick apart what the evidence 00:07:50.709 --> 00:07:53.290 does show. Starting with PRP again, as it's the 00:07:53.290 --> 00:07:55.629 most studied, where does it seem to stand? Right. 00:07:55.629 --> 00:07:57.990 PRP certainly has the largest volume of research, 00:07:58.170 --> 00:08:00.790 especially for common things like knee osteoarthritis 00:08:00.790 --> 00:08:03.730 or KOA. Several meta -analysis studies that pool 00:08:03.730 --> 00:08:05.970 data from multiple trials do report positive 00:08:05.970 --> 00:08:08.740 findings for KOA. Improvements in patient -reported 00:08:08.740 --> 00:08:11.040 outcomes, things like pain scores and functional 00:08:11.040 --> 00:08:14.540 ability. For example, a well -known meta -analysis 00:08:14.540 --> 00:08:17.560 by Shen and colleagues looked at 14 randomized 00:08:17.560 --> 00:08:20.779 controlled trials, or RCTs, involving over 1 00:08:20.779 --> 00:08:24.060 ,400 patients. They found that PRP injections 00:08:24.060 --> 00:08:25.980 led to statistically significant improvements 00:08:25.980 --> 00:08:29.240 in WAC, scores a standard measure for OA pain, 00:08:29.480 --> 00:08:31.899 stiffness, and function compared to control groups. 00:08:32.259 --> 00:08:35.639 At 3, six, and even 12 months follow -up. That 00:08:35.639 --> 00:08:37.700 sounds pretty positive, doesn't it? Significant 00:08:37.700 --> 00:08:40.419 improvements lasting up to a year. On the surface, 00:08:40.559 --> 00:08:42.980 yes, it does sound encouraging. However... And 00:08:42.980 --> 00:08:45.860 this is a crucial, however, the same meta -analysis 00:08:45.860 --> 00:08:47.940 performed a risk of bias assessment on those 00:08:47.940 --> 00:08:50.100 14 trials. Assessing the quality of the studies 00:08:50.100 --> 00:08:52.700 themselves. Exactly. And they found that 10 out 00:08:52.700 --> 00:08:55.100 of the 14 RCTs were judged to have a high risk 00:08:55.100 --> 00:08:57.740 of bias. The other four were at moderate risk. 00:08:58.000 --> 00:08:59.679 High risk of bias in most of the studies. What 00:08:59.679 --> 00:09:01.539 does that mean practically? It means we have 00:09:01.539 --> 00:09:03.759 to be cautious about how much we trust the results. 00:09:04.009 --> 00:09:07.370 High -risk bias could stem from issues like inadequate 00:09:07.370 --> 00:09:10.129 blinding patients or assessors, knowing who got 00:09:10.129 --> 00:09:12.549 which treatment, unclear methods for selecting 00:09:12.549 --> 00:09:16.250 patients, or inconsistent follow -up. These flaws 00:09:16.250 --> 00:09:18.769 can skew the results, potentially exaggerating 00:09:18.769 --> 00:09:21.580 the benefit. So, the overall signal might point 00:09:21.580 --> 00:09:24.220 towards a benefit for NEOA, but the foundations 00:09:24.220 --> 00:09:26.580 of that evidence aren't as solid as we'd ideally 00:09:26.580 --> 00:09:29.519 like, partly due to study quality and that variability 00:09:29.519 --> 00:09:32.279 in PRP itself. That sums it up well. There's 00:09:32.279 --> 00:09:34.679 potential benefits suggested, but the evidence 00:09:34.679 --> 00:09:37.080 quality is a significant concern. What about 00:09:37.080 --> 00:09:39.710 other common problems, like, say, tennis elbow 00:09:39.710 --> 00:09:42.769 lateral epicondylitis. Yes, that's another area 00:09:42.769 --> 00:09:45.690 where PRP has been studied quite a bit. A systematic 00:09:45.690 --> 00:09:48.529 review and meta -analysis by Nemec did report 00:09:48.529 --> 00:09:50.909 improvements in patient outcome scores that were 00:09:50.909 --> 00:09:53.090 considered clinically meaningful, meaning the 00:09:53.090 --> 00:09:54.809 average improvement was large enough for patients 00:09:54.809 --> 00:09:56.990 to actually notice a difference. Okay, so potentially 00:09:56.990 --> 00:10:00.570 helpful there, too. Potentially. But again, caveats 00:10:00.570 --> 00:10:03.889 apply. That particular review highlighted major 00:10:03.889 --> 00:10:06.559 inconsistencies in the studies it included. things 00:10:06.559 --> 00:10:10.159 like missing data on patient age or sex, or crucially, 00:10:10.559 --> 00:10:13.419 not specifying the exact PRP preparation used. 00:10:13.720 --> 00:10:16.340 Ah, that standardization issue again. Precisely. 00:10:16.700 --> 00:10:18.940 And importantly, that NEMEAC review didn't include 00:10:18.940 --> 00:10:21.620 a formal risk of bias assessment using standard 00:10:21.620 --> 00:10:24.679 tools. So while the results seem positive, it's 00:10:24.679 --> 00:10:26.580 harder to gauge the reliability without knowing 00:10:26.580 --> 00:10:28.679 the quality of the underlying studies. It's a 00:10:28.679 --> 00:10:31.059 recurring pattern, isn't it? Promising signals, 00:10:31.360 --> 00:10:33.960 but hampered by inconsistency in questions about 00:10:33.960 --> 00:10:36.320 research quality? What about plantar fasciitis, 00:10:36.440 --> 00:10:39.399 that heel pain condition? Indeed. A fairly recent 00:10:39.399 --> 00:10:42.419 meta -analysis from 2024 by Herber looked at 00:10:42.419 --> 00:10:46.019 21 RCTs with over 1 ,300 patients. They found 00:10:46.019 --> 00:10:48.940 the PRP injections seemed more effective at reducing 00:10:48.940 --> 00:10:51.399 pain compared to several other common treatments, 00:10:51.799 --> 00:10:54.139 corticosteroids, shockwave therapy, and even 00:10:54.139 --> 00:10:56.360 placebo injections. Better pain relief, that's 00:10:56.360 --> 00:10:58.779 significant. It is. They also found better scores 00:10:58.779 --> 00:11:00.860 on a specific foot and ankle function scale, 00:11:01.320 --> 00:11:04.179 the AOFAS Ankle Heimfoot score, when comparing 00:11:04.269 --> 00:11:07.470 PRP to steroid injections and placebo. So improvements 00:11:07.470 --> 00:11:10.509 in pain and function there? Well, better scores 00:11:10.509 --> 00:11:13.870 on that specific functional scale, yes. But interestingly, 00:11:14.450 --> 00:11:16.850 the same analysis found no significant difference 00:11:16.850 --> 00:11:19.450 between PRP and the other groups when looking 00:11:19.450 --> 00:11:22.149 at objective measures, like the actual thickness 00:11:22.149 --> 00:11:24.250 of the plantar fascia measured on ultrasound, 00:11:24.690 --> 00:11:26.529 or when using a different functional score called 00:11:26.529 --> 00:11:29.279 the foot function index. Hmm, so pain relief 00:11:29.279 --> 00:11:31.620 seems better, but maybe not changing the underlying 00:11:31.620 --> 00:11:34.600 tissue thickness or overall foot function consistently. 00:11:34.840 --> 00:11:37.679 That seems to be the implication. And echoing 00:11:37.679 --> 00:11:40.120 the findings in other areas, the authors explicitly 00:11:40.120 --> 00:11:42.899 noted significant variability in the PRP methods 00:11:42.899 --> 00:11:45.799 used across the trials and concluded that the 00:11:45.799 --> 00:11:48.740 overall quality of the included RCTs was low. 00:11:48.990 --> 00:11:51.590 low -quality evidence again. It really underlines 00:11:51.590 --> 00:11:53.570 the challenge, doesn't it? Even where results 00:11:53.570 --> 00:11:56.789 look positive, like pain relief for plantar fasciitis, 00:11:57.090 --> 00:11:59.509 the confidence in that finding is weakened by 00:11:59.509 --> 00:12:01.669 the study quality. Absolutely. It's a constant 00:12:01.669 --> 00:12:03.950 refrain in the literature. What about less common 00:12:03.950 --> 00:12:07.070 applications? We hear about PRP being used for 00:12:07.070 --> 00:12:09.970 ligament tears, other tendon problems, even spine 00:12:09.970 --> 00:12:13.279 issues, or during meniscus surgery. Yes. Clinical 00:12:13.279 --> 00:12:15.659 practice has certainly expanded into these areas, 00:12:16.019 --> 00:12:18.519 but the sources suggest that strong evidence 00:12:18.519 --> 00:12:20.799 -based consensus statements or clear guidelines 00:12:20.799 --> 00:12:24.340 are generally lacking here. Meta -analyses looking 00:12:24.340 --> 00:12:27.419 into these applications often find, well, a similar 00:12:27.419 --> 00:12:29.980 picture. Promising hints, but not definitive. 00:12:30.360 --> 00:12:33.259 Exactly. Some studies might suggest a benefit, 00:12:33.399 --> 00:12:35.860 for instance, lower failure rates after meniscus 00:12:35.860 --> 00:12:38.360 repair surgery when PRP is added, but then maybe 00:12:38.360 --> 00:12:40.419 no significant difference in functional outcome 00:12:40.419 --> 00:12:43.210 scores. Or for low back pain or spinal fusion, 00:12:43.450 --> 00:12:45.909 some studies report pain reduction or maybe faster 00:12:45.909 --> 00:12:48.909 signs of bone healing on scans, but don't necessarily 00:12:48.909 --> 00:12:51.350 show that PRP improves the overall success rate 00:12:51.350 --> 00:12:54.710 of the fusion compared to standard methods. The 00:12:54.710 --> 00:12:56.710 evidence tends to be quite mixed, often based 00:12:56.710 --> 00:12:59.129 on smaller studies and hampered by that same 00:12:59.129 --> 00:13:01.840 issue of heterogeneity. So, really, outside of 00:13:01.840 --> 00:13:04.639 maybe neo -A, where there's a larger volume of 00:13:04.639 --> 00:13:07.379 research, albeit flawed, the evidence for PRP 00:13:07.379 --> 00:13:09.840 across the board is quite patchy and often low 00:13:09.840 --> 00:13:12.120 quality. That's a fair summary of the current 00:13:12.120 --> 00:13:14.059 state, according to these reviews. And what about 00:13:14.059 --> 00:13:16.559 those PRP -like products you mentioned earlier, 00:13:16.679 --> 00:13:19.720 ACS and APS? Right. These are variations where 00:13:19.720 --> 00:13:22.600 the blood undergoes extra processing steps, aiming 00:13:22.600 --> 00:13:25.840 to perhaps enhance certain components, like anti 00:13:25.840 --> 00:13:28.740 -inflammatory factors in ACS or concentrating 00:13:28.740 --> 00:13:31.519 a broader range of proteins in APS. Is the evidence 00:13:31.519 --> 00:13:34.220 any clearer for them? Actually, it's much less 00:13:34.220 --> 00:13:36.799 developed. The key finding from the sources is 00:13:36.799 --> 00:13:39.820 stark. There are currently no randomized controlled 00:13:39.820 --> 00:13:42.440 trials published specifically evaluating these 00:13:42.440 --> 00:13:45.649 PRP -like products. The studies that do exist 00:13:45.649 --> 00:13:48.450 are generally preliminary, small pilot studies 00:13:48.450 --> 00:13:51.350 with limited statistical power to draw firm conclusions. 00:13:51.909 --> 00:13:54.169 So even less evidence to go on there compared 00:13:54.169 --> 00:13:56.750 to standard PRP? Considerably less, yes. Okay. 00:13:56.850 --> 00:13:58.710 That paints a rather complex picture for the 00:13:58.710 --> 00:14:01.370 blood -based therapies. Let's switch focus now 00:14:01.370 --> 00:14:04.470 to the other main category. The tissue and cell 00:14:04.470 --> 00:14:08.149 -based options like BMA, MFA, and MSC therapies. 00:14:08.710 --> 00:14:10.940 How does the evidence stack up for those? Well, 00:14:11.120 --> 00:14:12.799 generally speaking, the development pathway for 00:14:12.799 --> 00:14:15.179 these therapies tends to be longer and more expensive 00:14:15.179 --> 00:14:17.279 than for blood products like PRP. Makes sense. 00:14:17.340 --> 00:14:19.460 Dealing with tissues and cells seems more involved. 00:14:19.779 --> 00:14:22.360 It is. And while safety data from initial studies 00:14:22.360 --> 00:14:24.679 often looks acceptable for several of these products, 00:14:25.139 --> 00:14:27.139 the overall volume of high -quality research, 00:14:27.299 --> 00:14:30.240 especially large RCTs and meta -analyses, is 00:14:30.240 --> 00:14:32.600 significantly lower than what we see for PRP. 00:14:32.799 --> 00:14:35.080 And is a research focus similar, mainly knee 00:14:35.080 --> 00:14:38.080 OA? Yes. Much of the existing clinical trial 00:14:38.080 --> 00:14:41.399 evidence for BMH, MST and MSCs in orthopedics 00:14:41.399 --> 00:14:44.639 has also concentrated on knee osteoarthritis. 00:14:45.139 --> 00:14:47.639 Are they plagued by the same issues of study 00:14:47.639 --> 00:14:50.200 quality and potential bias that affect the PRP 00:14:50.200 --> 00:14:53.179 literature? Unfortunately, yes. The sources explicitly 00:14:53.179 --> 00:14:55.460 state that a high risk of bias is frequently 00:14:55.460 --> 00:14:57.700 identified in trials of cell and tissue based 00:14:57.700 --> 00:15:00.240 therapies. This can sometimes be linked to factors 00:15:00.240 --> 00:15:02.820 like industry funding, influencing study design 00:15:02.820 --> 00:15:05.580 or reporting, or simply due to poor methodological 00:15:05.580 --> 00:15:07.600 execution. It makes interpreting the results 00:15:07.600 --> 00:15:10.379 reliably quite challenging. So similar problems, 00:15:10.440 --> 00:15:12.299 just with less data overall. Can you give us 00:15:12.299 --> 00:15:14.700 some examples of the findings or lack thereof? 00:15:14.960 --> 00:15:17.200 Let's stick with KOA, as it's the most researched 00:15:17.200 --> 00:15:20.419 area. One of the reviews cited a meta -analysis 00:15:20.419 --> 00:15:22.679 that specifically searched for large randomized 00:15:22.679 --> 00:15:25.399 controlled trials. They defined large as having 00:15:25.399 --> 00:15:28.440 over 100 participants in each treatment group 00:15:28.440 --> 00:15:31.379 published between the years 2000 and 2023. OK, 00:15:31.460 --> 00:15:33.419 looking for the most robust evidence, what did 00:15:33.419 --> 00:15:36.450 they find? Quite strikingly, they found only 00:15:36.450 --> 00:15:39.090 one trial focused on a cell -based therapy for 00:15:39.090 --> 00:15:41.990 OA that met their size criteria. Just one in 00:15:41.990 --> 00:15:45.250 over two decades of research. Wow, only one large 00:15:45.250 --> 00:15:48.710 RCT. Which therapy was that? It was a trial investigating 00:15:48.710 --> 00:15:52.070 autologous adipose -derived MSC stem cells taken 00:15:52.070 --> 00:15:54.210 from the patient's own fat tissue, which were 00:15:54.210 --> 00:15:56.450 then expanded in culture, meaning grown to larger 00:15:56.450 --> 00:15:58.870 numbers in the lab, before being injected. That 00:15:58.870 --> 00:16:01.149 really highlights the scarcity of large -scale 00:16:01.149 --> 00:16:03.210 evidence for these therapies compared to PRP, 00:16:03.309 --> 00:16:05.450 doesn't it? It certainly does. And, adding another 00:16:05.450 --> 00:16:08.289 layer of complexity, even that single large trial 00:16:08.289 --> 00:16:10.730 was assessed in the meta -analysis as having 00:16:10.730 --> 00:16:14.009 a high risk of bias. Oh dear. Why was that? Issues 00:16:14.009 --> 00:16:15.970 were raised regarding how patients were allocated 00:16:15.970 --> 00:16:18.570 to the treatment groups and how the study handled 00:16:18.570 --> 00:16:21.750 missing data, which can introduce bias. When 00:16:21.750 --> 00:16:24.610 the meta -analysis pulled the data, Primarily 00:16:24.610 --> 00:16:27.669 from this one large high -bias study, it concluded 00:16:27.669 --> 00:16:30.250 there was no superior effect on pain relief at 00:16:30.250 --> 00:16:33.269 12 weeks compared to other interventions. So 00:16:33.269 --> 00:16:35.950 the big picture from that analysis wasn't overwhelmingly 00:16:35.950 --> 00:16:39.570 positive? Not from the pooled analysis, no. However, 00:16:39.610 --> 00:16:41.409 there's an important nuance mentioned in the 00:16:41.409 --> 00:16:43.929 source. The original publication of that specific 00:16:43.929 --> 00:16:46.889 large trial did report that significantly more 00:16:46.889 --> 00:16:49.990 patients treated with the expanded MSCs achieved 00:16:49.990 --> 00:16:52.490 what's called the minimal clinically important 00:16:52.490 --> 00:16:55.960 difference. or MCID, for both pain and function 00:16:55.960 --> 00:16:58.399 scores at the six -month mark. Meaning enough 00:16:58.399 --> 00:17:00.259 patients experienced a meaningful improvement 00:17:00.259 --> 00:17:02.919 at six months, even if the average difference 00:17:02.919 --> 00:17:05.480 wasn't significant at 12 weeks in the meta -analysis. 00:17:05.700 --> 00:17:08.079 Exactly. It shows how different analysis approaches 00:17:08.079 --> 00:17:10.500 or time points can sometimes lead to different 00:17:10.500 --> 00:17:12.740 headline conclusions, which adds to the confusion. 00:17:13.059 --> 00:17:15.480 That's a critical point. Was there any significant 00:17:15.480 --> 00:17:18.160 research published after that meta -analysis 00:17:18.160 --> 00:17:22.089 cutoff? Yes. A very important one. A large multi 00:17:22.089 --> 00:17:26.210 -center RCT with 480 patients was published in 00:17:26.210 --> 00:17:29.470 late 2023 by Motner and colleagues after the 00:17:29.470 --> 00:17:31.150 time frame cover by the previously mentioned 00:17:31.150 --> 00:17:33.210 meta -analysis. OK, what did that one look at? 00:17:33.470 --> 00:17:35.970 It directly compared intra -articular injections 00:17:35.970 --> 00:17:39.430 of BMAC and SVF stromal vascular fraction, which 00:17:39.430 --> 00:17:42.250 is another preparation derived from fat containing 00:17:42.250 --> 00:17:45.029 MSCs and other cells, but typically not culture 00:17:45.029 --> 00:17:47.210 expanded against the saline placebo injection 00:17:47.210 --> 00:17:49.980 for patients with knee OA. A head -to -head comparison 00:17:49.980 --> 00:17:52.980 with placebo in a large trial? That sounds like 00:17:52.980 --> 00:17:54.720 exactly the kind of study needed. What were the 00:17:54.720 --> 00:17:56.740 results? The primary outcome was knee pain at 00:17:56.740 --> 00:17:59.359 12 months, and the finding was quite clear. The 00:17:59.359 --> 00:18:01.940 study reported no superiority of either BMAC 00:18:01.940 --> 00:18:05.279 or SVF compared to the placebo injection. No 00:18:05.279 --> 00:18:07.079 statistically significant difference in pain 00:18:07.079 --> 00:18:09.170 improvement. No difference compared to placebo 00:18:09.170 --> 00:18:11.630 in a large, well -conducted trial. That's quite 00:18:11.630 --> 00:18:13.630 significant, isn't it? It seems to temper some 00:18:13.630 --> 00:18:16.369 of the enthusiasm. It certainly does. It represents 00:18:16.369 --> 00:18:18.769 a high -quality piece of evidence that challenges 00:18:18.769 --> 00:18:21.230 some of the positive findings reported in smaller, 00:18:21.650 --> 00:18:24.130 potentially less rigorous studies. It suggests 00:18:24.130 --> 00:18:27.009 that for knee -away pain, at least at 12 months, 00:18:27.279 --> 00:18:30.460 These specific preparations might not offer a 00:18:30.460 --> 00:18:33.079 benefit beyond a placebo effect. So while smaller 00:18:33.079 --> 00:18:35.720 studies might hint at benefits, the bigger, better 00:18:35.720 --> 00:18:38.539 trials aren't consistently backing that up for 00:18:38.539 --> 00:18:41.519 cell or tissue therapies in KOA. That seems to 00:18:41.519 --> 00:18:43.680 be the trend emerging from the high -level evidence 00:18:43.680 --> 00:18:46.019 landscape right now. Now, it's fair to say there 00:18:46.019 --> 00:18:48.839 are other smaller meta -analyses often looking 00:18:48.839 --> 00:18:51.259 at trials with fewer than 30 patients per group. 00:18:51.299 --> 00:18:53.779 Right. Some of these have reported positive findings 00:18:53.779 --> 00:18:56.000 regarding safety and efficacy for therapies like 00:18:56.000 --> 00:19:00.359 ADMS. MSCs, adipose -derived MSCs, or SVF. However, 00:19:00.519 --> 00:19:02.660 the sources caution that the criteria used to 00:19:02.660 --> 00:19:05.160 assess bias in these smaller reviews might be 00:19:05.160 --> 00:19:07.480 less strict, or many of the included studies 00:19:07.480 --> 00:19:09.599 themselves don't meet the criteria for low risk 00:19:09.599 --> 00:19:12.579 of bias across all important domains. So again, 00:19:12.759 --> 00:19:14.900 the quality of the underlying evidence is a concern. 00:19:15.180 --> 00:19:19.720 Yes, a recent 2024 meta -analysis pooled 15 RCTs 00:19:19.720 --> 00:19:22.819 on various cell therapies for OA, mostly small 00:19:22.819 --> 00:19:27.299 studies using VMSC -BME, ADMSE, or even umbilical 00:19:27.299 --> 00:19:30.259 cord MSCs. While its overall conclusion leaned 00:19:30.259 --> 00:19:32.539 towards safety and efficacy, it also noted that 00:19:32.539 --> 00:19:34.500 only about a third of the included studies were 00:19:34.500 --> 00:19:36.759 judged to have a low risk of bias. So if you 00:19:36.759 --> 00:19:38.319 had to summarize the evidence for these cell 00:19:38.319 --> 00:19:40.380 and tissue therapies? Based on the sources, the 00:19:40.380 --> 00:19:43.319 most studied are bone marrow -derived, BMSC -BMA, 00:19:43.440 --> 00:19:47.380 and adipose -derived ADMS CSVF products, mainly 00:19:47.380 --> 00:19:50.039 for an EOA. They appear generally safe in the 00:19:50.039 --> 00:19:52.339 context of these trials. However, the current 00:19:52.339 --> 00:19:55.180 high -level evidence from large, low -bias RCTs 00:19:55.180 --> 00:19:57.420 cannot definitively support clear mechanisms 00:19:57.420 --> 00:20:00.059 of action, leading to superior clinical outcomes 00:20:00.059 --> 00:20:02.420 compared to placebo or other treatments for many 00:20:02.420 --> 00:20:04.900 indications. Right. Therefore, the sources strongly 00:20:04.900 --> 00:20:07.059 emphasize the need for absolute transparency 00:20:07.059 --> 00:20:09.380 with patients about this limited high -level 00:20:09.380 --> 00:20:11.799 evidence when discussing these therapies as potential 00:20:11.799 --> 00:20:15.019 options. That makes perfect sense. So we have 00:20:15.019 --> 00:20:18.920 this complex picture of variable evidence, further 00:20:18.920 --> 00:20:21.319 complicated by issues of standardization and 00:20:21.319 --> 00:20:23.799 study quality, and then layered on top of that 00:20:23.799 --> 00:20:26.559 is the regulatory situation, which sounds like 00:20:26.559 --> 00:20:29.099 another minefield altogether. It absolutely is, 00:20:29.200 --> 00:20:32.339 particularly in the U .S., where the FDA, the 00:20:32.339 --> 00:20:34.319 Food and Drug Administration, is the main player. 00:20:34.680 --> 00:20:36.680 But it's not just them. Who else is involved? 00:20:36.819 --> 00:20:38.240 You've got the Federal Trade Commission, the 00:20:38.240 --> 00:20:40.720 FTC, which looks at advertising claims, making 00:20:40.720 --> 00:20:43.099 sure they aren't false or misleading. You have 00:20:43.099 --> 00:20:45.619 state medical boards overseeing how doctors practice. 00:20:46.019 --> 00:20:48.259 And then a whole host of professional societies 00:20:48.259 --> 00:20:51.240 and international groups issue guidelines or 00:20:51.240 --> 00:20:54.059 position statements, organizations like the APM 00:20:54.059 --> 00:20:57.819 &R, AMSSM, the ISSCR. A lot of cooks in the kitchen, 00:20:57.900 --> 00:21:00.599 potentially. How does the FDA actually categorize 00:21:00.599 --> 00:21:03.059 these orthobiologics? Is there a specific system? 00:21:03.220 --> 00:21:05.259 Yes, they have a framework specifically for what 00:21:05.099 --> 00:21:07.859 a term human cells, tissues, and cellular and 00:21:07.859 --> 00:21:11.660 tissue -based products, or HCTPs for short. It's 00:21:11.660 --> 00:21:14.180 outlined in Title 21 of the Code of Federal Regulations, 00:21:14.319 --> 00:21:17.619 Part 1271. Within that, There's essentially a 00:21:17.619 --> 00:21:19.819 tiered risk based system. Tier one is the lowest 00:21:19.819 --> 00:21:22.420 risk, focused mainly on preventing disease transmission 00:21:22.420 --> 00:21:25.259 through good tissue practices. Tier two falls 00:21:25.259 --> 00:21:27.319 under section 361 of the Public Health Service 00:21:27.319 --> 00:21:30.599 Act. These HCTPs need to meet specific criteria 00:21:30.599 --> 00:21:33.460 and require FDA registration and adherence to 00:21:33.460 --> 00:21:35.720 good tissue practices, but don't need pre -market 00:21:35.720 --> 00:21:38.200 approval. In tier three. Tier three is for higher 00:21:38.200 --> 00:21:41.990 risk products, regulated under section 351. These 00:21:41.990 --> 00:21:43.890 are treated much more like drugs or traditional 00:21:43.890 --> 00:21:46.589 biologics. They require an investigational new 00:21:46.589 --> 00:21:49.650 drug application, or IND, to even conduct clinical 00:21:49.650 --> 00:21:52.049 trials in humans. And before they can be marketed, 00:21:52.049 --> 00:21:54.269 they need a full biologics license application, 00:21:54.609 --> 00:21:56.990 or BLA, demonstrating safety and effectiveness. 00:21:57.130 --> 00:21:59.349 That's a very high bar. A huge difference between 00:21:59.349 --> 00:22:02.789 Tier 2 and Tier 3, then. Where do common orthobiologics 00:22:02.789 --> 00:22:06.230 like PRP, BMAC, and mFAT2 typically fit? This 00:22:06.230 --> 00:22:09.509 is where it gets particularly nuanced. PRP and 00:22:09.509 --> 00:22:12.369 PPP platelet -poor plasma derived solely from 00:22:12.369 --> 00:22:14.829 a patient's blood are generally not regulated 00:22:14.829 --> 00:22:17.569 by the FDA under the HCTP framework as Section 00:22:17.569 --> 00:22:20.529 361 products. They tend to fall under different 00:22:20.529 --> 00:22:23.430 less stringent regulatory oversight focused on 00:22:23.430 --> 00:22:25.769 blood product safety and device clearance for 00:22:25.769 --> 00:22:28.569 the preparation kits. So PRP has a relatively 00:22:28.569 --> 00:22:31.329 simpler regulatory path within this specific 00:22:31.329 --> 00:22:34.160 HCTP structure. Compared to cell and tissue products, 00:22:34.559 --> 00:22:37.480 generally yes, regarding the HTTP rules specifically. 00:22:38.099 --> 00:22:40.920 Now products like MFT and BMAC can potentially 00:22:40.920 --> 00:22:44.740 qualify as section 361 HTTPS, avoiding the stringent 00:22:44.740 --> 00:22:48.279 361 pathway, but only if they meet four key criteria. 00:22:48.380 --> 00:22:50.400 Four criteria, what are they? Okay, they are. 00:22:50.660 --> 00:22:52.359 One, the product must be minimally manipulated, 00:22:52.700 --> 00:22:54.160 meaning processing doesn't alter its relevant 00:22:54.160 --> 00:22:56.960 biological characteristics. Two, it must be intended 00:22:56.960 --> 00:22:59.259 for homologous use only, meaning it performs 00:22:59.259 --> 00:23:01.559 the same basic function in the recipient as it 00:23:01.559 --> 00:23:03.380 did in the donor. Right, like using bone graft 00:23:03.380 --> 00:23:06.400 for bone healing. Exactly. Three, the product 00:23:06.400 --> 00:23:08.480 isn't combined with other articles, apart from 00:23:08.480 --> 00:23:11.069 water, crystalloids, or certain sterilizing agents. 00:23:11.650 --> 00:23:14.309 And four, it either has no systemic effect and 00:23:14.309 --> 00:23:16.490 is independent on the metabolic activity of living 00:23:16.490 --> 00:23:20.250 cells for its primary function, or it's for autologous 00:23:20.250 --> 00:23:22.430 use, used in a first or second degree relative 00:23:22.430 --> 00:23:25.450 or reproductive use. That sounds quite specific 00:23:25.450 --> 00:23:28.309 and potentially open to interpretation. Very 00:23:28.309 --> 00:23:31.259 much so. The interpretation of minimal manipulation 00:23:31.259 --> 00:23:34.259 and homologous use is precisely where a lot of 00:23:34.259 --> 00:23:36.380 the regulatory debate and enforcement actions 00:23:36.380 --> 00:23:39.160 have focused, especially concerning fat -derived 00:23:39.160 --> 00:23:42.579 products like MF fat or SVF. Does the processing 00:23:42.579 --> 00:23:45.460 significantly alter the tissue? Is injecting 00:23:45.460 --> 00:23:48.519 it into a joint for cartilage repair truly homologous 00:23:48.519 --> 00:23:50.759 to the fat's original function? I see. And if 00:23:50.759 --> 00:23:53.279 a product doesn't meet all four criteria? Then, 00:23:53.359 --> 00:23:55.180 according to the FDA guidance outlined in the 00:23:55.180 --> 00:23:57.299 sources, it generally defaults to being regulated 00:23:57.299 --> 00:24:00.359 as a Section 351 product, a drug or biologic, 00:24:00.680 --> 00:24:03.660 requiring that full IND and BLA approval process 00:24:03.660 --> 00:24:05.680 before marketing. Which is a much longer and 00:24:05.680 --> 00:24:07.500 more expensive road. Is there any way around 00:24:07.500 --> 00:24:09.619 that, perhaps for treatments prepared and used 00:24:09.619 --> 00:24:12.500 immediately? Yes. There's a critical exception 00:24:12.500 --> 00:24:14.799 known as the same surgical procedure exception, 00:24:15.240 --> 00:24:19.400 detailed in Section 1 .71 .15b. of the regulations. 00:24:19.799 --> 00:24:21.900 Same surgical procedure? What does that cover? 00:24:22.460 --> 00:24:25.359 It applies when an HTTP like bone marrow or fat 00:24:25.359 --> 00:24:27.640 tissue is removed from a patient and implanted 00:24:27.640 --> 00:24:29.839 back into the same patient within the same single 00:24:29.839 --> 00:24:32.500 surgical procedure. The tissue must also remain 00:24:32.500 --> 00:24:35.539 in its original form and only be minimally manipulated 00:24:35.539 --> 00:24:38.099 as defined by the FDA. Okay, so if a surgeon 00:24:38.099 --> 00:24:40.500 takes some bone marrow during a knee operation, 00:24:41.000 --> 00:24:43.440 spins it down minimally, and injects it back 00:24:43.440 --> 00:24:45.720 into the knee during that same operation, that 00:24:45.720 --> 00:24:48.180 might fall under this exception. Precisely. If 00:24:48.180 --> 00:24:50.769 the criteria are met, This exception essentially 00:24:50.769 --> 00:24:52.809 supersedes the need to meet those four criteria 00:24:52.809 --> 00:24:55.829 for being a 361 product. It provides a regulatory 00:24:55.829 --> 00:24:58.309 pathway for many common autologous procedures. 00:24:58.589 --> 00:25:00.789 But the definition of minimal manipulation is 00:25:00.789 --> 00:25:03.109 still key here, too. Absolutely. And the FDA 00:25:03.109 --> 00:25:05.509 has issued guidance clarifying its interpretation. 00:25:06.089 --> 00:25:08.690 For example, using enzymes to digest fat tissue 00:25:08.690 --> 00:25:11.130 to isolate the stromal vascular fraction, SVF, 00:25:11.549 --> 00:25:13.529 is generally considered by the FDA to be more 00:25:13.529 --> 00:25:16.130 than minimal manipulation. Ah, so that would 00:25:16.130 --> 00:25:18.809 likely push SBF outside of this exception and 00:25:18.809 --> 00:25:21.630 potentially into the 351 category, needing full 00:25:21.630 --> 00:25:24.230 drug approval. That's the current FDA stance, 00:25:24.430 --> 00:25:26.930 yes. It's a really significant point of contention 00:25:26.930 --> 00:25:29.329 and regulatory focus. The source has also mentioned 00:25:29.329 --> 00:25:31.710 some products being advertised that aren't actually 00:25:31.710 --> 00:25:34.390 legal for widespread use. Yes, this is a major 00:25:34.390 --> 00:25:36.529 point of concern highlighted in the curriculum 00:25:36.529 --> 00:25:39.190 material. It warns practitioners and patients 00:25:39.190 --> 00:25:42.450 about products like many amniotic fluid or umbilical 00:25:42.450 --> 00:25:45.319 cord tissue products, culture expanded stem cells 00:25:45.319 --> 00:25:47.700 where cells are grown in a lab to multiply in 00:25:47.700 --> 00:25:49.920 exosomes? What's the issue with them? While these 00:25:49.920 --> 00:25:52.039 are areas of active research, they are frequently 00:25:52.039 --> 00:25:55.339 marketed directly to patients for various orthopedic 00:25:55.339 --> 00:25:58.390 conditions. However, according to the sources 00:25:58.390 --> 00:26:01.170 and current FDA enforcement, these products generally 00:26:01.170 --> 00:26:04.009 do not meet the criteria for Section 361 regulation 00:26:04.009 --> 00:26:06.369 and have not obtained the required BLA approval 00:26:06.369 --> 00:26:09.549 under Section 351 for these uses. Therefore, 00:26:09.869 --> 00:26:12.130 their marketing and use outside of an FDA -approved 00:26:12.130 --> 00:26:15.390 clinical trial under an IND is considered illegal. 00:26:15.569 --> 00:26:17.710 So things people might see advertised online 00:26:17.710 --> 00:26:19.809 or in clinics might not actually be compliant 00:26:19.809 --> 00:26:22.589 with FDA regulations. That's the stark warning. 00:26:22.809 --> 00:26:26.069 The FDA has particularly increased its enforcement 00:26:26.069 --> 00:26:28.329 actions against unapproved birth tissue products 00:26:28.329 --> 00:26:31.470 since 2021, making it clear they view most of 00:26:31.470 --> 00:26:35.089 these as 351 biologics requiring full approval. 00:26:35.470 --> 00:26:37.470 That's a huge disconnect. It also brings up the 00:26:37.470 --> 00:26:40.589 terminology FDA cleared versus FDA approved. 00:26:41.009 --> 00:26:42.970 They aren't the same, are they? Absolutely not. 00:26:42.990 --> 00:26:45.460 And it's a critical distinction. FDA cleared 00:26:45.460 --> 00:26:47.579 usually applies to medical devices, often through 00:26:47.579 --> 00:26:50.539 the 510K pathway. This means the device like 00:26:50.539 --> 00:26:53.500 a centrifuge or a kit used to prepare PRP or 00:26:53.500 --> 00:26:56.740 BMAC is deemed substantially equivalent to a 00:26:56.740 --> 00:26:59.000 device already legally on the market. It does 00:26:59.000 --> 00:27:01.299 not mean the FDA has evaluated the orthobiologic 00:27:01.299 --> 00:27:04.059 product itself for safety and effectiveness for 00:27:04.059 --> 00:27:06.460 specific clinical use. OK, so the kit might be 00:27:06.460 --> 00:27:08.420 cleared, but not the PRP itself for treating 00:27:08.420 --> 00:27:12.180 arthritis. Exactly. FDA approved is the standard 00:27:12.180 --> 00:27:15.940 for drugs and biologics. like Section 351 -HCTPs. 00:27:16.500 --> 00:27:19.619 This requires rigorous clinical trial data demonstrating 00:27:19.619 --> 00:27:23.019 safety and efficacy for a specific intended use 00:27:23.019 --> 00:27:25.539 or indication. And the sources are unequivocal 00:27:25.539 --> 00:27:28.859 on this point. Currently, no orthobiologic products 00:27:28.859 --> 00:27:31.680 or devices have received FDA approval specifically 00:27:31.680 --> 00:27:34.420 for treating osteoarthritis or tendinopathy. 00:27:34.779 --> 00:27:36.980 That is such a crucial piece of information for 00:27:36.980 --> 00:27:40.259 patients and clinicians. So... Technically, using 00:27:40.259 --> 00:27:43.000 PRP for knee arthritis is considered off -label 00:27:43.000 --> 00:27:45.819 use? Correct. Since PRP hasn't gone through the 00:27:45.819 --> 00:27:48.839 BLA process and received FDA approval specifically 00:27:48.839 --> 00:27:51.700 for the indication of knee osteoarthritis, using 00:27:51.700 --> 00:27:54.059 it for that purpose is off -label. But off -label 00:27:54.059 --> 00:27:56.400 doesn't necessarily mean bad or experimental, 00:27:56.519 --> 00:27:58.980 does it? Doctors use medications off -label quite 00:27:58.980 --> 00:28:01.099 often. That's true. The sources clarify that 00:28:01.099 --> 00:28:03.180 off -label use doesn't automatically imply a 00:28:03.180 --> 00:28:04.880 lack of supporting evidence, as we discussed. 00:28:05.180 --> 00:28:07.839 There is research on PRP for KOA, even with its 00:28:07.839 --> 00:28:10.119 limitations. However, it absolutely does mean 00:28:10.119 --> 00:28:12.240 the product hasn't met the FDA's highest bar 00:28:12.240 --> 00:28:14.539 for approval for that specific condition. It's 00:28:14.539 --> 00:28:16.900 about the regulatory status, not necessarily 00:28:16.900 --> 00:28:18.599 the scientific underpinning, although the two 00:28:18.599 --> 00:28:21.259 are related. Precisely. And this is where the 00:28:21.259 --> 00:28:23.900 FTC, the Federal Trade Commission, steps in regarding 00:28:23.900 --> 00:28:26.500 advertising. Clinics can't legally make claims 00:28:26.500 --> 00:28:30.019 that imply FDA approval for unapproved use, nor 00:28:30.019 --> 00:28:32.440 can they make unsubstantiated claims about curing 00:28:32.440 --> 00:28:35.660 diseases. Like broadly advertising stem cell 00:28:35.660 --> 00:28:39.480 cures. Exactly. Using misleading terms like stem 00:28:39.480 --> 00:28:41.839 cells for products that aren't primarily stem 00:28:41.839 --> 00:28:44.539 cells or overstating the evidence can attract 00:28:44.539 --> 00:28:48.579 FTC attention. Violating FDA or FTC regulations 00:28:48.579 --> 00:28:51.180 can have serious consequences, including warning 00:28:51.180 --> 00:28:53.980 letters, injunctions, and penalties. It really 00:28:53.980 --> 00:28:56.299 underscores why staying informed about the evolving 00:28:56.299 --> 00:28:59.140 regulatory landscape is so vital for practitioners. 00:28:59.640 --> 00:29:02.579 This complex web of evidence and regulation inevitably 00:29:02.579 --> 00:29:05.180 leads to significant ethical considerations, 00:29:05.180 --> 00:29:07.880 doesn't it? Absolutely. Ethics and transparency 00:29:07.880 --> 00:29:10.700 are arguably even more critical in orthobiologics 00:29:10.700 --> 00:29:12.779 than in areas with well -established approved 00:29:12.779 --> 00:29:15.240 treatments, precisely because of the variability 00:29:15.240 --> 00:29:17.839 in regulatory nuances. What are some of the key 00:29:17.839 --> 00:29:20.859 ethical challenges highlighted? A major one revolves 00:29:20.859 --> 00:29:23.779 around nomenclature, particularly the pervasive 00:29:23.779 --> 00:29:26.640 misuse of the term stem cells. Patients hear 00:29:26.640 --> 00:29:28.920 stem cells, and often equate it with powerful 00:29:28.920 --> 00:29:31.500 regenerative potential, maybe thinking of embryonic 00:29:31.500 --> 00:29:34.079 stem cells. But in orthobiologics, it's often 00:29:34.079 --> 00:29:37.000 used loosely to describe PRP, which contains 00:29:37.000 --> 00:29:40.539 no cells capable of differentiation, or BMSI 00:29:40.539 --> 00:29:43.500 and MIT. Which do contain some mesenchymal stromal 00:29:43.500 --> 00:29:46.660 cells, or MSCs. They do, yes. MSCs are a type 00:29:46.660 --> 00:29:49.579 of adult multipotent stromal cell, sometimes 00:29:49.579 --> 00:29:51.700 referred to as medicinal signaling cells now. 00:29:52.339 --> 00:29:55.140 But BMSC and MFA contain a whole mixture of cell 00:29:55.140 --> 00:29:58.200 types. And the MSCs present are typically in 00:29:58.200 --> 00:30:01.059 very low concentrations compared to culture expanded 00:30:01.059 --> 00:30:02.980 products. And they aren't being administered 00:30:02.980 --> 00:30:04.960 as a purified stem cell therapy in the way the 00:30:04.960 --> 00:30:07.480 term might imply. So using that stem cell label 00:30:07.480 --> 00:30:10.119 broadly can create unrealistic expectations. 00:30:10.480 --> 00:30:12.880 Definitely. It can significantly inflate patient 00:30:12.880 --> 00:30:14.859 hopes and misunderstandings about what's actually 00:30:14.859 --> 00:30:17.019 be administered and what it can realistically 00:30:17.019 --> 00:30:19.619 achieve based on current evidence. This relates 00:30:19.619 --> 00:30:22.420 to the broader problem of misleading public representations. 00:30:22.859 --> 00:30:25.359 Given the regulatory status, no FDA approval 00:30:25.359 --> 00:30:28.380 for common uses and the variable evidence, some 00:30:28.380 --> 00:30:30.660 marketing practices can cross ethical lines. 00:30:31.240 --> 00:30:33.299 The curriculum source actually lists several 00:30:33.299 --> 00:30:35.589 tactics that might be used to give their be an 00:30:35.589 --> 00:30:38.569 unearned air of legitimacy. What sort of tactics 00:30:38.569 --> 00:30:40.809 should people be aware of? They mentioned things 00:30:40.809 --> 00:30:43.829 like registering clinical trials, but then failing 00:30:43.829 --> 00:30:46.230 to publish the results, especially if they're 00:30:46.230 --> 00:30:49.029 negative. That creates a publication bias. Right. 00:30:49.049 --> 00:30:52.349 You only see the positive studies. Exactly. Also, 00:30:52.549 --> 00:30:54.789 publishing in predatory or low -impact journals 00:30:54.789 --> 00:30:58.269 that lack rigorous peer review, offering significant 00:30:58.269 --> 00:31:00.490 financial incentives for patients to pay cash 00:31:00.490 --> 00:31:03.680 upfront, bypassing insurance scrutiny. using 00:31:03.680 --> 00:31:06.579 carefully selected patient testimonials or celebrity 00:31:06.579 --> 00:31:09.000 endorsements that aren't representative of typical 00:31:09.000 --> 00:31:11.519 outcomes. And the misleading terminology we discussed. 00:31:11.920 --> 00:31:15.119 Yes, using terms like stem cells inaccurately. 00:31:15.599 --> 00:31:18.200 Even things like forming seemingly official sounding 00:31:18.200 --> 00:31:20.799 organizations that are essentially self -regulatory 00:31:20.799 --> 00:31:24.140 bodies without real oversight, or joining reputable 00:31:24.140 --> 00:31:27.839 academic societies, mainly for the implied credibility 00:31:27.839 --> 00:31:31.250 rather than active scientific contribution. These 00:31:31.250 --> 00:31:33.490 are always the appearance of legitimacy can be 00:31:33.490 --> 00:31:35.750 potentially manipulated. It paints a picture 00:31:35.750 --> 00:31:38.829 where patients really need robust, honest guidance. 00:31:39.369 --> 00:31:41.410 Absolutely. The cornerstone of ethical practice 00:31:41.410 --> 00:31:44.130 here is patient autonomy, which requires truly 00:31:44.130 --> 00:31:47.009 informed consent. That means having a detailed, 00:31:47.470 --> 00:31:49.250 transparent conversation covering everything. 00:31:49.509 --> 00:31:51.410 What needs to be included in that conversation? 00:31:51.630 --> 00:31:54.509 The practitioner must clearly explain. the specific 00:31:54.509 --> 00:31:56.690 indication based on the best available evidence 00:31:56.690 --> 00:31:59.750 or lack thereof, the potential benefits and limitations 00:31:59.750 --> 00:32:02.369 as shown in research, the known risks of the 00:32:02.369 --> 00:32:05.130 procedure and the product, all reasonable alternative 00:32:05.130 --> 00:32:07.470 treatments including standard non -surgical and 00:32:07.470 --> 00:32:10.170 surgical options, the costs involved, making 00:32:10.170 --> 00:32:12.450 it clear what is and isn't covered by insurance, 00:32:12.990 --> 00:32:16.029 and crucially, the FDA regulatory status explicitly 00:32:16.029 --> 00:32:18.329 stating that the product is not FDA approved 00:32:18.329 --> 00:32:21.069 for the condition being treated. That's comprehensive. 00:32:21.519 --> 00:32:24.420 The cost aspect also raises questions about access, 00:32:24.460 --> 00:32:26.819 doesn't it? It certainly does. Because these 00:32:26.819 --> 00:32:29.079 treatments are often not reimbursed by insurance, 00:32:29.519 --> 00:32:31.700 they are primarily accessible to those who can 00:32:31.700 --> 00:32:33.539 afford substantial out -of -pocket payments. 00:32:34.400 --> 00:32:36.680 This creates a significant potential for social 00:32:36.680 --> 00:32:39.680 inequity where access is dictated more by wealth 00:32:39.680 --> 00:32:42.480 than by clinical need or evidence of potential 00:32:42.480 --> 00:32:45.319 benefit. And conflicts of interest for the doctors 00:32:45.319 --> 00:32:47.660 themselves. That's another potential ethical 00:32:47.660 --> 00:32:50.940 pitfall. Physicians or clinics might have financial 00:32:50.940 --> 00:32:53.480 ties to the companies making the orthobiologic 00:32:53.480 --> 00:32:56.880 kits, or their business model might rely heavily 00:32:56.880 --> 00:33:00.140 on these cash -based procedures. Such conflicts 00:33:00.140 --> 00:33:02.900 need to be transparently disclosed and carefully 00:33:02.900 --> 00:33:04.980 managed to ensure treatment recommendations are 00:33:04.980 --> 00:33:07.539 driven by patient best interests, not financial 00:33:07.539 --> 00:33:09.759 gain. For a patient trying to cut through the 00:33:09.759 --> 00:33:11.940 hype and make a good decision, where can they 00:33:11.940 --> 00:33:14.519 turn for reliable information? It is challenging, 00:33:14.839 --> 00:33:17.890 but good resources exist. The FDA website has 00:33:17.890 --> 00:33:19.950 information on regulated products and warnings 00:33:19.950 --> 00:33:22.250 about unapproved therapies, though it can be 00:33:22.250 --> 00:33:24.910 technical. The International Society for Stem 00:33:24.910 --> 00:33:28.630 Cell Research, ISSCR, has excellent patient -focused 00:33:28.630 --> 00:33:31.470 resources, particularly regarding what constitutes 00:33:31.470 --> 00:33:34.430 legitimate stem cell therapy. The National Institutes 00:33:34.430 --> 00:33:38.009 of Health, NIH, in the US also provides reliable 00:33:38.009 --> 00:33:40.680 health information. Reputable patient advocacy 00:33:40.680 --> 00:33:42.880 groups for specific conditions might also offer 00:33:42.880 --> 00:33:45.319 guidance. Clinicians have an ethical duty to 00:33:45.319 --> 00:33:47.039 guide patients toward these credible sources. 00:33:47.680 --> 00:33:49.440 So if we pull all these threads together, the 00:33:49.440 --> 00:33:51.819 variable evidence, the regulatory maze, the ethical 00:33:51.819 --> 00:33:53.779 considerations, they all point towards significant 00:33:53.779 --> 00:33:56.619 limitations and challenges still facing orthobiologics. 00:33:56.960 --> 00:33:58.900 What are the biggest hurdles summarized across 00:33:58.900 --> 00:34:00.940 the sources? I think the first one has to be 00:34:00.940 --> 00:34:03.160 the inherent biological variability of the products 00:34:03.160 --> 00:34:06.140 themselves. As we've discussed, even using a 00:34:06.140 --> 00:34:08.460 patient's own blood or tissue doesn't guarantee 00:34:08.460 --> 00:34:12.179 a consistent product. Their age, health, genetics, 00:34:12.679 --> 00:34:15.519 even their immune profile. One source specifically 00:34:15.519 --> 00:34:17.980 mentions how immune cell counts influence PRP 00:34:17.980 --> 00:34:20.659 composition all play a role. It makes achieving 00:34:20.659 --> 00:34:23.840 a standardized dose incredibly difficult. The 00:34:23.840 --> 00:34:26.630 patient is the variable, in a way. In a significant 00:34:26.630 --> 00:34:29.869 way, yes. And then layered on top of that is 00:34:29.869 --> 00:34:31.909 the lack of standardization in everything else. 00:34:32.369 --> 00:34:34.510 Collection methods, processing protocols using 00:34:34.510 --> 00:34:36.829 different commercial kits, final preparation, 00:34:37.269 --> 00:34:39.809 dosing, administration techniques. It seems like 00:34:39.809 --> 00:34:42.170 this lack of standardization is the root of so 00:34:42.170 --> 00:34:44.550 many other problems, particularly with comparing 00:34:44.550 --> 00:34:46.809 research. It's absolutely fundamental. It directly 00:34:46.809 --> 00:34:48.809 contributes to inconsistent clinical outcomes 00:34:48.809 --> 00:34:51.070 and makes generating high quality, comparable 00:34:51.070 --> 00:34:53.710 evidence incredibly challenging, which leads 00:34:53.710 --> 00:34:56.670 to the next major limitation. the relative scarcity 00:34:56.670 --> 00:34:59.929 of large -scale, high -quality, long -term clinical 00:34:59.929 --> 00:35:02.610 trials. We need more big RCTs with low bias. 00:35:03.289 --> 00:35:06.309 Precisely. Trials that use standardized, clearly 00:35:06.309 --> 00:35:08.690 reported protocols and follow patients long enough 00:35:08.690 --> 00:35:11.909 to truly assess effectiveness and safety. Without 00:35:11.909 --> 00:35:14.769 that robust evidence base, it's hard to gain 00:35:14.769 --> 00:35:16.949 widespread acceptance from the medical community, 00:35:17.550 --> 00:35:19.869 difficult for regulators to grant specific approvals, 00:35:20.130 --> 00:35:23.070 and almost impossible to secure consistent insurance 00:35:23.070 --> 00:35:25.679 coverage. Which feeds directly into the cost 00:35:25.679 --> 00:35:28.900 issue. Exactly. The high out -of -pocket cost 00:35:28.900 --> 00:35:31.699 is a major limitation for patient access, and 00:35:31.699 --> 00:35:33.840 the high cost of conducting the necessary large 00:35:33.840 --> 00:35:36.519 trials is a barrier for researchers and companies. 00:35:37.079 --> 00:35:39.480 Are there other unresolved questions limiting 00:35:39.480 --> 00:35:42.099 progress? Yes, quite a few scientific unknowns 00:35:42.099 --> 00:35:44.960 remain. What's the optimal dose of platelets, 00:35:45.300 --> 00:35:47.320 cells, or growth factors for different conditions? 00:35:47.820 --> 00:35:49.980 What's the best way to deliver them simple injection 00:35:49.980 --> 00:35:53.199 combined with a scaffold, slow -release formulation? 00:35:53.780 --> 00:35:55.840 Are combination therapies better? We don't have 00:35:55.840 --> 00:35:58.280 definitive answers yet. And the underlying mechanisms 00:35:58.280 --> 00:36:00.719 aren't always fully mapped out either. That's 00:36:00.719 --> 00:36:03.360 another key area. While we have good hypotheses 00:36:03.360 --> 00:36:06.039 about growth factors and cell signaling, the 00:36:06.039 --> 00:36:09.039 precise biological pathways, how these therapies 00:36:09.039 --> 00:36:11.739 interact with the complex environment of an injured 00:36:11.739 --> 00:36:14.599 or degenerating joint, and crucially why some 00:36:14.599 --> 00:36:17.420 patients respond well and others don't. That's 00:36:17.420 --> 00:36:19.340 still not fully understood for many applications. 00:36:20.500 --> 00:36:22.579 Better mechanistic understanding could lead to 00:36:22.579 --> 00:36:25.420 much more targeted therapies. And are there lingering 00:36:25.420 --> 00:36:28.409 safety concerns or potential downsides? While 00:36:28.409 --> 00:36:30.590 the sources generally suggest serious adverse 00:36:30.590 --> 00:36:32.929 events are rare, with commonly used preparations 00:36:32.929 --> 00:36:36.349 like PRP and BMACM fat in clinical trials and 00:36:36.349 --> 00:36:39.469 practice, theoretical concerns exist. These include 00:36:39.469 --> 00:36:42.190 the potential for excessive scar tissue, fibrosis, 00:36:42.449 --> 00:36:44.809 unpredictable inflammatory reactions, or a concern 00:36:44.809 --> 00:36:46.650 primarily with cell -based therapies that might 00:36:46.650 --> 00:36:49.710 involve proliferation or differentiation, the 00:36:49.710 --> 00:36:52.369 theoretical risk of unwanted cell behavior, or 00:36:52.369 --> 00:36:54.889 even tumorigenicity if not properly controlled. 00:36:55.119 --> 00:36:57.659 These highlight the need for ongoing vigilance 00:36:57.659 --> 00:37:00.360 and long -term safety monitoring. Okay, so there 00:37:00.360 --> 00:37:02.840 are clearly significant hurdles still to overcome, 00:37:03.019 --> 00:37:05.840 but the field isn't stagnant. Where is Orthobiologics 00:37:05.840 --> 00:37:08.300 heading? What are the exciting future directions? 00:37:08.860 --> 00:37:11.179 Despite the challenges, it's a very dynamic field. 00:37:11.780 --> 00:37:13.800 Several innovative approaches are being actively 00:37:13.800 --> 00:37:17.199 pursued. One area gaining a lot of traction is 00:37:17.199 --> 00:37:20.320 exosome -based therapies. Exosomes. Tell us more. 00:37:20.559 --> 00:37:23.159 Exosomes are tiny nanoparticles naturally released 00:37:23.159 --> 00:37:25.760 by cells. They act like little delivery packages, 00:37:26.139 --> 00:37:28.340 carrying proteins, lipids, and RNA from one cell 00:37:28.340 --> 00:37:30.940 to another, basically mediating intercellular 00:37:30.940 --> 00:37:34.119 communication. The idea is to harness these natural 00:37:34.119 --> 00:37:36.480 messengers, potentially loaded with regenerative 00:37:36.480 --> 00:37:38.960 cargo, to deliver therapeutic signals without 00:37:38.960 --> 00:37:41.400 needing to inject whole cells. So cell -free 00:37:41.400 --> 00:37:44.139 therapy, using the message rather than the messenger. 00:37:44.380 --> 00:37:46.800 That's the concept. They might offer advantages 00:37:46.800 --> 00:37:49.760 like lower immunogenicity, less chance of triggering 00:37:49.760 --> 00:37:52.340 an immune reaction, and perhaps reduce concerns 00:37:52.340 --> 00:37:54.719 about cells surviving or behaving unpredictably 00:37:54.719 --> 00:37:57.119 after injection. It's still early days, needing 00:37:57.119 --> 00:37:59.639 large trials, but it's a very promising cell 00:37:59.639 --> 00:38:01.809 -free approach. Fascinating. What else is on 00:38:01.809 --> 00:38:04.269 the horizon? Gene -based and mRNA -based strategies 00:38:04.269 --> 00:38:07.030 are also being explored. The aim here is to actually 00:38:07.030 --> 00:38:09.110 instruct the patient's own cells at the injury 00:38:09.110 --> 00:38:12.190 site to produce specific healing factors or to 00:38:12.190 --> 00:38:14.710 modify their behavior in beneficial ways. Using 00:38:14.710 --> 00:38:17.929 things like CRISPR? Potentially, yes. Technologies 00:38:17.929 --> 00:38:20.730 like CRISPR -Cas9 offer the possibility of precise 00:38:20.730 --> 00:38:23.750 gene editing related to cartilage or bone biology. 00:38:24.809 --> 00:38:27.849 Or... using mRNA, similar to some vaccines, to 00:38:27.849 --> 00:38:30.309 temporarily make cells produce therapeutic proteins. 00:38:30.829 --> 00:38:32.809 These are definitely more futuristic, facing 00:38:32.809 --> 00:38:34.630 big challenges in terms of safe and effective 00:38:34.630 --> 00:38:36.809 delivery and ensuring the effects are controlled 00:38:36.809 --> 00:38:39.730 and durable. But the potential for programming 00:38:39.730 --> 00:38:42.210 tissue repair is immense. It sounds like science 00:38:42.210 --> 00:38:45.289 fiction becoming science fact. Beyond these novel 00:38:45.289 --> 00:38:47.750 therapies, are there efforts to refine existing 00:38:47.750 --> 00:38:51.170 approaches? Absolutely. A huge focus is on patient 00:38:51.170 --> 00:38:53.510 stratification, figuring out which patients are 00:38:53.510 --> 00:38:56.489 most likely to respond to which specific orthobiologic 00:38:56.489 --> 00:38:58.510 treatment. Moving away from a one -size -fits 00:38:58.510 --> 00:39:00.900 -all approach. Exactly. Researchers are hunting 00:39:00.900 --> 00:39:03.380 for biomarkers, maybe genetic markers, specific 00:39:03.380 --> 00:39:05.659 proteins or metabolites in blood or joint fluid, 00:39:06.059 --> 00:39:08.119 or particular patterns of immune cells that can 00:39:08.119 --> 00:39:10.639 predict treatment success. If we can identify 00:39:10.639 --> 00:39:13.119 responders beforehand, we can personalize treatment 00:39:13.119 --> 00:39:15.940 and improve overall success rates. That work 00:39:15.940 --> 00:39:19.139 on immune profiles influencing PRP is a step 00:39:19.139 --> 00:39:21.340 in this correction. Personalized regenerative 00:39:21.340 --> 00:39:24.059 medicine, that seems key. It does, and alongside 00:39:24.059 --> 00:39:27.099 that is the continued essential push for standardization. 00:39:27.739 --> 00:39:30.860 Developing and adopting clear, consistent, widely 00:39:30.860 --> 00:39:33.500 accepted protocols for how orthobiologics are 00:39:33.500 --> 00:39:36.019 prepared, characterized, and administered is 00:39:36.019 --> 00:39:38.860 seen as absolutely crucial for improving outcomes, 00:39:39.360 --> 00:39:41.639 enabling meaningful research comparisons, and 00:39:41.639 --> 00:39:44.239 ultimately achieving regulatory approvals and 00:39:44.239 --> 00:39:46.429 broader clinical adoption. It seems like that 00:39:46.429 --> 00:39:49.130 has to happen for the field to truly mature. 00:39:49.429 --> 00:39:51.469 It really does. We're also seeing more large 00:39:51.469 --> 00:39:54.070 -scale collaborative research efforts. The sources 00:39:54.070 --> 00:39:56.869 mention the European Propo Consortium, for example, 00:39:57.289 --> 00:39:59.369 which is bringing together multiple centers to 00:39:59.369 --> 00:40:02.289 rigorously investigate a specific placenta -derived 00:40:02.289 --> 00:40:06.010 cell therapy for knee OA. These kinds of structured 00:40:06.010 --> 00:40:08.510 multi -center collaborations are vital for generating 00:40:08.510 --> 00:40:10.889 high -quality evidence. What about improvements 00:40:10.889 --> 00:40:13.489 in actually delivering the therapies to the target 00:40:13.489 --> 00:40:16.659 tissue? Yes, that's another active area. Developing 00:40:16.659 --> 00:40:19.320 advanced delivery systems, like embedding the 00:40:19.320 --> 00:40:22.380 orthobiologic factors or cells within smart biomaterials, 00:40:23.039 --> 00:40:25.599 perhaps injectable hydrogels that solidify in 00:40:25.599 --> 00:40:29.019 place, or using nanoparticles to allow for slow, 00:40:29.400 --> 00:40:31.719 sustained release over time directly where needed. 00:40:31.929 --> 00:40:35.150 This could enhance efficacy and potentially reduce 00:40:35.150 --> 00:40:37.070 the number of treatments required. And combining 00:40:37.070 --> 00:40:39.289 therapies? Combination approaches are definitely 00:40:39.289 --> 00:40:41.730 being explored using multiple orthobiologics 00:40:41.730 --> 00:40:44.210 together, or combining them with physical scaffolds, 00:40:44.369 --> 00:40:46.449 specific growth factors, or even traditional 00:40:46.449 --> 00:40:49.269 rehabilitation therapies to achieve a synergistic 00:40:49.269 --> 00:40:51.750 effect greater than any single component alone. 00:40:51.969 --> 00:40:54.809 And technology like 3D printing fitting in? Yes. 00:40:55.210 --> 00:40:58.030 3D bioprinting holds promise for creating patient 00:40:58.030 --> 00:41:00.510 -specific scaffolds that mimic the structure 00:41:00.510 --> 00:41:03.170 of the tissue being repaired. These scaffolds 00:41:03.170 --> 00:41:05.090 could potentially be seeded with the patient's 00:41:05.090 --> 00:41:08.070 own cells or infused with growth factors before 00:41:08.070 --> 00:41:10.809 implantation, offering both structural support 00:41:10.809 --> 00:41:14.530 and biological stimulation. And overarching all 00:41:14.530 --> 00:41:17.230 of this is the potential role of artificial intelligence 00:41:17.230 --> 00:41:19.929 and machine learning to analyze large data sets, 00:41:20.369 --> 00:41:22.510 identify patterns, predict outcomes, and help 00:41:22.510 --> 00:41:24.730 tailor these increasingly complex treatments 00:41:24.730 --> 00:41:28.090 to individual patients. So the future looks towards 00:41:28.090 --> 00:41:30.530 much more targeted, predictable, and personalized 00:41:30.530 --> 00:41:33.090 treatments, leveraging biology and technology 00:41:33.090 --> 00:41:35.130 together. That's certainly the long -term vision. 00:41:35.489 --> 00:41:37.809 But, and it's a consistent message from the sources, 00:41:38.389 --> 00:41:40.530 getting there depends entirely on continued rigorous 00:41:40.530 --> 00:41:43.190 science, robust clinical trials, a commitment 00:41:43.190 --> 00:41:46.409 to standardization, and unwavering ethical practice. 00:41:46.949 --> 00:41:48.889 The potential is enormous, but there's still 00:41:48.889 --> 00:41:51.030 a lot of work to do to fully realize it. Well, 00:41:51.210 --> 00:41:53.789 as we wrap up this deep dive, it's clear orthobiologics 00:41:53.789 --> 00:41:56.849 represent a really exciting frontier in musculoskeletal 00:41:56.849 --> 00:41:59.110 medicine aiming to harness the body's own healing 00:41:59.110 --> 00:42:02.829 power. Absolutely. But as we've explored, understanding 00:42:02.829 --> 00:42:04.889 this field means grappling with the different 00:42:04.889 --> 00:42:07.929 therapy types. The often complex and variable 00:42:07.929 --> 00:42:10.849 evidence base, the intricate regulatory landscape, 00:42:10.949 --> 00:42:13.929 and the very real limitations we currently face 00:42:13.929 --> 00:42:16.289 regarding standardization and predicting outcomes. 00:42:16.860 --> 00:42:19.360 There's definitely a gap, isn't there, between 00:42:19.360 --> 00:42:23.219 the growing clinical use and enthusiasm and the 00:42:23.219 --> 00:42:25.619 still developing high -level evidence and clear 00:42:25.619 --> 00:42:28.260 guidelines, particularly once you move beyond 00:42:28.260 --> 00:42:31.679 the most studied areas like PRP for NEOA. That 00:42:31.679 --> 00:42:34.940 gap is undeniable. The future looks bright with 00:42:34.940 --> 00:42:37.659 emerging technologies like exosomes in gene therapy 00:42:37.659 --> 00:42:40.320 and the push towards personalized medicine. But 00:42:40.320 --> 00:42:43.199 progress hinges on continued high quality research, 00:42:43.539 --> 00:42:45.760 agreed upon standards, and complete transparency 00:42:45.760 --> 00:42:48.039 with patients. If you found this deep dive valuable, 00:42:48.400 --> 00:42:50.360 please do consider rating the show or sharing 00:42:50.360 --> 00:42:52.280 it with a colleague who might find it interesting. 00:42:52.619 --> 00:42:54.219 And perhaps the final thought to leave you with 00:42:54.219 --> 00:42:58.519 is, could that convergence better patient stratification? 00:42:58.840 --> 00:43:01.380 standardized combination therapies, advanced 00:43:01.380 --> 00:43:04.239 delivery systems, could that finally be the key 00:43:04.239 --> 00:43:07.059 to unlocking the full potential of orthobiologics, 00:43:07.239 --> 00:43:09.280 moving them from promising but variable options 00:43:09.280 --> 00:43:12.239 to truly predictable personalized regenerative 00:43:12.239 --> 00:43:15.059 solutions? A fascinating question, and one we'll 00:43:15.059 --> 00:43:16.900 surely be revisiting. Thank you for joining us 00:43:16.900 --> 00:43:17.619 on the Deep Dive.