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J Family Med Prim Care. 2025 Jun;14(6):2180-2186.
doi: 10.4103/jfmpc.jfmpc_1206_24. Epub 2025 Jun 30.

The comparative effects of injecting intra-articular platelet-rich plasma and hypertonic dextrose prolotherapy in osteoarthritis knee - A randomized control trial​


Abstract​

Introduction: Knee osteoarthritis is an age-dependent disease caused by degenerative and healing processes in subchondral tissue of articular and bone cartilage, resulting in changes of its biochemical properties that eventually causes pain, stiffness, and decreased articular function. Therefore, this study aims to compare the effectiveness of platlet-rich plasma (PRP) therapy and 25% hypertonic dextrose (Dextrose) prolotherapy in patients with knee osteoarthritis.

Material and methods: Single-blind randomized control trial was conducted for 18 months. Patients satisfying the inclusion and exclusion criteria were enrolled from the indoor/outdoor facility of the Department of Physical Medicine and Rehabilitation, King George's Medical University (KGMU), Lucknow, India. The informed consent form was duly signed by all the enrolled patients, who were randomly assigned into two groups by the computer-generated system, A total of 85 study participants in this group I (43 patients) received 5 ml Platelet-Rich Plasma (PRP) and Group II (42 patients) received 5 ml of 25% hypertonic dextrose prolotherapy (Dextrose). To compare the effect in terms of reduction of pain, according to the Numeric pain rating scale (NPRS) and Pain/Discomfort, Walking and Activities of Daily Living (ADL) according to the Lequesne Knee Index (LKI) and assessment of each patient was done at specified period, i.e., 0 weeks (Baseline means immediately before intervention), and 6 weeks after the intervention.

Result: Overall, the baseline to 6 weeks change of LKI-Pain in group I (PRP) was significantly more than the group II (DEXTROSE) (P < 0.001). On considering the parameter of LKI-Pain at baseline and 6 weeks for PRP and Dextrose, it was found that in Group I, the mean ± SD reduced more at 6 weeks from 4.81 ± 1.55 to 2.44 ± 1.76 as compared to participants in Group II with 4.83 ± 1.17 at baseline to 6 weeks 3.64 ± 0.98, LKI-Activities of Daily Living (ADL) for group I PRP the Mean ± SD score dropped more from 4.66 ± 1.40 to 2.95 ± 1.35 whereas for group II Dextrose the Mean ± SD score dropped from 4.68 ± 1.40 to 3.65 ± 1.51 at baseline and 6 week respectively and At baseline, the mean LKI-Total score in group I was 12.85 ± 3.59 while in group II the mean score was 13.11 ± 3.15. At 6 weeks, the mean LKI-Total score in group I was 7.63 ± 3.85; in group II the mean score was 10.11 ± 2.93. A significant difference was found in the mean LKI-Total score between the groups at 6 weeks (P = 0.001) and found to be lesser in group I.

Conclusion: It could thus be concluded that on considering the effect of platelet-rich plasma and 25% hypertonic dextrose prolotherapy in patients with knee osteoarthritis, significant improvement was seen in participants administered with both platelet-rich plasma and dextrose with the higher effect being with platelet-rich plasma.

Keywords: Knee osteoarthritis; platelet-rich plasma (PRP); prolotherapy.

Copyright: © 2025 Journal of Family Medicine and Primary Care.

PubMed Disclaimer
 
only 6 weeks duration.

not blinded - looks like people knew what they were getting.

small group size.

did not see report of complications. maybe there were none.



so take home conclusion: dextrose injections can help. 🙂
 
Eur Radiol. 2025 Jul 26.
doi: 10.1007/s00330-025-11867-9. Online ahead of print.

Shear wave elastography to assess healing in lateral epicondylosis: randomized controlled trial with platelet-rich plasma​


Abstract​

Objective: To compare ultrasound and shear wave elastography (SWE) changes in the common extensor tendon over time after platelet-rich plasma (PRP) or corticosteroid (CS) treatment, and to assess for correlations between patient-reported outcomes (PROs) and US/SWE changes of the common extensor tendon.

Materials and methods: A secondary analysis of a prospective double-blinded, randomized controlled trial comparing US and SWE changes after a single treatment of PRP or CS for the treatment of lateral epicondylosis was conducted. Subjects 18-65 years with recalcitrant lateral elbow pain were enrolled between 3/1/2017 and 4/1/2019 and randomized to a treatment group. US/SWE of the common extensor tendon was performed at baseline, 26 weeks, and 52 weeks, and PROs were also recorded. Treatment effects between groups were compared using linear mixed effects models.

Results: Fifty elbows in 47 subjects (mean 48 years ± 8; 25 women) were randomized to two groups-PRP (N = 26) and CS (N = 24). Shear wave speed (SWS) increased with PRP more than with CS at both 26 weeks (2.02 m/s ± 0.61; p = 0.002) and 52 weeks (2.98 m/s ± 0.49; p < 0.01). At 26 weeks, no differences were detected between treatments by conventional US. At 52 weeks, echogenicity and hyperemia improved with PRP relative to CS (p < 0.05). Increased SWS correlated with improvement in all PROs (p < 0.05). For conventional US changes, the only correlation to PROs was that of echogenicity with pain (p = 0.04).

Conclusion: SWS increased more with PRP than CS at 26- and 52-week post-treatment for lateral epicondylosis, and increased SWS correlated with clinical improvement.

Key points: Question Can SWE detect healing changes in the common extensor tendon associated with clinical improvement of lateral epicondylitis in patients treated with PRP or CS injection? Findings Higher common extensor tendon SWSs were associated with clinical improvement and improved more in those treated with PRP than with CS. Clinical relevance statement SWE may be able to quantitatively detect treatment changes in tendons associated with clinical improvement.

Keywords: Elbow tendinopathy; Platelet-rich plasma; Sonoelastography (ultrasonography); Tennis elbow.
 
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secondary analysis, extended data.

no control group.

as noted with most studies involving lateral epicondylitis, PRP seems superior to CS when time frames are >3 months.


i havent done a CS injection for lateral epicondylitis in at least 3+ years.
 

I found their 60 second patient screening quiz.

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TIme for Regen Fellowships?

Analysis & Perspective

Call for a Translational Orthobiologics Fellowship in the Era of Regenerative Medicine​

Strader, Shannon DO, MS1; Villaseñor, Andrew DO, MS2; Wyles, Saranya MD, PhD3; Chandan, Priya MD, PhD4; Terzic, Carmen MD, PhD5; Bean, Allison C. MD, PhD6; Master, Zubin PhD7

Author Information
American Journal of Physical Medicine & Rehabilitation 104(9)😛 831-837, September 2025. | DOI: 10.1097/PHM.0000000000002782
AbstractPlain Language Summary

Regenerative medicine is a rapidly advancing field, particularly within the field of physical medicine and rehabilitation. While orthobiologics are currently being used in clinical practice, there remains a need for high-quality clinical trials and translational research to standardize treatments and improve patient outcomes. Education is vital for streamlining development of evidence-based, practical, and effective treatments. In this article, we highlight the need for a 1-yr advanced fellowship in translational orthobiologics aiming to create a standardized core curriculum targeting physicians involved in treating musculoskeletal diseases. The fellowship’s objectives include advancing translational orthobiologics research, ethical considerations, and promoting effective communication regarding orthobiologic therapies. Such a program would serve as a foundation for physicians interested in conducting clinically oriented orthobiologics research for musculoskeletal disorders while improving the development of safe and effective therapeutics related to musculoskeletal disorders.
 
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Ignorant.
yeah right?

make a fellowship to gouge money by using fellows for cheap labor and do research.


then decide that only fellowship trained docs can do regenerative medicine.


then eventually decide that fellowship trained physicians need to take a board exam and recertify every 10 years that rake in oodles more money.



try this instead - have fellowships train regenerative medicine so that all fellowship trained pain docs get trained in them.
 
Even if there was a fellowship there will be naturopaths and APPs that still do them because they've been "trained"
 

Purpose​

The study compared a non-surgical injection treatment using a person’s own bone marrow concentrate and platelets (BMC + PRP) against standard exercise therapy for treating partial and some complete ACL tears that were not completely pulled apart (“non-retracted”).

How the Study Worked​

  • 51 people with ACL tears were randomly assigned to either:
    • Exercise therapy only, or
    • BMC + platelet injection directly into the ACL under imaging guidance.
  • After 3 months, patients in the exercise group who weren’t improving could switch to the BMC treatment.
  • Patients were followed for 2 years with:
    • Pain and function questionnaires (IKDC, LEFS, SANE, NPS)
    • MRI scans before and after treatment.

Key Findings​

  • At 3 months, patients who received BMC injections improved much more in:
    • Function (LEFS)
    • Overall knee improvement (SANE)
      compared with those who only did exercise therapy.
  • The exercise-only group showed little to no improvement before crossing over.
  • Over 2 years, those who received BMC:
    • Had sustained improvement in knee function and pain.
    • Reported an average of 90% overall improvement.
    • 80–87% were able to return to strenuous or very strenuous activities (like running, skiing, basketball).
  • MRI scans showed visible healing and better ligament structure in the ACL after BMC treatment.
  • No serious side effects occurred.
    A few mild cases (temporary swelling, soreness) resolved on their own.
  • Older injuries (over 12 months old) improved less, suggesting earlier treatment works best.
  • Only 4 patients eventually went on to surgical reconstruction (8%), similar or better than typical surgery failure rates.

What It Means​

  • BMC + platelet injections can help ACL tears heal naturally, improving pain and function without surgery for many patients.
  • This approach may preserve the native ligament, maintaining normal knee movement and proprioception.
  • It’s minimally invasive, has a low complication rate, and could reduce risk of future arthritis compared to surgery.
  • It’s not ideal for everyone, especially for fully torn or retracted ligaments, or for very old injuries.

Bottom Line​

Bone marrow concentrate and platelet therapy offers a safe and effective non-surgical option for select ACL injuries — helping patients regain stability, reduce pain, and return to high-level activity — with lasting results over two years.
 
265 screened. total 50 patients. they did do a power analysis.

they did change the criteria midway through so 34 in injection, 17 in exercise.

injections were not blinded. people knew they were getting injection vs no injeciton.


it appears their exercise regimen was "extensive". patients in the exercise group met (maybe once?) with PT and given 2 sets of take home exercise sheets.

otoh, here is the exercise regimen given to those who got the injection:
For the first month, patients were directed to perform range of motion exercises, light strength training, and balance training while protecting the knee. Afterwards (weeks 5–12), patients participated in resistance training, targeting the hip abductor and hamstring with light squats and leg presses, along with core strengthening using a balance board. If not experiencing pain, straight jogging, single leg exercises, and progression to combo strength/balance exercises were encouraged. Over the next eight weeks (weeks 13–20), patients began guided sport-specific movements and noncutting sports. Finally (weeks 21–52), the Santa Monica Sports Medicine Prevent Injury and Enhance Performance program was recommended and ultimately returned to full sport only with physician clearance.



all crossed over. so the comparison of duration are between how they were at 2 years after with how they did at 3 months - noone did conservative therapy for 2 years. this would affect whether patients could have improved with just conservative therapy. this is a limitation that the researchers specifically mentioned.




overall, is an injection better than giving a patient an exercise sheet? are people better off 2 years out regardless of outcome? probably yes to both. is it better than surgery? no idea.
 

Purpose​

The study compared a non-surgical injection treatment using a person’s own bone marrow concentrate and platelets (BMC + PRP) against standard exercise therapy for treating partial and some complete ACL tears that were not completely pulled apart (“non-retracted”).

How the Study Worked​

  • 51 people with ACL tears were randomly assigned to either:
    • Exercise therapy only, or
    • BMC + platelet injection directly into the ACL under imaging guidance.
  • After 3 months, patients in the exercise group who weren’t improving could switch to the BMC treatment.
  • Patients were followed for 2 yearswith:
    • Pain and function questionnaires (IKDC, LEFS, SANE, NPS)
    • MRI scans before and after treatment.

Key Findings​

  • At 3 months, patients who received BMC injections improved much morein:
    • Function (LEFS)
    • Overall knee improvement (SANE)
      compared with those who only did exercise therapy.
  • The exercise-only group showed little to no improvement before crossing over.
  • Over 2 years, those who received BMC:
    • Had sustained improvement in knee function and pain.
    • Reported an average of 90% overall improvement.
    • 80–87% were able to return to strenuous or very strenuous activities (like running, skiing, basketball).
  • MRI scans showed visible healing and better ligament structure in the ACL after BMC treatment.
  • No serious side effects occurred.
    A few mild cases (temporary swelling, soreness) resolved on their own.
  • Older injuries (over 12 months old) improved less, suggesting earlier treatment works best.
  • Only 4 patients eventually went on to surgical reconstruction (8%), similar or better than typical surgery failure rates.

What It Means​

  • BMC + platelet injections can help ACL tears heal naturally, improving pain and function without surgery for many patients.
  • This approach may preserve the native ligament, maintaining normal knee movement and proprioception.
  • It’s minimally invasive, has a low complication rate, and could reduce risk of future arthritis compared to surgery.
  • It’s not ideal for everyone, especially for fully torn or retracted ligaments, or for very old injuries.

Bottom Line​

Bone marrow concentrate and platelet therapy offers a safe and effective non-surgical option for select ACL injuries — helping patients regain stability, reduce pain, and return to high-level activity — with lasting results over two years.
Targeting ACL/PCL using fluoro with contrast is something I haven't seen before. Pretty cool contrast patterns. Overall promising study that has a lot of confounders and potential for bias. I also wonder what proportion of ACL tears carry this morphology they studied. But I also understand that without a matrix to inject BMAC into, those cells are gonna migrate away wherever they please (probably do anyway). Needs to be compared to surgical correction...
 

​

Grade II Hamstring Tears: PRP Does Help​

Efficacy of platelet-rich plasma in grade 2 hamstring muscle injuries: results from a randomized controlled trial

Hamstring injuries are a major cause of time-loss in athletes, often leading to prolonged recovery and high recurrence rates.

This randomized controlled trial evaluated the efficacy of ultrasound-guided platelet-rich plasma (PRP) injections in accelerating return to play (RTP) and enhancing radiological healing in grade 2 hamstring injuries.

N=60, PRP plus standard therapy (n = 30) and standard therapy alone (n = 30).

The PRP group showed
i) significantly faster RTP (26.4 ± 4.5 vs. 34.2 ± 5.7 days; p < 0.001) and
ii) greater MRI healing at 21 days (70% vs. 36.7%; p = 0.003).
iii) Re-injury rates were lower in the PRP group (3.3% vs. 16.7%), though not statistically significant (p = 0.09).
iv) No adverse events were reported.

1760104674825.png
 

This 2025 study from Istanbul University compared platelet-rich plasma (PRP) injections with corticosteroid and saline (placebo) injections for people with lateral epicondylitis (tennis elbow)—a common cause of pain on the outside of the elbow.

What they did:

50 patients (55 elbows) were randomly assigned to one of three groups: PRP, steroid, or saline.

Everyone had elbow pain for at least 3 months and had not tried prior injections.

They measured pain and arm function before treatment, and again at 3 and 6 months, using standard scales (VAS, DASH, PRTEE).

They also used ultrasound to look at blood flow and tendon changes.

What they found:

PRP worked best: Patients who got PRP had the biggest and most lasting improvements in pain and function at both 3 and 6 months.

Steroids helped temporarily: People improved early on but their pain returned somewhat by 6 months.

Saline did the worst: Many didn’t feel much better and some dropped out to get other treatments.

No visible difference on imaging: Even though PRP patients felt better, ultrasound scans didn’t show major changes in tendon blood flow or structure.

What it means:

PRP gave patients longer-lasting pain relief and better function than steroid or saline injections, even though ultrasound didn’t show a clear difference in tendon healing.
In simple terms—PRP helped people feel and use their arms better, but the imaging didn’t fully explain why.

Bottom line:

PRP appears to be a more effective, durable, and safe treatment for tennis elbow than steroid injections, even though it may cost more and doesn’t yet show obvious imaging changes.
 

Corticosteroids versus platelet-rich plasma injections for knee osteoarthritis: Where is there more evidence? A systematic review of 60 years of literature​

Angelo Boffa<a>a</a> ∙ Giacomo Moraca<a>b</a> ∙ Alessandro Sangiorgio<a>b</a> ∙ Alessandro Di Martino<a>c</a> ∙ Alessandro Bensa<a>b</a>,<a>d</a> [email protected] ∙ Giuseppe Filardo<a>b</a>,<a>d</a>

Background​

Corticosteroid (CS) injections are often recommended by international societies for knee osteoarthritis (OA) treatment, but platelet-rich plasma (PRP) has shown higher safety and efficacy in comparative analyses. Despite this, PRP use is often not endorsed by scientific societies due to perceived insufficient body of evidence. This study aims to quantify clinical data documenting CS and PRP intra-articular injections for knee OA.

Methods​

A systematic review of the literature was conducted on CS and PRP injections for knee OA. The search, performed in March 2024, used PubMed, Cochrane, and Web of Science databases, following PRISMA and Cochrane guidelines. Data collected included publication trends, number of articles, patients evaluated, and study designs documenting CS or PRP injections.

Results​

Of 16,979 records, 356 studies were analyzed, covering 24,435 knee OA patients. Both treatments showed an increasing publication trend, with PRP surpassing CS in 2020. The analysis included 9,322 CS patients and 15,113 PRP patients. Among CS studies, there were 103 RCTs with 5,478 patients, 18 comparative studies with 1,095 patients, and 31 case series with 2,749 patients. Among PRP studies, there were 119 RCTs with 6,028 patients, 33 comparative studies with 2,011 patients, and 72 case series with 7,074 patients.

Conclusions​

PRP injections for knee OA have been documented in more studies and in larger patient numbers compared with CS injections. The higher number of high-level trials for PRP, combined with the lower safety and efficacy documented for CS by previous meta-analyses directly comparing the two products, strongly suggests reconsidering current guidelines that favor CS, highlighting PRP’s body of evidence and the potential role in the effective and safe treatment of knee OA.
 
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kind of an odd study. it is specifically set up to to dispute the talking points of not enough PRP studies, yet...


1. a lot of records were eliminated.
2. out of all those records, 16 were found to be RCTs that compared CS and PRP.
3. or 3. the authors state for "comparative studies (prospective or retrospective)" only 3 compared PRP to CS.
4. the 2 authors were ones who did the study. might there be some bias?


my takeaway - need more RCT of PRP directly comparing to CS that are high quality, as the major societies apparently do not deem these few studies to be high enough quality to recommend PRP
 
Orthop J Sports Med. 2026 Jan 15;14(1):23259671251386862.
doi: 10.1177/23259671251386862. eCollection 2026 Jan.

A Randomized Controlled Trial of 1-Year Clinical Outcomes of a Single Platelet-Rich Plasma Injection Versus Corticosteroid for the Treatment of Lateral Elbow Tendinopathy​

John J Wilson <a title="University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA." href="A Randomized Controlled Trial of 1-Year Clinical Outcomes of a Single Platelet-Rich Plasma Injection Versus Corticosteroid for the Treatment of Lateral Elbow Tendinopathy - PubMed">1</a>, Kenneth S Lee <a title="University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA." href="A Randomized Controlled Trial of 1-Year Clinical Outcomes of a Single Platelet-Rich Plasma Injection Versus Corticosteroid for the Treatment of Lateral Elbow Tendinopathy - PubMed">1</a>, Rachel Erickson <a title="Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA." href="A Randomized Controlled Trial of 1-Year Clinical Outcomes of a Single Platelet-Rich Plasma Injection Versus Corticosteroid for the Treatment of Lateral Elbow Tendinopathy - PubMed">2</a>, Stephanie Kliethermes <a title="University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA." href="A Randomized Controlled Trial of 1-Year Clinical Outcomes of a Single Platelet-Rich Plasma Injection Versus Corticosteroid for the Treatment of Lateral Elbow Tendinopathy - PubMed">1</a>
Affiliations Expand

Abstract​

Background: Platelet-rich plasma (PRP) treatment for chronic lateral elbow tendinopathy (LET) has increased because of its potential for prolonged symptom relief and improved function. Limited studies have definitively documented long-term benefits.

Purpose: To assess the efficacy of a single intratendinous PRP injection compared to a corticosteroid injection for the treatment of LET.

Study design: Randomized controlled trial; Level of evidence, 1.

Methods: In total, 48 participants (n = 50 elbows), aged 18 to 65 years, were randomly assigned to ultrasound-guided PRP (n = 26) or corticosteroid (control, n = 24) injection. Patient-Rated Tennis Elbow Evaluation (PRTEE) and Quick version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) were compared at baseline and 4, 8, 12, 16, 26, and 52 weeks. Secondary outcomes were assessed via grip strength, visual analog scale (VAS) scores, and overall satisfaction with treatment. Wilcoxon rank-sum tests and longitudinal analysis of covariance models were used to assess outcomes over time.

Results: At 4 weeks, mean PRTEE scores were 47.6 ± 3.7 in the PRP group compared to 14.8 ± 3.9 in the CSI group (P < .001). At 8 weeks, PRTEE scores were 32.1 ± 3.7 for PRP and 15.2 ± 4.0 for CSI (P = .003). At 12 weeks, scores were 26.3 ± 3.9 for PRP versus 16.0 ± 4.1 for CSI (P = .07). By 26 weeks, mean scores favored PRP (17.7 ± 6.5 vs 35.3 ± 6.8; P = .07), and by 52 weeks, PRP scores remained lower (14.4 ± 6.3 vs 29.6 ± 6.3; P = .10). At 4 weeks, mean QuickDASH scores were 22.4 ± 1.1 in the PRP group versus 15.5 ± 1.1 in the CSI group (P < .001). At 8 weeks, PRP scores were 19.3 ± 1.1 compared to 15.8 ± 1.2 for CSI (P = .04). No significant differences were observed at 12 weeks (17.7 ± 1.1 vs 16.6 ± 1.2; P = .49) or 16 weeks (16.8 ± 1.1 vs 18.4 ± 1.2; P = .35). At 26 weeks, QuickDASH scores favored PRP (15.7 ± 1.6 vs 20.3 ± 1.7; P = .05), and this difference persisted at 52 weeks (14.0 ± 1.6 vs 18.6 ± 1.6; P = .05). However, VAS scores were on average 1.5 points lower in the PRP group across all time points.

Conclusion: Our study demonstrated that corticosteroids resulted in greater short-term improvement, while PRP demonstrated superior longer-term outcomes at 6 and 12 months. PRP was associated with lower average VAS scores over time.
Keywords: biological healing enhancement; elbow; platelet rich plasma; tendinosis.
 
Interesting Science article from Stanford researchers


Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration​

Abstract​

Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments. We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice. Both systemic and local inhibition of 15-PGDH with a small molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain. Using single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations. Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix-synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in pre-existing chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis.

Grok review of paper follows - I don't have the full article

Background & Rationale

Osteoarthritis (OA) involves progressive degeneration of articular (hyaline) cartilage, the smooth, load-bearing tissue in joints, with no effective disease-modifying treatments currently available. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) — dubbed a "gerozyme" because its levels rise with age — degrades prostaglandin E2 (PGE2), a molecule important for tissue repair and anti-inflammatory effects. Previous work showed that inhibiting 15-PGDH promotes regeneration in several tissues (muscle, bone, liver, etc.). The authors tested whether this pathway could restore cartilage in aging and injury-related OA.

Key Findings
  • 15-PGDH is upregulated in diseased cartilage — Levels roughly doubled in the knee articular cartilage of aged mice compared to young mice, and also increased after joint injury.
  • Inhibition regenerates cartilage — Using a small-molecule inhibitor (PGDHi):
    • Systemic (e.g., intraperitoneal) or local (intra-articular) administration for ~1 month in aged mice significantly thickened worn cartilage across the joint surface.
    • It restored hyaline cartilage (smooth, functional, rich in extracellular matrix) rather than fibrocartilage (inferior scar-like tissue).
    • In injury models (e.g., post-surgical destabilization), it protected against further degeneration and reduced OA-associated pain behaviors.
  • Mechanism — Single-cell RNA sequencing revealed that 15-PGDH inhibition:
    • Reduced hypertrophic/degrading chondrocyte subtypes (which express high 15-PGDH and contribute to cartilage breakdown).
    • Increased healthy, matrix-synthesizing articular chondrocytes.
    • Reprogrammed existing chondrocytes toward a more youthful, regenerative state — notably, no stem cell recruitment was required.
  • Human relevance — In ex vivo experiments using cartilage from OA patients (e.g., knee replacement tissue), short-term treatment with the inhibitor reduced degradation markers and showed early signs of matrix regeneration.
Conclusions & Implications

Blocking 15-PGDH elevates PGE2 levels, reactivating natural cartilage repair mechanisms and reversing age- and injury-related degeneration. The authors propose this as a potential disease-modifying regenerative therapy for osteoarthritis, distinct from stem-cell or surgical approaches.Importantly, related 15-PGDH inhibitors (oral formulations) have already completed Phase 1 safety trials in humans for other age-related conditions (e.g., muscle weakness), suggesting a feasible path toward clinical trials for joint disease.This study offers exciting preclinical proof-of-concept that targeting a single aging-related enzyme could one day help delay or prevent the need for joint replacements in OA patients. It remains preclinical (mouse models + human tissue ex vivo), with further safety and efficacy studies needed before human trials for cartilage repair.
 
so one type of 15-PGDH inhibitors are steroids.


in effect it may be that steroids may cause 15-PGDH inhibition and can cause reduced OA pain.

of note, anabolic steroids seem to be more active in this front. maybe we are using the wrong steroid for our steroid injections.


additionally, the focus of these studies are on specific inhibitors that are not considered steroids. i suspect that these compounds are more likely to get "approved" for injection than other current "substances".


of course, this is in the mouse model.
 
A patient told me about an outfit near me that charged $6000 for a kimera amniotic product. My patient mentioned it at the end of a visit. She said that she has done all of the research and she absolutely wants to do luxir and nothing else (from kimera). She has a spine issue. I called the "outfit" and they said that they were going to inject it into her deltoid ....for $6000!!!

She actually was ready to pay but I told her that she can do what she wants but I don't think that would help in that manner. I told her that if her mind is made up that she wants luxir at a minimum I am happy to order it and I would charge 2x my acquisition cost. She decided to do this but it took her two weeks to decide. Acquisition cost was $400 so I charged $800 for something that they were going to charge $6000 for and simply inject the deltoid in a flu shot like manner. Surprisingly, it actually helped her.

I don't do a lot of regenerative (but I do some). I am happy that there are guys like drrusso out there. Otherwise these "outfits" will be the norm and our patients will suffer likely mostly financially. They seem to have very very strong marketing techniques.
 

UNIT 1. INTRODUCTION TO ORTHOBIOLOGICS​

Module 1. Basic Principles of Regenerative Medicine​

  1. Definition
    • a. What is regenerative medicine
    • b. Components in orthobiologics: hematologic, cellular
  2. Basic science (see Module 8)
    • a. Regenerative capacity of human musculoskeletal tissues
    • b. Wound healing phases: (1) inflammatory, (2) proliferative, (3) remodeling
    • c. Limitations in the healing process and abnormal response to injury
  3. Types of orthobiologic therapies in regenerative medicine
    • a. Hematologic: PRP, autologous conditioned plasma (ACP), platelet-poor plasma (PPP)
    • b. Cellular: bone marrow aspirate concentration (BMAC), microfragmented adipose tissue (MFAT)
  4. Types of nonbiologic therapies in regenerative medicine
    • a. Injectable: hyper- and hypo-osmolar dextrose
    • b. Other: Extracorporeal shockwave (focused shockwave, radial pressure wave), laser
  5. Tissue pathology
    • a. Bone: acute fracture, fracture nonunion, avascular necrosis
    • b. Cartilage: osteoarthritis, chondral defect(s)/chondromalacia, torn meniscus/labrum
    • c. Tendon: tendonitis, tendinopathy, partial thickness tears
    • d. Muscle: strain, partial tears
    • e. Ligament: sprain, partial thickness tear, capsule injury
    • f. Other: plantar fasciopathy, surgical augmentation
  6. Indications
    • a. Pathology refractory to typical conservative management
    • b. Pathology for which surgery may not be indicated or timely
    • c. Treatment supported by high-level evidence suggesting better long-term outcomes
    • d. Patient is a poor surgical candidate
    • e. Faster return to sport/accelerated rehabilitation timeline
    • f. Patient preference

Module 2. Key Concepts on the Responsible Use of Orthobiologics​

  1. How to counsel patients
    • a. What it is: definition of orthobiologic therapies and regenerative medicine (see Module 1)
    • b. What it is not: totipotent/pluripotent embryonic “stem cells” and/or complete tissue regeneration
    • c. Awareness of common unethical practices: grossly overpriced, nonevidence-based therapies, misleading advertisement, etc.
  2. Limitations in understanding
    • a. Mechanism of action
    • b. Number or series of injections
    • c. Timing of injections (eg, stage of injury/disease)
    • d. Optimal dose range for each indication
    • e. Medication use or abstinence pre- and postprocedure
  3. Other treatment options
    • a. Do nothing/wait-and-see approach
    • b. Oral pharmacologic therapies
    • c. Corticosteroid injection(s)
    • d. Physical therapy or individualized exercise prescription
    • e. Surgical intervention
  4. Patient selection
    • a. Absolute versus relative contraindications: systemic infection, local infection
    • b. Comorbid conditions: cancer, bleeding diathesis, anemia, thrombocytopenia, pregnancy, uncontrolled autoimmune condition
    • c. Concurrent medications: anticoagulants, antiplatelets, anti-inflammatories, statins
    • d. Considerations in personalized treatment plan: severity of condition (eg, grade 4 osteoarthritis), patient and provider expectations
  5. Informed consent and patient discussion
    • a. Risks and benefits
    • b. Preprocedure preparation
    • c. Postprocedure recovery
    • d. Current research involvement of the provider and/or conflicts of interest
    • e. Quality control
    • f. Oncologic implications
    • g. Associated cost
  6. Expected outcomes: dependent on unbiased synopsis of the available literature
  7. Billing concerns: lack of insurance coverage because of heterogeneity in preparation and heterogeneity in the literature

UNIT 2. ORTHOBIOLOGIC THERAPIES​

Module 3. Hemoderivative Therapy: Platelet-Rich Plasma​

  1. Overview: definition and history
  2. Basic science: components and proposed mechanisms of action
    • a. PRP
    • b. ACP
    • c. PPP
  3. Classification schemes for reporting and documentation
    • a. Basic: leukocyte rich/poor and platelet count or concentration
    • b. PAW: (1) platelet count [absolute number], (2) activation method, (3) white blood cells/leukocytes present or absent
    • c. PLRA: (1) platelets per microliter, (2) leukocytes present or absent, (3) neutrophil percentage, (4) red blood cells/erythrocytes present or absent, (5) activating platelet agent use or nonuse
    • d. DEPA: (1) dose of platelets [in billions], (2) efficiency of production [in percentage], (2) purity of concentrate [erythrocyte contamination], (4) activating platelet agent
    • e. MARSPILL: (1) machine or handmade preparation method, (2) activated or inactivated platelets, (3) red blood cell/erythrocyte presence or absence, (4) spin count [1 or 2], (5) platelet concentration times baseline, (6) imaging guidance [with or without], (7) leukocyte rich or poor, and (8) light activation [with or without]
  4. Optimization
    • a. Relative and absolute contraindications
    • b. Patient comorbidities
    • c. Stage or severity of condition
    • d. Preprocedural concerns: hydration, medication use, or abstinence
    • e. Timing of procedure
  5. Injectate preparation
    • a. Processing kits
    • b. Venipuncture and blood volume
    • c. Use of platelet activators
    • d. Component separation and extraction
  6. Procedural considerations
    • a. Risk and safety
      • i. Standard injection risks: local site pain, infection, ecchymosis, iatrogenic nerve injury
      • ii. Unique patient risks/challenges: bleeding diathesis, allergic response to component(s)
      • iii. Failure to provide relief
    • b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
    • c. Use of anesthetics
    • d. Injection frequency
    • e. Immediate postprocedural care: pain management, rest, modified weight bearing, follow-up (see Module 9)
  7. Documentation and billing
  8. Clinical applications
    • a. Hyaline cartilage/fibrocartilage
      • i. Upper extremity osteoarthritis: shoulder, elbow, wrist, hand
      • ii. Lower extremity osteoarthritis: hip, knee, ankle, foot
      • iii. Spine: osteoarthritis of the facet/zygapophyseal joint, intradiscal pathology, osteoarthritis of the sacroiliac joint
    • b. Tendon
      • i. Upper extremity tendinopathy: rotator cuff, common extensor at the lateral epicondyle of the humerus, common flexor/pronator mass at the medial epicondyle of the humerus
      • ii. Lower extremity tendinopathy: gluteus, patella, hamstring, Achilles
    • c. Muscle
      • i. Lower extremity: quadriceps, hamstring, gastrocnemius, soleus
    • d. Ligament
      • i. Upper extremity: ulnar collateral ligament of the elbow
      • ii. Lower extremity: anterior cruciate ligament of the knee, medial collateral ligament of the knee, anterior talofibular ligament of the ankle
    • e. Other: plantar fasciopathy
  9. Practical hands-on instruction
    • a. Patient selection
    • b. Venipuncture technique
    • c. PRP/PPP/ACP kit use
    • d. Case-based simulation
    • e. Management of side effects and complications
    • f. Return-to-play considerations (for which minimal evidence is available)

Module 4. Cellular Therapy: Bone Marrow Aspirate Concentrate​

  1. Overview: definition and history
  2. Basic science
    • a. Marrow components (eg, cell types, “red” vs “yellow” marrow)
    • b. Relationship with multipotent adult mesenchymal stem cells
    • c. Proposed mechanisms of action (in vitro vs in vivo)
  3. Classification schemes for reporting and documentation
    • a. Site of injection
    • b. Harvest technique: aspiration site(s), type of needle/syringe/anticoagulant, number of insertions, total volume harvested
    • c. Cell count: leukocytes, hematopoietic, and mesenchymal stem cells
    • d. Cytokine dosage: growth factors and interleukins
    • e. Colony forming unit count (ie, indirect quantification of mesenchymal stem cells)
    • f. Phenotype of hematopoietic and mesenchymal stem cells (requires flow cytometry)
    • g. Cell differentiation evaluation (requires induction of chondrocytes, adipocytes, and osteocytes)
    • h. Functional assays: wound healing, lymphocyte proliferation, population doubling time
  4. Optimization
    • a. Relative and absolute contraindications
    • b. Patient comorbidities: age, weight, body mass index, hematocrit, bone density, positioning difficulties
    • c. Stage or severity of condition
    • d. Preprocedural concerns: medication, dietary, or supplement use/avoidance (eg, corticosteroids, statins, nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelets, curcumin, alcohol)
    • e. Timing of procedure
  5. Injectate preparation
    • a. Harvest site(s)
    • b. Aspiration tools and technique
    • c. Volume required for application
    • d. Manipulation/processing: commercial kits, anticoagulant type, centrifugation
    • e. Component separation and extraction
  6. Procedural considerations
    • a. Risk and safety
      • i. Standard injection risks: local site pain, clot formation, iatrogenic nerve damage, hemorrhage, ecchymosis, infection
      • ii. Unique patient risks/challenges: bone density, body habitus, bleeding diathesis
      • iii. Failure to provide relief
    • b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
    • c. Use of anesthetics: careful selection to avoid cellular toxicity, maximize patient comfort
    • d. Injection frequency
    • e. Immediate postprocedural care: wound bandage, pain management, rest, modified weight bearing, follow-up (see Module 9)
  7. Documentation and billing
  8. Clinical applications
    • a. Bone: avascular necrosis, subchondral bone pathology
    • b. Hyaline cartilage/fibrocartilage: meniscus tears in the knee, knee osteoarthritis, other osteoarthritis
    • c. Tendon: rotator cuff tendinopathy, partial thickness tear
  9. Practical hands-on instruction
    • a. Patient selection
    • b. Harvest technique and processing
    • c. Case-based simulation
    • d. Management of side effects and complications
    • e. Return-to-play considerations (for which minimal evidence is available)

Module 5. Cellular Therapy: Adipose Tissue Derivatives​

  1. Overview: definition and history
  2. Basic science: components and proposed mechanisms of action
    • a. Roles and cellular contents of adipose tissue [incl. mesenchymal stem cells (MSCs), supportive cells, extracellular matrix fragments, bioactive secretomes]
    • b. Mechanisms of action: immunomodulation, angiogenesis, paracrine signaling, mechanical cushioning, extracellular matrix remodeling, in vivo versus in vitro differences
    • c. Adipose tissue derivatives
      • i. MFAT
      • ii. Stromal vascular fraction (SVF) (more than minimal manipulation, use requires biologic license application from Food and Drug Administration [FDA])
      • iii. Nanofat: autologous fat particles < 0.1 mm diameter
      • iv. Whole fat graft/transfer
  3. Classification schemes for reporting/documentation
    • a. Harvest site and aspiration method
    • b. Washing, mechanical fragmentation/emulsification, filtration
    • c. Centrifugation
    • d. Enzymatic treatment (more than minimal manipulation, use requires biologic license application from FDA)
    • e. Culture expansion (more than minimal manipulation, use requires biologic license application from FDA)
  4. Optimization
    • a. Relative and absolute contraindications
    • b. Patient comorbidities (incl. body mass index, history of abdominal surgery)
    • c. Stage or severity of condition
    • d. Preprocedural concerns: hydration, medication use or abstinence, preprocedural exercise
    • e. Timing of procedure
  5. Injectate preparation
    • a. Harvest site(s)
    • b. Processing kits
    • c. Active product
  6. Procedural considerations
    • a. Risks and safety
      • i. Standard injection risks: local site pain, infection, ecchymosis
      • ii. Unique patient risks/challenges: bleeding diathesis, allergic response to component, cosmetic defect at site of aspiration, fat embolism
      • iii. Failure to provide relief
    • b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
    • c. Injection frequency
    • d. Immediate postprocedural care: wound bandage, abdominal brace, pain management, rest, modified weight bearing, follow-up (see Module 9)
  7. Documentation and billing
  8. Clinical applications
    • a. Joint/Hyaline cartilage: chondral defect, osteoarthritis of the shoulder, hip, knee
    • b. Tendon: rotator cuff tendinopathy, partial thickness tear
  9. Practical hands-on instruction
    • a. Patient selection
    • b. Harvest technique
    • c. Case-based simulation
    • d. Management of side effects and complications
    • e. Return-to-play considerations (for minimal evidence is available)

Module 6. Nonbiologic Therapies in Regenerative Medicine​

  1. Prolotherapy
    • a. Basic science and history
      • i. Usage of various agents and needling techniques: dextrose (d-isomer of glucose), glycerin, sodium morrhuate, phenol
      • ii. Rationale for injecting ligaments, fascia, enthesis, periosteum
      • iii. Transition to hyperosmolar dextrose
      • iv. Proposed mechanism of action: dextrose concentration 5% to 10% versus 15% to 25%
    • b. Procedural considerations
      • i. Needle selection
      • ii. Patient positioning
      • iii. Injectate preparation
      • iv. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
      • v. Series versus single injection
      • vi. Comprehensive regional treatment
    • c. Role of concomitant needling/tenotomy
      • i. Soft tissue microtrauma stimulates healing tissues
      • ii. Needle contacting bone/periosteum
    • d. Indications for treatment
      • i. Osteoarthritis: mild, moderate, severe
      • ii. Tendinopathy: mild, moderate, severe
      • iii. Chronic postsurgical pain
      • iv. Chronic back, neck pain
      • v. Hypermobility/joint laxity
      • vi. In-season athlete
    • e. Practical considerations
      • i. Relative and absolute contraindications to prolotherapy
      • ii. Rehabilitation considerations
      • iii. Return-to-play considerations (in season, off season)
      • iv. Adverse effects
      • v. Billing and coding
  2. Hypo-osmolar (5%) dextrose in water: nerve hydrodissection, other applications
  3. Extracorporeal shockwave therapy: radial pressure wave, focused shockwave
  4. Emerging nonbiologic therapies (included for awareness only): Botulinum toxin type A, low-level laser light therapy/photobiomodulation, low-intensity pulsed ultrasound therapy, low-dose radiation therapy

UNIT 3. PRACTICE AND APPLICATION​

Module 7. Technical and Procedural Considerations​

  1. Device and equipment selection
    • a. Ultrasound: transducer types and selection, settings and image manipulation to optimize target image, needle localization, key images to save for the medical record
    • b. Compare/contrast commercially available devices for platelet-rich plasma, bone marrow aspirate concentrate, microfragmented adipose tissue
    • c. Supplies
      • i. Sterile versus nonsterile supplies
      • ii. Needle gauge and syringe size selection
      • iii. Activating agent(s)
      • iv. Anticoagulant use
      • v. Local anesthetic(s)
      • vi. Biohazard waste receptacle(s)
      • vii. Storage considerations
    • d. Procedural concerns
      • i. Infection prevention
      • ii. Proper handling of blood products and biologic tissues (eg, labeling specimens, storage)
      • iii. Patient positioning and comfort
      • iv. Setting up the sterile field (incl. draping, skin preparation, arrangement of supplies at the bedside)
      • v. Expectations and limitations of a clinical assistant
      • vi. Disposal of biohazardous waste
      • vii. Role of the trainee during procedures
  2. Practical hands-on instruction
    • a. Introduction to the ultrasound cart and related supplies
    • b. Review of institutional procedure room policies and protocols
    • c. Demonstration of basic scanning techniques: image optimization, transducer movements, patient positioning and draping, physician ergonomics
    • d. Demonstration of sterile field setup and maintenance
    • e. Interaction with clinical assistant
    • f. Simulated patient interaction for an orthobiologics consultation

Module 8. Science of Injury: Beyond the Basics​

  1. General response to injury in a normal state
    • a. Effective stages of the inflammatory response and regenerative capacity of human musculoskeletal tissues
      • i. Wound healing phases
      • 1. Inflammatory: hours to days
      • 2. Proliferative: days to weeks
      • 3. Remodeling: months to years
      • ii. Important cells and chemicals involved in healing
      • 1. Cells: monocytes, macrophages, mesenchymal stem cells, fibroblasts, tenocytes, osteoblasts, myoblasts, muscle satellite cells
      • 2. Cytokines: growth factors, interleukins
      • 3. Enzymes/precursors: metalloproteases, antiproteases, plasminogen
    • b. Important physiologic constituents of specific tissues and general healing timeline: tendon, ligament, muscle, bone, hyaline cartilage, fibrocartilage (eg, meniscus, labrum)
  2. Impaired healing response
    • a. Pathophysiology
      • i. Tendinopathy: general features of acute inflammation versus chronic degradation, specific watershed zones (eg, Achilles tendon midsubstance)
      • ii. Muscle: role of cytokines such as TGF-B1 and myostatin
      • iii. Bone: factors influencing osteoblast and osteoclast activity
    • b. Risk factors for impaired healing
      • i. Intrinsic
      • 1. Nonmodifiable: age, sex, genetic musculoskeletal disorder
      • 2. Comorbid conditions: body mass, autoimmune disease, hypercholesterolemia, osteoporosis, anemia, thrombocytopenia, uncontrolled hyperglycemia, end-stage renal disease, cirrhosis, impaired nutrition status
      • ii. Extrinsic
      • 1. Medications: NSAIDs, chronic immunosuppressant use, corticosteroids, statins, antibiotics, hormone supplementation
      • 2. Abnormal loading: repetition to fatigue, ill-fitting equipment, rapid training progression, high force movements, inadequate rest/recovery
      • 3. Specific injuries/pathology
    • a. Tendon: acute tendon rupture, acute inflammation (eg, tendonitis, tenosynovitis), degenerative tendinopathy, enthesopathy (incl. diseases that predispose to this condition)
    • b. Ligament: grading of acute ligament sprains, chronic ligamentous laxity (post-traumatic and/or hereditary), capsule derangement (eg, rupture, laxity)
    • c. Muscle: grading of acute muscle strains/rupture, chronic muscle injury, myositis ossificans
    • d. Bone: bone stress injury (Fredericson classification), fractures (acute/traumatic, subchondral insufficiency, pathologic, chronic/nonunion, osteoporotic), avascular necrosis
    • e. Joint/hyaline cartilage: osteoarthritis, inflammatory/autoimmune arthritis, septic arthritis, osteochondral lesion
    • f. Fibrocartilage: knee menisci, triangular fibrocartilage complex of the wrist, glenoid labrum, acetabular labrum, temporomandibular joint, acromioclavicular joint
    • g. Nerve: injury (neurapraxia, axonotmesis, neurotmesis), inflammatory and noninflammatory neuritis, neuropathy, entrapment/compressive mononeuropathy

Module 9. Rehabilitation and Return-To-Sport Considerations After Orthobiologics Treatment​

  1. Acute inflammatory phase
    • a. Duration: hours to days
    • b. Characterized by formation of hematoma, recruitment of inflammatory cells, and edema produced from vasoactive mediators
    • c. Use of analgesics
      • i. NSAIDs: evidence for holding because of inhibition of growth factor release and impaired platelet aggregation, variation on duration of abstinence pre- and postprocedure, literature lacks definitive guidance
      • ii. Acetaminophen
      • iii. Opioid-derived analgesics (eg, tramadol): short course, not required for all patients
    • d. Cryotherapy (ice): may be avoided because of theoretical reduction of blood flow and platelet activity
    • e. Immobilization, weight-bearing modifications, and/or protected use of the limb (incl. durable medical equipment)
      • i. Joint: no consensus in the literature because of heterogeneity of studies, wide variation in practice
      • ii. Soft tissue: (see “Joint” above) a period of immobilization is recommended, followed by early loading for mechanotransduction to augment healing (ideal parameters unknown)
  2. Repair/proliferative phase
    • a. Duration: days to weeks
    • b. Characterized by fibroblast proliferation at the site of injury, synthesis of collagen and extracellular matrix
    • c. Joint interventions: begin range of motion as soon as tolerated, progress aerobic activities as pain/swelling allow
      • i. Days 7 to 21: controlled stimulation to healing cartilage, correct biomechanical deficits leading to abnormal joint forces, restore/correct strength deficits, proprioceptive/balance activities
      • ii. Days 21+: individualized loading program based on procedure target site and specifics of sport/activity, begin sport-specific training
    • d. Soft tissue interventions: begin range of motion as tolerated, maintain pain <3/10, timeline of starting sport-specific training depends on sport, procedure target site, athlete, timing of season
      • i. Weeks 2 to 4: Isometric, isotonic exercise
      • ii. Weeks 4 to 6: Concentric exercise, followed by eccentric exercise
      • iii. Weeks 6+: Eccentric exercise with heavy slow resistance
      • iv. Weeks 8+: Closed kinetic chain plyometrics and sport-specific training

Module 10. Orthobiologics as Orthopedic Surgical Adjuncts​

  1. Fundamental characteristics of osseous healing: (1) osteoconduction, (2) osteoinduction, (3) osteogenesis
  2. Additional orthobiologic compounds used in orthopedic surgery
    • a. Demineralized bone matrix
    • b. Bone morphogenic protein-2
    • c. Recombinant human platelet-derived growth factor-BB
  3. Indications for potential use
    • a. Fracture nonunion/osseous atrophic nonunion: platelet-rich plasma, bone morphogenic protein-2
    • b. Joint fusion/arthrodesis: bone marrow aspirate concentrate, recombinant human platelet-derived growth factor-BB, bone morphogenetic protein-2
    • c. Avascular necrosis: bone marrow aspirate concentrate
    • d. Tendon repair/debridement: bone marrow aspirate concentrate, platelet-rich plasma
    • e. Meniscus repair: platelet-rich plasma
    • f. Ligament repair/reconstruction: bone marrow aspirate concentrate in ACL reconstruction

UNIT 4. UNDERSTANDING THE LANDSCAPE​

Module 11. Research​

  1. Critical appraisal of orthobiologics literature
    • a. Scientific rigor: levels of evidence, quality of data collected, alpha level (α), power (β), minimal clinically important difference (MCID), number needed to treat (NNT), short- versus long-term outcomes among published studies
    • b. Challenges to conducting high-quality randomized controlled trials (RCTs): time, feasibility, cost/funding (eg, funding from industry might carry stipulations that bias findings)
    • c. Compare/contrast meta-analyses and systematic reviews
    • d. Statistical methods and graphs used to compare treatments/therapies: analysis of variance, post hoc tests, forest plot
    • e. Risk of bias and attraction of “novelty” therapies
  2. Levels of evidence
    • 1. Level 1: RCTs, meta-analysis of homogeneous RCTs
    • 2. Level 2: prospective cohort studies, meta-analysis of level 2 studies
    • 3. Level 3: retrospective cohort studies, case control studies; many treatments in orthopedics and sports medicine
    • 4. Level 4: case series
    • 5. Level 5: expert opinion, case report/personal observations
  3. Role of basic science in orthobiologics research
    • a. Topics: mechanisms for cellular signaling, platelet/pericyte/MSC biology, role in healing
    • b. Cell and tissue behavior: in vivo versus in vitro
    • c. Progression: laboratory studies to animal studies to human studies
    • d. Limitations: advancements in clinical research require advancements in basic science research
  4. Common challenges in orthobiologics research
    • a. Heterogeneous or uncharacterized formulations limit comparison, conclusions, and applicability (see “Classification Schemes” in Modules 3, 4, 5)
    • b. Nocebo and placebo effects
    • c. Control group validity: potential treatment effects of saline injection, masked roles of the patient and/or physician
    • d. Variations on injection technique/procedure
      • i. Use/nonuse of local anesthetic and types
      • ii. Imaging guidance: palpation/anatomic/landmark, ultrasound, fluoroscopy
      • iii. Concomitant tenotomy/needling
    • e. Periprocedural protocols vary or are not described in the literature
      • i. Preprocedure variations: NSAID abstinence, exercise versus relative rest, hydration
      • ii. Postprocedure variations: NSAID abstinence, limb immobilization versus unrestricted movement, weight-bearing status, rehabilitation protocol
  5. Research integrity and integration into clinical practice
    • a. Consider evidence and conclusions: Are the findings applicable to my patient? Are there fundamental differences between the population studied and my patient(s)?
    • b. Assess the risk of bias: control group validity, funding from industry versus independent source(s), author conflicts of interest, standardization of treatment(s), confounding factors properly addressed (eg, adequate sample size and randomization)
    • c. Do the results show the treatment to be consistently safe? Consistently effective?
    • d. Financial implications of the procedure/method/intervention for the patient and practitioner/organization
  6. Current trends and principles of orthobiologics research
    • a. Utilization of patient-reported outcome measures (PROM)
    • b. Comparison of data registries with real-world evidence
    • c. Strengths/advantages of biorepositories
  7. Apply the research: a tiered approach to orthobiologics use
    • a. Consider: best available clinical evidence, personal clinical expertise, capabilities, and limitations, patient values, and preferences
    • b. Tier I: proven safety with robust evidence of effectiveness (level 1 evidence)
      • i.PRP for osteoarthritis of the knee
      • ii.PRP for tendinopathies: lateral epicondyle, rotator cuff, gluteal
    • c. Tier II: Proven safety with growing evidence of effectiveness (levels 2 and 3 evidence)
      • i. BMAC for knee osteoarthritis and femoral head osteonecrosis
      • ii. PRP for patellar and Achilles tendinopathy
      • iii. MFAT for knee osteoarthritis
      • iv. PPP for muscle injury
      • v. Patient should be well informed and guided on reasonable expectations
    • d. Tier III: Less evidence and regulatory approval still required
      • i. Perinatal products
      • ii. Products only offered as part of an IRB-approved study

Module 12. Regulation​

  1. US FDA guidelines
    • a. Good clinical practice (GCP) concepts: ensure safety, avoid disease transmission, avoid contamination
    • b. US Code of Federal Regulations Title 21: Food and Drugs
      • i. Part 1270: regarding human tissue for transplantation, revoked in 2022
      • ii. Part 1271: defines human cells, tissues, and cellular and tissue-based products (HCT/P); outlines “Current Good Tissue Practice” to minimize disease
    • c. FDA's Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health: risk-based regulatory approaches
    • d. Biologics License Application
      • i. Public Health Service Act (PHS Act) section 361
      • ii. FDA pathway 351: if the HCT/P is more than minimally processed
      • iii. PHS Act 351(k) for biosimilar products
      • iv. Investigational New Drug and Regenerative Medicine Advanced Therapy designations: for a HCT/P “intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition” and labeled as a “regenerative medicine therapy”
    • e. Preparations system/device regulation: FDA 510(k) pathway versus 510(f)<sup><a data-reference-links="R2">2</a></sup> pathway
    • f. Limitations: products that require more than minimal processing (eg, perinatal products, exosomes) are not currently “legal”
    • g. FDA INTERACT toolkit: Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs
  2. Federal Trade Commission (FTC) marketing regulations
    • a. Role of the Bureau of Consumer Protection
    • b. FTC has specific incentives to intervene
    • c. All products sold and procedures performed within the United States are eligible
  3. Legal challenges and notable court cases
    • a. March 2024: “Stem Cell Institute of America” etc. was found liable for defrauding consumers by the US District Court for the Northern District of Georgia
    • b. September 2024: US Ninth Circuit Court of Appeals found that California Stem Cell Treatment Center, Inc.'s manufacture and labeling of SVF violated the FDA's Food, Drug, and Cosmetic Act
  4. Patient counseling on the above

CONCLUSIONS​

The use of orthobiologic treatments in clinical sports medicine practice continues to expand. The rapid growth of orthobiologics research and clinical use requires current and future sports physicians and trainees to access high-quality clinical education along with hands-on procedural training. Wherever evidence is emerging or lacking, expert opinion should be used carefully and thoughtfully. The AMSSM Orthobiologics Toolkit offers SM fellowship directors 12 flexible modules for custom curriculum integration so that trainees may gain the scientific insight needed for responsible application of orthobiologic therapies in their medical practices.

RECOMMENDED READING FOR FELLOWS​

Module 1—Basic Principles of Regenerative Medicine​

Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of action of mesenchymal stem cells (MSCs): impact of delivery method. Expert Opin Biol Ther. 2022;22(4):449-463.

Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.

Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal stem cell mechanisms of action and clinical effects in osteoarthritis: a narrative review. Genes. 2022;13(6):949.

Murphy M, Moncivais K, Caplan A. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.

Module 2—Key Concepts on Responsible Use of Orthobiologics​

Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.

Shapiro SA, Master Z, Arthurs JR, Mautner K. Tiered approach to considering orthobiologics for patients with musculoskeletal conditions. Br J Sports Med. 2023;57(3):179-180.

Module 3—Hemoderivative Therapy: Platelet-Rich Plasma​

Belk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC. Platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Am J Sports Med. 2021;49(1):249-260.

Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA. Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med. 2009;37(11):2259-2272.

Mishra AK, Skrepnik NV, Edwards SG, Jones GL, Sampson S, Vermillion DA, Ramsey ML, Karli DC, Rettig AC. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-71.

Module 4—Cellular Therapies: Bone Marrow Aspirate Concentrate​

Dragoo JL, Guzman RA. Evaluation of the consistency and composition of commercially available bone marrow aspirate concentrate systems. Orthop J Sports Med. 2020;8(1):2325967119893634.

Friedlis MF, Centeno CJ. Performing a better bone marrow aspiration. Phys Med Rehabil Clin N Am. 2016;27(4):919-939.

Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen-year follow-up. Int Orthop. 2021;45(2):365-373.

Purita JL, Kolber M, Rodrigues BL, Mosaner T, Santos GS, Caliari-Oliveira C, Huber SC. Bone marrow-derived products: A classification proposal—bone marrow aspirate, bone marrow aspirate concentrate or hybrid? World J Stem Cells. 2020;12(4):241-250.

Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O'Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017;45(1):82-90.

Module 5—Cellular Therapies: Adipose Tissue​

Greenwood V, Clausen P, Matuska, AM. Micro-fragmented adipose tissue cellular composition varies by processing device and analytical method. Sci Rep. 2022;12:16107.

Riggle C, McLellan M, Bohlen H, Wang D. Complications of stem cell-based injections for knee osteoarthritis: a systematic review. HSS J. 2024 Aug 16:15563316241271058.

Tremolada C, Colombo V, Ventura C. Adipose tissue and mesenchymal stem cells: state of the art and Lipogems technology development. Curr Stem Cell Rep. 2016; 2, 304-312.

Module 6—Nonbiologics in Regenerative Medicine​

Hsu C, Vu K, Borg-Stein J. Prolotherapy: a narrative review of mechanisms, techniques, and protocols, and evidence for common musculoskeletal conditions. Phys Med Rehabil Clin N Am. 2023;34(1):165-180.

Sit RWS, Wu RWK, Rabago D, Reeves KD, Chan DCC, Yip BHK, Chung VCH, Wong SYS. Efficacy of intra-articular hypertonic dextrose (prolotherapy) for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2020;18(3):235-242.

Zhu M, Rabago D, Chung VC, Reeves KD, Wong SY, Sit RW. Effects of hypertonic dextrose injection (prolotherapy) in lateral elbow tendinosis: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2022;103(11):2209-2218.

Module 7—Technical and Procedural Considerations​

None.

Module 8—Science of Injury: Beyond the Basics​

Cottrell JA, Turner JC, Arinzeh TL, O'Connor JP. The biology of bone and ligament healing. Foot Ankle Clin. 2016;21(4):739-761.

Hildebrand KA, Gallant-Behm CL, Kydd AS, Hart DA. The basics of soft tissue healing and general factors that influence such healing. Sports Med Arthrosc Rev. 2005;13(3):136-144.

Kaeding C, Best TM. Tendinosis: pathophysiology and nonoperative treatment. Sports Health. 2009;1(4):284-292.

Module 9—Rehabilitation and Return-To-Sport Considerations After Orthobiologics Treatment​

Honbo ES, Mattfeld R, Khadavi M, Podesta L. Clinical rationale and rehabilitation guidelines for post biologic therapy. Phys Med Rehabil Clin N Am. 2023;34(1):239-263.

Kruse RC, Rossmiller KD, Fleagle TR. Post-procedure protocols after intraarticular orthobiologic injections—A scoping review. PM R. 2025;17(4):463-468.

McKay J, Frantzen K, Vercruyssen N, Hafsi K, Opitz T, Davis A, Murrell W. Rehabilitation following regenerative medicine treatment for knee osteoarthritis-current concept review. J Clin Orthop Trauma. 2019;10(1):59-66.

Sussman WI, Mautner K, Malanga G. The role of rehabilitation after regenerative and orthobiologic procedures for the treatment of tendinopathy: a systematic review. Regen Med. 2018;13(2):249-263.

Townsend C, Von Rickenbach KJ, Bailowitz Z, Gellhorn AC. Post-procedure protocols following platelet-rich plasma injections for tendinopathy: a systematic review. PM R. 2020;12(9):904-915.

Module 10—Orthobiologics as Orthopedic Surgical Adjuncts​

Dancy ME, Marigi EM, Krych AJ, Werner BC, Camp CL. Impact of biologic augmentation on revision surgery rates after meniscus repair: a matched-cohort analysis of 3420 patients. Orthop J Sports Med. 2023;11(8):23259671231186990.

Forsythe B, Chahla J, Korrapati A, Lavoie-Gagne O, Forlenza E, Diaz CC, Chung CB, Bae WC, Bach BR, Cole B, Yanke AB, Vermal NN. Bone marrow aspirate concentrate augmentation may accelerate allograft ligamentization in anterior cruciate ligament reconstruction: a double-blinded randomized controlled trial. Arthroscopy. 2022;38(7):2255-2264. [Published correction appears in Arthroscopy. 2023 Jun;39(6):1595].

Schoch BS, Werner BC, Shapiro SA, Camp CL, Chalmers PN, Cancienne JM. Effect of bone marrow aspirate concentrate and platelet-rich plasma augmentation on the rate of revision rotator cuff repair. Orthop J Sports Med. 2022;10(11):23259671221127004.

Module 11—Research​

Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.

Shapiro SA, Master Z, Arthurs JR, Mautner K. Tiered approach to considering orthobiologics for patients with musculoskeletal conditions. Br J Sports Med. 2023;57(3):179-180.

Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1993 Dec 1;270(21):2598-601.

Murad MH, Montori VM, Ioannidis JP, Jaeschke R, Devereaux PJ, Prasad K, Neumann I, Carrasco-Labra A, Agoritsas T, Hatala R, Meade MO, Wyer P, Cook DJ, Guyatt G. How to read a systematic review and meta-analysis and apply the results to patient care: users' guides to the medical literature. JAMA. 2014 Jul;312(2):171-9.

Module 12—Regulation​

Jang K, Berrigan WA, Mautner K. Regulatory considerations of orthobiologic procedures. Phys Med Rehabil Clin N Am. 2023 Feb;34(1):275-283.
 

meta-analysis.
6 total studies included in meta-analysis. 5 double blind and 1 open trial. 355 participants, 193 got PRP. different doses of PRP. 3 were leuko poor, 3 did not specify, 1 did have a leuko-rich arm. all used saline for placebo arm.


Results:​

Six RCTs with 355 patients were included. PRP did not provide significant pain relief at 4 weeks (SMD, 0.08; 95% CI, –0.17 to 0.34; P = .526), 8 to 12 weeks (SMD, –0.36; 95% CI, –0.99 to 0.27; P = .263), or 24 to 26 weeks (MD, –1.58; 95% CI, –4.74 to 1.58; P = .328). Functional improvement was also not significantly different at 4 weeks (SMD, 0.09; 95% CI, –0.18 to 0.37; P = .518), 12 weeks (SMD, –0.09; 95% CI, –0.39 to 0.21; P = .565), or 24 to 26 weeks (SMD, 0.13; 95% CI, –0.18 to 0.43; P = .413). No significant difference was found in adverse events (risk ratio, 1.66; 95% CI, 0.65-4.19; P = .287).

Conclusion:​

PRP does not provide significant pain relief or functional improvement in patients with lateral epicondylitis in the current study of available RCTs as compared with placebo at all evaluated time points. These findings do not support PRP as a recommended treatment for this condition.
 
I'm confused. All but one study included blood draws under 20mL, mostly 15mL. I'm going to assume presumed 60% platelet recapture, that means prob a total platelet dose of under 2 billion, which is insufficient. And recapture might be less since the old ACP machine used for all but one of those is crap. Some of those studies are not going past 3 months.

Can you imagine if we did a study of ESIs but only using 1mg of dex and only looking at the outcomes after 5 days?

Dose matters. Need better standardizion of formulation.
 

meta-analysis.
6 total studies included in meta-analysis. 5 double blind and 1 open trial. 355 participants, 193 got PRP. different doses of PRP. 3 were leuko poor, 3 did not specify, 1 did have a leuko-rich arm. all used saline for placebo arm.


Results:​

Six RCTs with 355 patients were included. PRP did not provide significant pain relief at 4 weeks (SMD, 0.08; 95% CI, –0.17 to 0.34; P = .526), 8 to 12 weeks (SMD, –0.36; 95% CI, –0.99 to 0.27; P = .263), or 24 to 26 weeks (MD, –1.58; 95% CI, –4.74 to 1.58; P = .328). Functional improvement was also not significantly different at 4 weeks (SMD, 0.09; 95% CI, –0.18 to 0.37; P = .518), 12 weeks (SMD, –0.09; 95% CI, –0.39 to 0.21; P = .565), or 24 to 26 weeks (SMD, 0.13; 95% CI, –0.18 to 0.43; P = .413). No significant difference was found in adverse events (risk ratio, 1.66; 95% CI, 0.65-4.19; P = .287).

Conclusion:​

PRP does not provide significant pain relief or functional improvement in patients with lateral epicondylitis in the current study of available RCTs as compared with placebo at all evaluated time points. These findings do not support PRP as a recommended treatment for this condition.

GIGO.
 
Platelet dose. Hmmm. Would love to see the clinical outcome studies that 10 billion >5>2> plasma.

“Dose matters”sounds the LinkedIn ads(yes they are all ads dressed up as expert opinion) on my feed.
 
Platelet dose. Hmmm. Would love to see the clinical outcome studies that 10 billion >5>2> plasma.

“Dose matters”sounds the LinkedIn ads(yes they are all ads dressed up as expert opinion) on my feed.

I always agree with having healthy skepticism. I don't know if that exact head to head study has ever been done.

I'm not a subject matter expert, but when I purchased machines, I had to review a lot of lit and as well as get quotes and white papers from different companies.

Regarding platelet dose: I like
 
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Platelet dose. Hmmm. Would love to see the clinical outcome studies that 10 billion >5>2> plasma.

“Dose matters”sounds the LinkedIn ads(yes they are all ads dressed up as expert opinion) on my feed.
The Effect of Platelet Dose on Outcomes after Platelet Rich Plasma Injections for Musculoskeletal Conditions: A Systematic Review and Meta-Analysis

This outlines why many use 10 billion platelets as a good benchmark for PRP.

Agree that "dose matters" sounds like an ad, but when you have such a huge heterogeneity PRP quality in the market, I do think its appropriate to distinguish between the two.
 
Platelet dose. Hmmm. Would love to see the clinical outcome studies that 10 billion >5>2> plasma.

“Dose matters”sounds the LinkedIn ads(yes they are all ads dressed up as expert opinion) on my feed.

Hot off the press: AAPMR guidance on PRP for knee OA


 

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