What the Evidence Shows on Regenerative Injections for Pain: PRP, Stem Cells, Exosomes and Prolotherapy

“Regenerative” gets attached to almost anything injected with the promise of rebuilding tissue instead of quieting it. Four treatments get sold under that word for joint, tendon and back pain: platelet-rich plasma (PRP), stem cells, exosomes and prolotherapy. Their evidence differs, and so does their legal standing.

So, up front: Modal Pain offers PRP, as a self-pay procedure. We do not offer stem cell injections, exosome injections or prolotherapy. For stem cells and exosomes there are two reasons. No stem cell or exosome product is FDA-approved to treat joint, spine, tendon or other orthopedic pain, and the controlled trials haven’t shown that these injections beat what we already have. Prolotherapy is a different case. It is usually a sugar (dextrose) solution, sometimes mixed with other irritants, not a cell or tissue product, and our reason for leaving it out is the evidence: small trials, inconsistent methods, and a guideline that advises against it for knee and hip arthritis (Kolasinski 2020).

Where the FDA stands on stem cells and exosomes

The FDA publishes a list of every approved cellular and gene therapy product. The stem cell products on it are blood-forming stem cells, either donated stem cells, mostly umbilical cord blood, used in transplants for blood disorders and blood cancers, or a patient’s own blood stem cells modified to treat inherited blood, immune or metabolic diseases such as sickle cell disease, and one mesenchymal stromal cell product, remestemcel-L (Ryoncil), approved in December 2024 for steroid-refractory acute graft-versus-host disease in children 2 months and older. That is a transplant complication, not a knee or back problem. The one cell product on the list aimed at a joint, MACI, is a membrane of the patient’s own cultured cartilage cells used to repair full-thickness knee cartilage defects. It is not a stem cell product or an office injection.

The FDA’s consumer alert on stem cells and exosomes is blunt. Stem cell products, exosome products and related products made from fat (stromal vascular fraction), umbilical cord blood, Wharton’s jelly or amniotic fluid “have not been approved for the treatment of any orthopedic condition, such as osteoarthritis, tendonitis, disc disease, tennis elbow, back pain, hip pain, knee pain, neck pain, or shoulder pain.” On exosomes, the agency’s December 2019 safety notification says “There are currently no FDA-approved exosome products.”

How do clinics sell them anyway? Many claim their product is exempt from approval as a minimally processed tissue. The FDA disagrees for most of them. The rules for human cell and tissue products sit in 21 CFR Part 1271. Under section 1271.10, a product avoids premarket approval only if it meets all four criteria, apart from a few narrow exceptions in section 1271.15, such as tissue removed and put back during the same surgery. It must be minimally manipulated, used for the same basic function it had in the donor (homologous use), not combined with another article beyond water, crystalloids or a sterilizing, preserving or storage agent, and either free of systemic effect and not dependent on the activity of living cells for its main function, or used in the same person, a close blood relative, or for reproduction. Fail any one and the product is regulated as a drug, device or biologic. It then needs an approved license, or an investigational new drug application (IND) for a clinical trial, before it goes into a patient.

A grace period for manufacturers ended on May 31, 2021, after which the FDA said it no longer intends to exercise enforcement discretion on those requirements. Its patient information page adds a practical warning. If you are being charged for one of these products outside a clinical trial, “you are likely being deceived and offered a product illegally,” and a clinic’s FDA registration or a listing on clinicaltrials.gov does not mean the product is legally marketed.

What the stem cell trials show

A 2017 systematic review found five randomized trials and one non-randomized trial of stem cell injections for knee arthritis. All reported benefit, and all were at high risk of bias. The authors did not recommend the treatment (Pas 2017).

The best test since then is the MILES trial (Mautner 2023, Nature Medicine). It randomized 480 people with knee arthritis to one of three cell injections, either bone marrow aspirate concentrate, fat-derived stromal vascular fraction or umbilical cord tissue stromal cells, or to a cortisone injection. At one year, no cell injection beat another, none beat cortisone, and no group’s MRI arthritis score changed significantly from baseline. The 2019 American College of Rheumatology guideline strongly recommends against stem cell injections for knee and hip arthritis, citing how little standardization there is in what actually gets injected (Kolasinski 2020).

Exosomes: a lab result sold as a treatment

Exosomes are tiny membrane packets that cells release, carrying proteins and RNA. In a culture dish, vesicles from bone marrow stromal cells blunted inflammatory signaling in arthritic cartilage cells and pushed those cells to make more cartilage matrix (Vonk 2018). That is a laboratory finding, not a clinical one.

In people, the evidence is thin and not encouraging. In a triple-blind trial, 31 patients with arthritis in both knees had placental stromal-cell vesicles injected into one knee and saline into the other. Pain and function were no different between the two knees at 2 and 6 months, and neither were MRI findings at 6 months (Bolandnazar 2024).

What can go wrong at unregulated clinics

The FDA lists blindness, tumor formation, bacterial infections including blood infections, and contamination during processing among the harms it has received reports of (FDA patient information). In December 2019 it reported serious adverse events in patients in Nebraska treated with unapproved products marketed as containing exosomes (FDA safety notification).

The case most physicians know comes from the New England Journal of Medicine. Three patients with macular degeneration had fat-derived “stem cells” injected into their eyes at a US clinic. All three developed severe vision loss in both eyes, with complications that included retinal detachment and bleeding inside the eye. A year later their vision ranged from 20/200 to no light perception (Kuriyan 2017). It was an eye procedure, not a joint injection, but it shows what an unapproved cell product can do without a trial’s safeguards.

If a clinic quotes you for stem cells or exosomes, the FDA suggests asking for the product’s IND number and the FDA letter acknowledging it before treatment. A legitimate trial will have both, along with a consent form naming the review board that oversees it.

Prolotherapy: small trials, mixed answers

Prolotherapy means injecting an irritant solution, usually dextrose, around ligaments and tendons or into a joint, on the theory that local irritation sets off repair. The best-known trial randomized 90 adults with knee arthritis to dextrose injections, saline injections or home exercise. At 52 weeks the dextrose group’s WOMAC score had improved by 15.3 points, against 7.6 with saline and 8.2 with exercise (Rabago 2013). A 2022 meta-analysis of 14 trials and 978 patients also favored dextrose over placebo, but the authors flagged marked heterogeneity and risk of bias and asked readers to interpret the results cautiously (Chen 2022). For chronic low back pain, a Cochrane review found prolotherapy injections alone no more effective than control injections (Dagenais 2007).

The ACR guideline conditionally recommends against prolotherapy for knee and hip arthritis, noting small effects and injection schedules, sites and comparisons that vary from trial to trial (Kolasinski 2020).

PRP: what we offer, and what the evidence says

PRP is your own blood, spun down to concentrate the platelets and injected into a tendon, joint or tear under image guidance. We prepare leukocyte-poor PRP, meaning most of the white blood cells are removed. We use kits from more than one manufacturer, and the blood draw is 10 to 60 mL depending on the kit. We use it for tendon problems such as tennis elbow and rotator cuff tendinopathy, including partial tears, for knee and hip arthritis, for hip labral tears and impingement (FAI), and for partial muscle tears. It is self-pay. Medicare’s New York contractor and UnitedHealthcare do not cover it, and other plans set their own policies.

The evidence is mixed, and we say so.

• Knee arthritis. A 2021 meta-analysis of 34 trials favored PRP over saline and hyaluronic acid on some scores at 6 to 12 months, but the evidence was low quality and the gains were not clinically meaningful on every measure (Filardo 2021). The placebo-controlled RESTORE trial gave 288 patients three injections of PRP or saline and found no difference in pain or cartilage volume at 12 months (Bennell 2021). The ACR guideline strongly recommends against PRP for knee and hip arthritis (Kolasinski 2020), and the 2019 OARSI guideline also strongly recommends against it (Bannuru 2019).
• Tennis elbow. In the largest trial, 230 patients, tendon needling with PRP did no better than needling alone at 12 weeks and better at 24 weeks (Mishra 2014). A 2026 meta-analysis of six placebo-controlled trials found no benefit over placebo at any time point (Antunes Júnior 2026).
• Other tendons. PRP beat a cortisone injection at 12 weeks for gluteal tendon pain (Fitzpatrick 2018) and at 3 to 6 months for plantar fasciitis (Zuo 2025). Against saline, trials in the Achilles, patellar, rotator cuff and gluteal tendons found no difference (de Vos 2010, Scott 2019, Kesikburun 2013, Atchia 2025).
• Leukocyte-poor versus leukocyte-rich. The positive tennis elbow and gluteal trials used leukocyte-rich PRP (Mishra 2014, Fitzpatrick 2018). Whether leukocyte-poor PRP, which we use, does as well in those tendons hasn’t been tested head to head, and the leukocyte-poor arms of RESTORE and the patellar trial were no better than saline (Bennell 2021, Scott 2019).
• Muscle and labral tears. A 2018 review found PRP has not been shown to work for muscle injuries (Le 2018). Labral tears have very little trial data.

Part of the noise is that PRP isn’t one product. Of 105 clinical studies reviewed in 2017, only 11 described their preparation well enough for someone else to repeat it (Chahla 2017).

Some PRP systems now also make a filtered plasma protein concentrate, sold as alpha-2-macroglobulin (A2M) or simply as a “protein concentrate.” A2M is a plasma protein that inhibits cartilage-degrading enzymes. A double-blind trial randomized 75 patients with mild to moderate knee arthritis (Kellgren-Lawrence grade 2 or 3) to an A2M-rich concentrate, standard PRP or a methylprednisolone (cortisone) injection. At 12 weeks, the change from baseline did not differ between the three groups. Given the higher cost of preparing it, the authors concluded A2M “may not be a justifiable option for routine treatment of knee OA” (Thompson 2024). We don’t offer it.

One practical rule: avoid anti-inflammatories such as ibuprofen and naproxen for 2 weeks before and 2 weeks after the injection. It is a precaution. In lab studies these drugs reduce platelet function, but no one has tested whether that changes results in patients. Acetaminophen is fine. Activity, flare care and the rest of the schedule are in our PRP aftercare instructions.

Deciding what to try

If knee arthritis hasn’t responded to exercise and weight management, a cortisone injection is the option the ACR guideline strongly recommends, and PRP is a self-pay alternative worth weighing only with the trials above in view. If a tendon has stayed painful through months of loading exercise, PRP is worth discussing, knowing that some tendons respond better than others.

Bring your imaging to a consultation. Dr. Movshis will tell you plainly whether PRP fits your problem, or whether a cortisone injection, physical therapy or a surgical opinion makes more sense. Our joint pain page covers the rest of the options.

References

This article is reviewed against the peer-reviewed literature. Citations retrieved from PubMed.

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