I spoke to a couple of old friends from Harvard Medical School at ARVO in Baltimore today about my idea of injecting stem cells into the Meibomian Glands. To my surprise, they were both excited about the idea. One is a professor at Harvard and the other a professor at Bascom Palmer (he was my fellow during his rotation on my service when I was a brand new attending at MEEI).


One warned against the unknown in this field in general and noting the terrible, devastating case where three women in Florida went blind when a Physician’s Assistant (not an MD, not an RN, but a PA) injected Stem Cells into these women’s vitreous: totally malpractice. A write up of this tragic event is below. 


She noted that the risk of blindness with injecting stem cells into the meibomian glands is likely 0% but there still may be unknowns for the future. Is there a risk the glands scar more? Is there a risk of cancer? No one knows. No one has tried it yet.


The other friend has been working with stem cells for almost a decade in animals and in petri dishes. He found the idea fascinating. He thinks it is a good idea. 


Still, it was clear speaking to others MDs and phD at ARVO that there are 2 camps:
1. Very Cautious
2. We will not know if this works until we try it.


The “Very Cautious” Camp view stem cell research where MDs and researchers charge the patient for the treatment as the “dark side.” I totally understand this as this is how I was trained. Most research at Harvard was paid by grants. But all to often now, even at Harvard, research is paid by the drug companies or the MDs are paid by the drug companies (on the side). Objective outcomes are at times, in question when the company, whose product a researcher is studying, is paying for the study. I have never been a consultant for a drug company. The issue of seeing my patient’s meibomian glands die away, make me wonder if I should find a company to pay for the study. 


The “We will not know if this works until we try it” Camp are more likely to see the issue at hand: the FDA and pure Academia (non-adulterated with drug company money) will take years to really prove stem cells work or do not work compared to controls. It will take millions of dollars and there may be some papers that show it does not work and others that show it does. It will take years for the truth to come out. In the meantime, many people who may have been helped, who have ALS, Alzheimer’s, etc will have since died.


By putting this technology in practicing MD’s hands, we are more likely to get an answer faster, they say.  Likely results will show that Stem Cells do work in certain conditions and in certain patients with certain genetic profiles (and certain proteins on their cell surface and no mutations pre-programmed in their stem cells), but not in others. For now, we have no idea if the chance is 50/50% it will work or 70/30% it will work. Still, many patients are coming forward saying that Stem Cells Injections prevented them from shoulder surgery, knee surgery, cured their Lyme disease, etc, etc. 


What are we to make of these testimonies? Is this a placebo effect or a true effect of Stem Cell Injection: we do not know for sure in many disease states as the outcome is subjective: did the patient really improve on cognitive tests for Alzheimer’s or was it a “good day” for the patient? Do we have any objective outcomes on Stem Cell Injections published? There have been papers reporting it to be safe (except for these cases below which are devastating), but many of the papers saying stem cell injections work have a great deal of bias or the MD, nurses, or researchers are not blinded to treatment versus control (see below excellent BMJ paper by Pas, et.al.)


With Stem Cell Injections into the Meibomian Glands, there are 2 Options:


1. Join one of the Stem Cell Centers that already has an IRB for Ophthalmology.
This will also cost about $35,000-$40,000 or a micro-liposuction machine, a study-approved centrifuge, and an incubator as the stem cells have to be maintained at a particular temperature. Each patient requires collagenase enzymes and surgical packs to be used for the procedure. Plus there is the cost of the time of the staff and surgeon for each procedure. 


Most MDs who do this pass on the cost to the patient. Most MDs charge $5000-20000 depending on where the injection is planned. The positive of this option is that there is already a network of MDs using Stem Cells in their practice. They already have an IRB. You can collect your data from the database to publish in the future. They also offer cell banking to patients for the future which an academic IRB study would not be able to do privately. 


The negatives are: charging patients for a procedure which is still experimental. 

Also, if it turns out the Stem Cell Injection does not work, the practice is stuck with purchased machines, supplies, etc: I suspect this could be a reason why negative studies have not be forthright in coming as there is a big financial investment to use Stem Cells in a practice.


Still, I am very interested in injecting Stem Cells in the Meibomian Glands of patients with Meibomian Gland Dysfunction. The beauty of the Meibomian Gland is that you can clearly and objectively see whether it works or not with LipiScan or Meibography. There is less of a need for subjective questionnaires and subjective assessments: either the glands grow back or they do not. Also we can use one eye’s glands as a control. We would only inject the left lower lid glands and leave the right lower lid glands as a control initially. If we see an improvement and the patients notices an improvement in symptoms, we could then inject the rest of the eye lid glands. 


2. Wait to get a large grant and submit my IRB to Georgetown or Medstar in the DC area: we need about $60,000-$80,000 to study about 10 patients. This money would be allocated for a micro-liposuction machine, a study-approved centrifuge, and an incubator as the stem cells have to be maintained at a particular temperature (all of this is about $35,000 to purchase). Each patient requires collagenase enzymes and surgical packs to be used for the procedure. Plus there is the cost of the time of the staff and surgeon for each procedure. The IRB may take 4-8 months to be approved. If anyone wants to donate funds to my project, please let me know: I would obviously not to charge patients for this study.


I believe so much that this will work, I would have my glands injected myself first. I would undergo the whole protocol. The issue is that there are no surgeons in my area that do Meibomian Gland probing. The closest surgeon near me that does this is Dr. Maskin in Florida.




Like the Ideal Protocol for a Study on the Evaluation of Stem Cell Injection Into Meibomian Glands is as follows. But as you will see, some parts of this are so unappealing (ie, being assigned to the control group without knowing you are not getting stem cells but just a placebo).


1. Informed consent will be reviewed explaining risk, benefits, and alternatives, including the risk of increased risk for cancer and unknown risk we do not know about. Risk of loss of vision is extremely low but we do not know all the risks as it has not been performed yet, not even in animals. Still, stem cells have been injected in many other parts of the body with published reports regarding safety (see below). This part would be part of Option 1 and 2
2. Reports kept in line with the CONSORT (Consolidated Standards of Reporting Trials) statement. This would be part of Option 1 and 2.
3. Randomize allocation. This is hard to do but more an option with Option 2 as patients are not paying for receiving a “Placebo/Control”.
4. Blind the researcher responsible for randomization to the patient at randomization: so multiple patients will get the liposuction and stem cells isolated. But only those randomized to Cases will get their stem cells injected into the Meibomian Glands. Controls will have a “sham” injection: only steroid or BSS (ie, salty water) will be injected into the Meibomian Glands and no one except a masked researcher or outside consultant will know who gets what. Not even the MD injecting would know. This is only an option with Option 2 as patients are not paying for receiving a “Placebo/Control/Sham Probing.” But in Option 1, the other eye is the control eye which makes the study more compelling as there can be no placebo bias as the LipiScan/Meibography will show if the Stem Cell Injection into the gland worked or not. 
5. Blind participants, medical personnel, outcome assessor and statistician to secure unbiased estimates of effect. This is only an option with Option 2 as patients are not paying for receiving a “Placebo/Control/Sham Probing.” But in Option 1, the other eye is the control eye which makes the study more compelling as there can be no placebo bias as the LipiScan/Meibography will show if the Stem Cell Injection into the gland worked or not. 
6. Protocols would be published in trial registers before the study’s start to enable the assessment of reporting bias and outcome switching for individual trials and to enable the detection of publication bias in general. This is an done in Option 1 and Option 2. 
7. Characterization of the stem cells (MSCs) should be done in accordance with international recommendations in order to provide heterogeneous samples and allowing, eventually, for dose–effect analyses to be possible. This is an option for Option 1 and Option 2
8. All treated patients will be followed for an extended period of time, to assure the safety of MSC: Cell Surgical Network and US Stem Cell Inc. do this for the researcher. This is harder to do for Option 2 as grant funds are limited. 

2.
http://www.advancedstemcellrx.com/learn2/




3.


https://www.washingtonpost.com/news/to-your-health/wp/2017/03/15/three-women-blinded-by-unapproved-stem-cell-treatment-at-south-florida-clinic/?utm_term=.1c7fae32be59

By Laurie McGinley March 15 

(iStock)

Three women with macular degeneration became permanently blind after undergoing an unproven stem-cell treatment touted as a clinical trial at a South Florida clinic. Medical experts said the episode raises questions about whether the government and doctors are doing enough to protect patients from the dangers of unapproved therapies.

The episode, described Wednesday in an article in the New England Journal of Medicine, represents one of the most egregious examples of patient injury involving a stem-cell clinic. These facilities have sprung up by the hundreds across the country over the past several years. Many offer supposed experimental treatments for ailments ranging from hip problems to autism to ALS.

Of special concern, said Jeffrey Goldberg, professor of ophthalmology at the Stanford University School of Medicine and one of the authors of the report, was the clinic’s ability to list its study on a comprehensive database of clinical trials called ClinicalTrials.gov, which is run by the National Institutes of Health. At least one of the patients — and maybe more — believed that she was taking part in a government-sanctioned study, he said.

Goldberg called the incident a “wake-up call across the spectrum” — for patients, physicians and government regulators. “Surely,” he said, “it’s an opportunity for the FDA to increase patient safety for these unapproved clinical trials.”

Thomas Albini, a University of Miami ophthalmologist and another one of the authors, said that he and his colleagues at the Bascom Palmer Eye Institute had treated two of the patients for severe complications in 2015, shortly after they had undergone the stem-cell procedures at a clinic in Sunrise, Fla. The severe complications included detached retinas, hemorrhages and vision loss.

“It’s a disaster,” Albini said, noting that the patients, before the stem-cell treatments, had only moderate vision loss. “Buyer beware: These stem-cell clinics that function in this very unregulated way are doing procedures that are not approved … and they can be quite dangerous.”

The NEJM article did not identify the clinic or the patients, but its listing on the ClinicalTrials.gov website shows the sponsor as Bioheart Inc., also known as U.S. Stem Cell Inc., and says that the study was “withdrawn” before patients were enrolled. The clinic still has other stem-cell studies listed on the site, including for chronic obstructive pulmonary disease and degenerative disc disease.

[Stem-cell clinics face new scrutiny from regulators]

Repeated calls to U.S. Stem Cell and to Kristin Comella, who is listed as the chief scientific officer, have not been returned. In a NPR story last year, Comella said that two of the clinic’s patients had suffered detached retinas following treatments, prompting the clinic to stop doing eye procedures.

According to Florida court filings, two of the patients involved, ages 72 and 78 at the time, sued the clinic and some individuals involved in the procedures. Their attorney, Andrew Yaffa of Coral Gables, said that the case “was resolved to the mutual satisfaction of the parties” but that neither he nor his clients could comment beyond that. The third patient was an 88-year-old Oklahoma resident who sought medical help a week after the stem-cell procedure at the Dean McGee Eye Institute in Oklahoma City.

Albini said the eye damage could have been the result of contamination during preparation of the stem cells. He also said it was possible that the stem cells could have changed into cells that are associated with scarring. Even if the solution had been prepared correctly, he said, there’s no evidence that it could have helped restore the patients’ vision.

Albini said the three patients paid $5,000 each for the stem-cell procedure, which involved conducting mini-liposuction procedures to remove fat from the abdominal area, isolating the stem cells from the fat and injecting those cells directly into eyes. Charging the patients was a “red flag,” he said, that this was not a traditional clinical trial. A second was treating both eyes at the same time, rather than seeing how one eye responded before treating the other.

[Huge NIH clinical-trials data base lacks key details.]

Age-related macular degeneration is the leading cause of vision loss in people older than 75 in the United States. While researchers are making “tremendous” progress using stem cells to treat the disease, the field requires careful study with meticulously designed trials, the authors of the paper said. The FDA has approved only a few stem-cell therapies, mostly for blood disorders.

The proliferation of stem-cell clinics — there are more than 570 of them, according to a study published last year — has ignited a fierce debate among physicians, patients and scientists about how they should be regulated. FDA rules allow the use of patients’ own stem cells for treatments, without agency approval, but only if the procedures meet stringent conditions. The stem cells, for example, cannot be more than “minimally manipulated” and must be intended for the original function. That would not typically include using stem cells from fat to repair eye cells.

Albini said that the FDA had started an investigation into the case but a spokeswoman said the agency does not discuss potential or ongoing investigations. She added that consumers are encouraged to contact the FDA and state authorities to report any potentially illegal or harmful activity related to stem-cell-based products. The FDA has issued several drafts of guidance for the stem-cell industry to try to outline its thinking on the matter, but the documents have not been finalized, and many clinic operators oppose FDA regulation.

[Unregulated stem-cell clinics are proliferating across the United States.]

Paul Knoepfler, a stem-cell scientist at the University of California at Davis who is a frequent critic of the clinics, said he didn’t understand why the FDA and the NIH have not moved more aggressively to ensure patient safety.

“It’s puzzling and concerning,” he said. He said that allowing the clinics to list their trials on ClinicalTrials.gov is “almost like a form of advertising for products that don’t have FDA approval. That’s really problematic.”

In a statement, the NIH said that the information on ClinicalTrials.gov is provided by study sponsors and that posting on the site doesn’t reflect endorsement by the NIH, which doesn’t independently verify the scientific validity of the trial. It also said that every study includes links to an NIH disclaimer. “However, we agree that such caveats need to be clearer to all users and we will be adding a more prominent disclaimer in the future.”