Having been involved in the Stem Cell field for several years I have seen quite a few changes and luckily these changes are for the better. Sure there are still hucksters out there promising they will cure everything with stem cells. These type of individuals are becoming fewer and fewer. Last week I witnessed a watershed development in the field of Stem Cell regenerative medicine at least as it applies to Orthopedics.
This development was from an article published in the Journal of Bone and Joint Surgery. This is probably the one of the most prestigious journals in the world when it comes to orthopedic conditions. This article was the lead article giving it even more importance. It was entitled ” Adult Human Mesenchymal Stem Cells Delivered via Intra-Articular Injection to the Knee Following Partial Medial Meniscectomy”. This was a double blind study which means that some patients received stem cells and some did not. More importantly, the treating physicians did not know which patient received the stem cells. The patients that were chosen were patients who had a partial menisectomy. In another words they had a portion of their meniscus surgically removed in an arthroscopy operation. I have performed thousands of these operations over my years as an orthopedic surgeon. Most patients did well at least in the beginning but as time moved on I began to see that a certain number of patients began developing osteoarthritis. As was brought out in the article after a partial menisectomy there is at least a ten to twentyfold increase in osteoarthritis. I have noted similar findings with ACL reconstructions. I am now seeing in both my stem cell and orthopedic practice that these patients tend to develop osteoarthritis down the road. Should these patients been given the advice of not having the surgery? I do not think this is the solution. Maybe we are now realizing that arthroscopy alone may not be the answer. In most of these cases surgery was necessary to help eliminate symptoms. The question is what have we achieved in the long run? Quite honestly I am not sure. But I am sure of one thing, eventually stem cells will provide the missing link. If they do not eliminate the need for surgery (and I suspect they will) they will greatly alter the course of post operative results. I have performed stem cell procedures on many patients with torn meniscus injuries for a number of years now with excellent results. However, stem cells will not fix all meniscus tears!
Getting back to the study. It was actually divided into three groups. One group received stem cells, the second group received three times as many stem cells, and the third group only received hyaluronic acid. Hyaluronic acid is very commonly used to treat the symptoms of osteoarthritis. It does not cure arthritis but can on a temporary (anywhere from six months to a few years) basis ameliorate some of the symptoms. The study compared two important aspects. One aspect compared the amount of meniscus regrowth in the three groups and the other comparison dealt with pain.
In the comparison of meniscus regrowth there was some surprises for the uninitiated. In the groups that received mesenchymal stem cells there was definitely regrowth. However the group that received the larger amount of mesenchymal stem cells paradoxically had much less meniscus growth. This is not the first time this has been reported. It seems that higher levels of mesenchymal stem cells seem to cause inhibition of cell growth. This has been documented in other studies. This is a similar finding to what we observe in PRP preparations.
When looking at pain scores the two groups which received mesenchymal stem cells had approximately twice the amount of pain relief as the control group. Another very important aspect of the study was that osteoarthritis increased in at least 21% of the patients who were in the control group but only 6% in the patients treated with mesenchymal stem cells.
There are some very important findings we can take away from this study. First it is considered a Level 1 study. This means that the evidence is very objective. We are not looking at the results thru rose colored glasses. Secondly, It shows the safety of using stem cells. Essentially no adverse reactions were seen from the stem cells.
One concept that the authors brought out was that “there was an ability to protect the impact of the removal of meniscus tissue particularly in patients that already have some signs of osteoarthritic changes”. This is potentially a game changer.
What can we take away from this article? First, I believe this truly significant since stem cells have finally taken center stage. The lead article in JBJS is definitely center stage. The observations that the authors of this article made are very consistent with many of the results we have observed in our own clinical practice. I have seen that stem cells have made a significant change in the symptoms of patients with osteoarthritis. The authors of the article were restricted in their approach in treating the patient. I would like to see a similar study only in this case I would use many of the regimens we have incorporated into our practice. I suspect the results would be much better utilizing mesenchymal and hematopoietic stem cells together. Remember that hematopoietic stem cells are thought to be the drivers of tissue regeneration. What effect would these cells have on the regrowth of the meniscus tissue? The cells that were utilized in the study were cultured adult human mesenchymal stem cells. These were not the patients own cells but were adult cells that were grown in a lab. There is a school of thought that when cells are cultured they lose some of their effectiveness. Also one cell does not seem to do the job alone. There is a symphony of cells that accomplish repair. Perhaps the next study should be a combination of cells say utilizing both bone marrow and fat together. In this case we are getting the major players both mesenchymal and hematopoietic stem cells. Also how about the use of a PRP (Platelet Rich Plasma) to help activate the stem cells that were injected into the knees. Remember the stem cells are the seeds and the PRP acts like the fertilizer. What about the use of oral, injectable, and transdermal cytokines? What effect might they have on the overall results? How about the use of exosomes and supplements? These are questions that stimulate the mind and wet the appetite for those involved in the field of stem cells. I wish to stress that I am in no way shape or form trying to belittle the accomplishments of the authors of the article. Like I stated in the beginning of this blog, this is a watershed article and we should all be indebted to the authors. I hold them in the highest esteem.
Thanks Dr. P
We have made some significant strides in the stem cell field but we still have more improvements to make. We have discussed many aspects of stem cells and will continue to do this. What typically is not discussed outside of scientific circles concerns tissue engineering. When we talk about engineering we are talking about designing something. Much research has been done in this field. Some of this research is exciting and promising. Tissue engineering may be the missing link in stem cell therapies as far as orthopedics is concerned. In orthopedic conditions it is fairly easy to deliver the cells to the area but sometimes it is difficult to have the cells remain exactly where we want them. The idea behind tissue engineering is to eliminate this problem.
Tissue engineering concerns designing a scaffold or environment that the stem cells can adhere to and become established. We many times call the scaffold a matrix. Tissue engineering is actually not a new concept. I have been using tissue engineering for over thirty years. When I was a resident in orthopedic training we would many times do bone grafts. The bone grafts would either be from the patient or from a “bone bank”. Typically, these cases were done when the bone would not heal or bone was missing from an accident. The bone graft was done to act as a scaffold to allow new bone cells to grow into the area. We have developed new substitutes for bone grafts. When all is said and done bone is still a very good scaffold since it matches what is already there.
When we look at tendons and joints the tissue engineering is much more difficult. First we have to look at the problem we are dealing with. When someone has a small portion of the joint involved we may not have as much of a tissue engineering challenge as we do with a large portion of the joint involved.
The engineered tissue materials must fulfill some fundamental requirements. At first they have to be immune-compatible and nontoxic. We do not want the body attacking the area. When the body attacks the area typically the stem cells will also perish. When the bio-material begins to degrade it must not release toxic substances which will undue all healing that has taken place. The last thing we want to do is make the stem cell niche inhospitable to the various stem cells. We must also make sure that the bio-materials survive a sufficient amount of time.
Beside these qualities, matrices formed from bio-materials must have distinct properties with regard to the desired kind of tissue they are programed to produce. Some of these properties concern mechanical strength, bioactivity, the speed of degradation, and drug/cell release significantly varies between different repair tissues. The repair of a tendon differs somewhat from the repair of cartilage tissue. Besides the used bio-materials themselves, the 3-dimensional structures of scaffolds have great influence on cell growth and differentiation. Scaffolds must be highly porous with interconnected pores. Some of the scaffolds will be coated with various growth factors. These coatings will encourage further growth and differentiation of the stem cells.
When we get down to the nitty gritty we still have a long way to go with bio scaffolds. We do have one bio scaffold that seems to be working very well. It has all the various attributes mentioned above and it is fairly inexpensive and has no chance of immune rejection. This scaffold is fat tissue that is taken from the patient. Fat has many of the the aspects we are looking for in a scaffold. It has a 3D structure, it contains growth factors, immune issues are non existent, and as an extra bonus is contains very powerful stem cells. Until something better comes along fat tissue seems to be the best and most logical choice.
Thanks Dr. P
The above diagram was sent to me by Dr. Halasa. Dr. Halasa shares many of the same thoughts as my self concerning photo modulation and nitric oxide. We are now at a point that we are beginning to see that laser stimulation is going to be very important in the field of stem cell medicine. Lasers, the immune system and nitric oxide all seem to be tied together. I suspect we will be seeing increasing importance in the links between these systems and stem cells. I would like to take a bit of time and discuss each of these entities.
Recently, I had the good fortune to be invited by Dr. Alan Bauman to be part of the faculty for a pre conference workshop on hair loss. For those of you who know me or have seen me this is somewhat of an oxymoron. As you may have surmised I am rather sparse on top of my head. Yet I suspect that stem cells may some day restore the head of hair. We are getting a bit off track. I had the good fortune to meet a fellow faculty member Dr. Michael Hamblin of Mass General and Harvard Univ. Dr. Hamblin specializes in a new field of medicine called Photomedicine. The facility at Mass General is called the Wellman Center. We have known for many years that lasers and light therapy have been important in stimulating hair regrowth. It was one of those things I knew about but I really did not understand how it worked. We need to realize that growing hair is not that much different from growing cartilage cells.
Lasers or as we sometime call it low laser light therapy (LLLT) are instrumental in the stem cell field. I have been using them for a number of years. Light therapy has many profound effects. We know that it seems to have an effect on the production of Exosomes. It seems to activate what are called senescent cells. It also seems to activate Very Small Embryonic Like Stem Cells. We knew these things were happening but we were not sure why.
The pieces of the puzzle are now starting to fit together But I want to borrow a phrase from one of my slides in my talks “THE MORE WE KNOW THE MORE WE DON’T KNOW”. I think this is a very appropriate description of the field of stem cells and for that matter all of science. As I learn more I realize there are many more things I don’t know about concerning what I just learned. This is a never ending cycle. What I think I have learned about lasers and light is that they have a profound effect on many aspects of the cell. Light therapy goes down to the basics of cell biology. What we now know is that the mitochondria which are the powerhouses of the cells have photoreceptors. In light therapy there is absorption of photons in a portion of the mitochondria cells. This has a direct effect on the cellular electron respiratory transport chain. This involves the Krebs cycle which brings us back to biochemistry days. The result in the improvement in the electron transport chain is greater production of ATP. ATP is the essential energy of most cells. If cells are exposed to more energy than they will typically be more efficient at doing their job. LLLT seems to paradoxically increase reactive oxygen species (ROS) in healthy tissue but most importantly it decreases ROS in those tissues which suffer from oxidative stress. So we have little effect adverse effects on normal cells from ROS but a significant positive effect on ROS in diseased tissue. The use of LLLT in patients involves mainly red and near infrared (NIR). The wavelength of this light is between 600-950 nm.
We find that low level light therapy have many profound effects on the cells. It appears that all genes from the antioxidant related category and genes related to energy metabolism and the respiratory chain were up regulated. It is thought that low level light therapy stimulates cell growth by influencing both directly and indirectly related to DNA synthesis and repair and cell metabolism. Stem cells are finicky enough. Anything we can do to nudge them along is so important. There is definitely more to come on this subject. Thanks Dr. P
If you are looking to herbal supplements to help improve your memory or vitality or help you to sleep, you may want to save your money. The New York State attorney general’s office is asking four major retailers — GNC, Target, Walmart and Walgreens — to stop selling herbal supplements after tests found that many of them did not contain the herbs listed on their labels.
In a press release, New York Attorney General Eric T. Schneiderman said DNA tests were run on supplements claiming to contain ginko bilboa, St. John’s wort, ginseng and echinacea. Samples of the supplements were purchased from various locations around New York, and each sample was tested five times. In four out of five cases, the tests showed that the pills contained nothing more than fillers such as asparagus, rice, wheat or houseplants.
“This investigation makes one thing abundantly clear: the old adage ‘buyer beware’ may be especially true for consumers of herbal supplements,” said Schneiderman. He added that the herbal supplements “also pose unacceptable risks to New York families — especially those with allergies to hidden ingredients.”
Schneiderman says mislabeling, contamination and false advertising are illegal, and he’s asking each company to provide more detail on the production, testing and quality control of the herbal supplements sold at their stores.
Walgreen immediately agreed to the attorney general’s request to pull the supplements off their shelves. Walmart said it would reach out to its suppliers and take appropriate action. GNC told the New York Times that the company would cooperate with the attorney general “in all appropriate ways,” but that it stood behind the quality and purity of its store brand supplements.
The response from the herbal supplement trade association, the Council for Responsible Nutrition, was not as supportive. It called the attorney general’s actions a “sting,” and described them as reckless, which “smack of a self-serving publicity stunt under the guise of protecting public health.”
But David Schardt, senior nutritionist of the Center for Science in the Public Interest says, “the evidence for these herbs’ effectiveness is sketchy to begin with.” Schardt, quoted in the attorney general’s press release, says if the advertised herbs are in many of the products, it’s a sign the “this loosely regulated industry is urgently in need of reform.”
The US Food and Drug Administration requires companies to verify their products are safe and properly labelled. But a federal law was passed in 1994 which exempted herbal supplements from following the same stringent guidelines.
The New York Times says the chief architect of that law was Republican Sen. Orrin Hatch of Utah. The newspaper says Hatch “has accepted hundreds of thousands of dollars in campaign contributions from the industry and repeatedly intervened in Washington to quash proposed legislation that would toughen the rules.”
The above post appeared last week. This was no surprise to me. I am a total believer in supplements. I am not a believer in that all supplements are created the same. I have known for years that certain brands were not to be bought at any cost. Unfortunately, the general public does not think this way. The perception is that all supplement are created equal. This thinking is correct if we are on a level playing field. Unfortunately, the main motivation for many corporations is pure and simple profit. The task at hand is to find a source that is trustworthy and at the same time a fund of knowledge. In these big box stores you are typically dealing with a clerk who has little knowledge or desire to steer you in the right direction. Would you go to Walmart to seek advise from a clerk on a medical question? I think the answer to this question is no. The same holds true with supplements. In this case you are much better off in dealing with a smaller store where the personal know the “right companies” and “the right products”. In the long run they will save you money but more importantly possibly your life.
To condemn supplements is to talk foolishly. Those charlatans that condemn supplements need to look no further the botanical world. Many of our pharmaceuticals come from the world of botanicals. I could give pages of examples of pharmaceuticals coming from botanicals. Think about digitalis which comes from the fox glove plant. How many lives have been saved from taking digitalis? Another example is tamoxifen which is a potent medication used in the treatment in breast cancer. It comes from the Yew plant. The list goes on and on. For those so called experts who condemn supplements they should also condemn pharmaceuticals. I would say that they would be practicing like witch doctors but witch doctors are smart enough to utilize supplements (botanicals). Pharmaceutical companies know that the botanicals are cornucopia of medicines. They will invest billions of dollars on research on these. Reputable supplement companies will also devote large amounts of money testing the efficacy and safety of supplement products. I can say this first hand since I have experience in designing certain supplements.
I have been very meticulous in doing my research on the supplements that I prescribe for my stem cell patients. For instance StemXCell has extensive research that was performed at the Univ. of South Florida. Neo-40 has extensive research at the Univ. of Texas. CH-Alpha has research at a number of universities. The list goes on and on. The best bit of advise I can give on supplements is do your research not only on the supplements but where you can find a reliable and honest source of information. Perhaps one guiding light is to look for USP Verified dietary supplements. These are products that have been voluntarily submitted to the USP Dietary Supplement Verification Program and have successfully met the program’s stringent testing and auditing criteria. The program was established by USP to help dietary supplement manufacturers ensure the production of quality products for consumers. USP is a scientific nonprofit organization that establishes federally recognized standards for the quality of drugs, dietary supplements, and foods. It is the only such organization that also offers voluntary verification services to help ensure dietary supplement quality, purity, and potency. USP standards are used in more than 140 countries and are federally recognized per the Federal Food, Drug and Cosmetic Act and the Dietary Supplement Health and Education Act. Hopefully this sheds some light on a confusing topic.
Thanks Dr. P