Biologic therapies have shown great promise.
Much is known but far more is unknown.
Governmental regulation in the US has lagged behind the implementation of biologic therapies, in part because there is a paucity of high confidence scientific evidence.
Scientific evidence can be stratified into low, mid and levels of confidence in the results.
Level one studies include randomized control trials and meta-analysis of RCT with homogenous
Level four is case series.
Level five evidence is case reports, expert opinion, and personal observation.
Unfortunately, much of the evidence for biologic treatments is level four or level five studies.
This just isn’t a lot of level one evidence. This can lead to the need for hope or the failure of conventional treatments as the reason to adopt unproven therapies such as biologic therapies.
Since training, I have tried to practice evidence based medicine. Much of what I have done in my career was based upon the experience of those who trained me or those who trained the people who trained me. I accepted what was in textbooks and performed procedures and radiologic interpretations based upon what generally accepted practice. More often that I would care to admit, these medical assumption were not based upon level one evidence. Treatment with biologics is in it’s infancy. We wont have a federal guidance or a complete set of guidelines from the FDA until November 2020. Until then, all of who are practicing regenerative medicine are doing their best to do their best. To the general public, many medical practices may seem to be the obvious choice, based simply upon common sense or familiarity. Too often in medicine, however, theory and promise did not match carefully evaluated results. For example, in many cases we are just now figuring out what tests are and are not appropriate in the evaluation of emergency room patients. Often the medical decision making is based avoiding malpractice claims, rather than true, scientifically proven appropriateness criteria.
As a result, in an effort to stay on the right side of the FDA as well practice medicine at the highest level, I am providing a reference library for patients on my web site. You will have access to the same science that I do.
I will attempt identify parts of my practice that are evidence based.
I will attempt to identify parts of my practice that are based upon what I believe to be a firm scientific background.
I will also attempt to identify parts of the practice that are based upon my own opinions as well as opinions of experts in the field.
The long and the short of the discussion is this……..we don’t know very much. We don’t know what we don’t know. We don’t know the correct doses of the biologics we use to treat patients.
We don’t know the mechanisms of action on the molecular level (although we have some good guesses that are supported by basic science research). We don’t know the longevity of the treatments. We don’t know the long term outcomes, although we have some really good guesses that seem to match the personal experience of long term practitioners. We don’t know what the FDA will approve and what they will base their decisions upon. We do know that, in many cases biologics seem to work. They are based upon amplifying your body’s ability to heal.
The are based upon creating a controlled injury and helping your body identify and respond to the injury. We do know that the inflammatory and immune responses are critical to regeneration. We do know that we have built into our own bodies the ability to self repair and regenerate. We do know that our capacity to regenerate is far greater than previously believed. We do know that things we thought could not be repaired, in fact, under the correct cellular signaling can be markedly improved. Pathways that we once thought were one way streets, we now know can be reversed. In my training, I learned that in development, cells move inexorably towards greater differentiation and maturity and eventually towards senescence. The Nobel prize in medicine went to Drs Yamanka and Gurdon for discovering that this process can be reversed. That is, mature, adult cells could be induced to become less mature, younger acting, more flexible in their behavior cells. That is, we could reverse aging on a cellular level.
The promise is that we may be able to reverse the trend of degeneration and move towards regeneration on the cellular and molecular levels. We can induce cells suffering from old age to become young again metaphorically speaking. We are moving towards 3d printing of tissues and subsequently organs derived from a patients own cells.
Many have heard of stem cells. Dr Arnold Caplan coined the term in 1991. Since that time he has changed the interpretation of his initial data. He has changed the name from mesenchymal stem cells to medicinal signaling cells. Where we once thought treating someone with biologics was tantamount to a transplant on a cellular level, we now know that we are instead, providing the recipient with the genetic information and signals to turn on their own cells regenerative processes.
Let me start with the weakest evidentiary parts of my practice: My Opinion.
I believe that we should prepare our bodies to regenerate. We should maximize the efficacy of the regenerative biologics that you are buying. Based upon opinion in the field and my own opinions, I believe that patients should change their diet to a low carbohydrate, anti- inflammatory diet for two weeks prior to the treatment. (link here) It is my belief that limiting total body inflammation may help keep the precisely injected localized treatment in place. (link here) Limiting the signals indicating locations of inflammation may allow local factors to control the utilization of the biologic. In short, since we want local effects, fewer systemic signals competing for the regenerative process may help repair process of the symptom causing process. (link here) This is pure speculation on my part. Fewer free radicals and a lower oxidative stress elsewhere in the body may enhance your response.(link here)
I believe that fasting for 24 hours prior to the injection of biologics may help amplify the regenerative response. This is based upon studies in MICE that showed that medicinal signaling cells stressed by dietary limitations had an amplified response.(link here)
Hydration and replacement of micronutrients may be of benefit. The basis of regenerative therapy is linked to vascular system. In order to repair tissues, we must have a delivery system to provide the building blocks and remove cellular wastes. The story of healing is often the story of blood supply and vessel generation. (link Here) What nutrients are essential? This is a trick question. Whatever nutrient is deficient in the body will be the rate limiting step. Vitamin D, Vitamin C, Vitamin E have all been shown to be essential in wound healing. Magnesium, proteins, amino acids (in particular leucine) have been shown to be essential in healing.(Link here) Is an excess of these nutrients beyond the minimum required level going to enhance the regenerative process? Who knows? But, in an attempt to maximize your regenerative response, we give a broad spectrum of nutrients we suspect may help. We offer these as recommendations rather than requirements. We suggest a high leucine protein shake, we suggest a set of oral vitamins two weeks before the treatment as wells as month after. We also recommend a micronutrient rich hydration be administered before or during the treatment.
Our experience suggests that these measures make patients feel better. What is the evidence that it actually helps the regenerative process? Most of it is based upon wound healing literature and not regenerative medicine studies. (link here)
The science based recommendations.
We don’t know how many medicinal signaling cells and we how many platelets it takes to achieve the maximum benefit. We have a sense of possible minimums to be effective. We don’t know how many viable cells will be in your biologic sample. We don’t know their effectiveness or potency.
We don’t know how many exosomes it takes to achieve the desired effect. We don’t know if exosomes derived from planned c-sections have the right signals for the regeneration we want to amplify. That is, do they have the signals we want? We don’t know if your fat cells or your bone marrow will give better results. We don’t know how effective your signaling cells will be. We don’t know the optimal supporting environment or biologic scaffolding to use. We don’t know the timing of the doses.
We do, however, have some experiential guidelines. We have some scientific reports of results.
In general, it seems that multiple treatments with PRP may be required. (link here)It may be that treatment with signaling cells and exosomes requires fewer treatments. (link here) It may be that signal cells last longer in the body. In general, it seems that treating the functional unit and not just the internal aspects of a joint may give better results. (link here)The regulatory pathways are not yet established by the FDA. (link here) It seems that autologous biologic treatments are more acceptable than when the tissues are donated from screened populations. It seems there may be advantages to using younger, more vital signaling cells. It also seems that fat derived signaling cells may be more resilient than bone marrow cells. There is work being done on signaling cells (MUSE CELLS) that may be very resilient and therefore better suited to low oxygen and otherwise less hospitable target tissues. (link here)
We do know that the FDA has not approved exosomes. We know they show promise, but again the science and practice is way ahead of the clinical trial results.
Based upon the combined PRP and Cell Signaling and Exosome literature, I have concluded that combination therapy with PRP (for which there is the most outcome based evidence) and exosomes or signaling cells may be best. Many practitioners use all three or four (adipose derived, marrow derived signal cells, exosomes, and prp).(link here)
The firmest ground: Randomized trials and meta-analysis homogenous results.
I refer you to the reference lists included on this site. This is what I think I know.
Signaling cells exist in our bodies in the spaces surrounding our smallest vessels. They exist in the form of pericytes. These cells are exposed to the microenvironments of the blood vessels they adjoin. In response to a complex cellular signaling ecosystem, the pericytes change into exactly the cells we need to locate, repair and regenerate damage in our body. These are miraculous cells. Once stimulated by the microclimate of the blood flowing past their neighborhood, they somehow know where to go and what to do when they get there. These cells send signals to their new neighbors and coordinate the action plans to repair the damage.
When we place biologics into your body, it is likely that we are simply creating the right message environment to amplify the normal repair mechanisms that already exist in your body.
Almost every biochemical and molecular process in your body exists in a state of balance. The process is ready to go forward or backwards depending upon what is needed. The net effect results from a slight shift in the factors that either push or pull the process. If the homeostasis mechanisms shift slight to the right, the whole process shifts to the right. Built into the process, however, a readily accessible shift to left. If the process goes too far one way, it will shift back when exposed to the signals to shift back. Until recently, we believed that aging and senescence was always pushed forward, like time. It is reasoned that the injection of biologics, if present in the right quantities can overwhelm the “to-fro’ flow of degeneration and repair.
In short, in regen med, we are trying to create conditions that favor healing, repair and regeneration. Almost by definition, we cannot permanently shift the balance. Repeat treatments will be required. We have to train your body to shift towards pro-generation and regeneration and away for degeneration, one injection at a time.