Journal of Stem Cells Research Development & Therapy Category: Medical Type: Review Article
Autologous Stromal Vascular Fraction: A New Era of Personal Cell Therapy
- Elliot B Lander1*, Mark H Berman2
- 1 California Stem Cell Treatment Center, Cell Surgical Network Inc., 72780 Country Club Drive #301, Rancho Mirage, California, United States
- 2 California Stem Cell Treatment Center, Cell Surgical Network Inc., California, United States
*Corresponding Author:Elliot B Lander
California Stem Cell Treatment Center, Cell Surgical Network Inc., 72780 Country Club Drive #301, Rancho Mirage, California, United States
Received Date: Nov 16, 2018 Accepted Date: Dec 03, 2018 Published Date: Dec 19, 2018
HISTORY OF SVF
Mesenchymal cells derived from fat have apparently been studied for several decades but in 2001 Zuk PA et al., at the UCLA laboratory for regenerative bioengineering and repair formally described them when they determined that a population of stem cells could be isolated from lipoaspirate processed from human adipose tissue via liposuction . The investigative team noted that these cells could be maintained in-vitro for extended periods and that the cells appeared to be of mesenchymal origin. The following year they published a second paper continuing their research and showing isolation of a putative stem cell population from human adipose tissue containing stroma . In 2002, Stafford KM et al., showed that adipose derived human stem cells can be induced to undergo neuronal differentiation and were ideal for tissue regeneration . The cells appeared to have particular capability of forming cardiomyocytes and also appeared to be effective in mitigating autoimmune conditions. Froehlich H et al., at Mayo Clinic reported that adipose tissue is also an abundant source of endothelial cells including stem and progenitor cells . These cells had excellent angiogenic properties both in-vitro and in-vitro and they apparently had the ability to rapidly improve re-endothelialization. Over the next few years, hundreds of publications have confirmed and described similar results demonstrating the presence and utility of mesenchymal stem cells found in adipose tissue.
Despite many elegant articles coming from laboratory studies, the scientific history of stromal vascular fraction is truly rooted in the cosmetic surgery world since the science was driven by a need to improve fat grafting. Although cosmetic and reconstructive fat transfers had significant functional and cosmetic advantages, limitations included unpredictable and often non-sustainable outcomes. The concept of cell assisted lipo-transfer to improve cosmetic outcomes developed when it became apparent that if you combine a free fat graft with stromal vascular fraction derived from fat, the stem cell rich environment stimulated by hypoxic transplant conditions appeared to improve the long-term viability of the transferred fat tissue . Nevertheless, it became apparent during early clinical experience of using stromal vascular fraction that it could also be used for therapeutics and the utility extended far beyond cosmetics.
ISOLATION OF SVF
CSN as a clinical research organization has accumulated safety data on over 9500 personalized surgical procedures performed under IRB as off all 2018 without a single infection caused by adulterated processing of SVF. While SVF in humans is most commonly used clinically as an autologous product during a point of care procedure, notably, on rare occasions (e.g. special circumstances with a primary relative in which the patient cannot undergo the liposuction procedure) allogeneic donated SVF may also be used for cell therapy.
CONTENT OF SVF
Although there are a variety of methods for obtaining adipose derived stem cells, the combination of liposuction and collagens enzyme is particularly efficient. Together they not only separate cells from collagen but they also release cells from the vascular component of stromal vascular fraction and this likely provides the most variety and quality of stem cells. CSN contracted independent laboratories have performed flow cytometric immuno-phenotyping of multiple samples of autologous stromal vascular fraction demonstrating four distinct robust stem cell lines in varying ratios including mesenchymal stem cells, hematopoietic stem cells, endothelial progenitor cells, and pericyte (lying on top of blood vessels) progenitor cells , and a number of non-progenitor cells such as T-reg cells, macrophages, epithelial cells, and red and white blood cells as well as a rich soup of cytokines. Similar findings have been reported in previous studies of SVF composition  IFATS and ISCT reviewed the literature and published a position paper defining SVF as containing cells that are phenotypically identified by the following surface antigen markers: CD45-, CD 235a-, CD31-, CD34+, CD13+, CD73+, CD90+ CD105+ .
The cell markers help define international standards and reproducible parameters when evaluating the literature but much more important is to understand that SVF is not just adipose tissue but mesenchymal supporting tissue found in and around the adipose layer. See Michelek’s description of SVF from his paper summarizing the Czech Republic experience with 1856 intra-articular SVF injections on 1128 patients.
In the vast majority of scientific publications only the term adipose tissue is used, but the true source of SVF cells is not the adipose part but only the stromal (i.e., loose connective tissue) part of the fat obtained typically by liposuction. Histologically, the fat lobules are surrounded by a loose connective tissue and the SVF cells reside in the loose connective tissue that also home capillaries and small vessels. Stroma is a broadly used term for the loose connective tissue that contains mesenchymal stem cells and other cells like fibroblasts, macrophages, adipocytes, mast cells and leukocytes. Synovia of articulated joints is also intimately associated with the loose connective tissue which is homologous to the loose connective tissue of the adipose tissue .
MECHANISM OF ACTION OF SVF
CLINICAL USE OF SVF
The concept behind deployment of SVF is to amplify of our natural repair system by exogenously introducing increased numbers of autologous healing cells as a biologic “surge” in proximity to the damaged tissue. The SVF cells have always been present and capable of repair but not bio-accessible since they were locked in a sub-cutaneous collagen matrix. The subcutaneous collagen matrix locks them in place where they heal lacerations and respond to caloric challenge by making pre-adipocytes. They also have numerous endocrine functions and fat is now officially described as an endocrine organ as opposed to an inert tissue that stores fat as was once previously thought . The ability to liberate these cells in the form of SVF and exploit their profound healing properties will ultimately expand our traditional sources of healing and synergize with any other medical treatment physicians and surgeons currently provide.
Considering the “cell factor” efforts have been underway to determine which stem cells are most effective for a particular condition. Despite many claims that certain types of stem cells are greatly superior to those from alternate sources, little proof exists that there are great differences between sources of non-engineered progenitor stem cells if you compare the cells on a functional basis. Any mammalian stem cells regardless whether the source is from bone marrow, neonatal tissues, or adipose likely have relatively similar differentiation and proliferative functional capabilities. All cells can probably function similarly to mitigate cellular damage although they may have slightly different antigenic cell markers. Several in vitrostudies have been published supposedly showing that one type of stem cell is seemingly better than another type for certain purposes but many of these studies are industry biased and used to market a particular product. It remains unclear whether such cell source differences are accurate in vitro and clinically relevant. Further, most laboratory based studies on SVF have been done with fat obtained following traditional liposuction. Such studies often show sub-optimal adipose stem cell activity and may even suggest that adipose stem cells may be inferior to other biologic sources. Unfortunately, such cell samples are typically withdrawn using tumescent local anesthesia, most frequently, lidocaine, which is cytotoxic and the actual reason for the perceived poor cell function. This issue can be essentially eliminated by using a sub-dermal method of local anesthesia and rapid procurement to isolate the adipose tissue for production of SVF. Ultimately, the “cell factor” which distills down to how can we get large quantities of healthy stem cells, extract them and re-deploy them into target tissue in a timely, safe and sterile manner.
Having addressed the “cell factor,” it is vital to underscore the importance of the “patient factor” to the clinical success of cell therapy. Clinically, based on our nearly 10,000 patient experiences, we’ve learned that the state of the injury is probably the most important determinant for success in treatment. This is the likelihood that the target tissue regenerative milieu will support the homing and activation of the repair cells. Under these circumstances, very extensive and very acute injuries giving off “loud damage signals” will likely be more successful with cell therapy than chronic indolent smoldering low-grade “quiescent” degenerative problems. Clinical efforts can be made to influence the “patient factor” to optimize cell therapy and one example is the addition of low intensity shock waves to SVF for the cell therapy treatment of erectile dysfunction (a relatively indolent non-inflammatory condition). The concept is to make the penile tissue signals “louder” in an iatrogenic attempt to enhance the homing and activation of exogenously supplied stem cells in the form of autologous SVF .
As far as autologous versus allogeneic sources of cells, it would seem prudent to use autologous cells if at all possible since they share the person’s own DNA and if prepared in a sterile manner, there’s no risk of transmissible disease from another source. As far as bone marrow versus adipose derived cells, a mini liposuction can be done essentially painlessly yielding higher quantities of stem cells. Furthermore, older and sicker patients tend to have suppressed bone marrow function. This issue may be less important in younger people with orthopedic injuries but in much older patients with systemic disease, the use of stem cells from depleted bone marrow become less compelling. Adipose stem cells aren’t constantly replicating as are bone marrow cells. Adipose stem cells replicate under the pressure of increased caloric intake, under the influence of certain medications, such as steroids, or when signaled by a dying or injured adipose cell. This suggests that these cells are replicating a few dozen times during most people’s lifetime, something rather insignificant for the life of a cell.
SAFETY OF SVF
Regarding human safety, SVF continues to have superb safety rates in clinical use. In one review of over 1000 clinical trials on stem cells, the conclusion was that there were no publications that present stem cells as harmful and that it is therefore nonessential to repeat clinical trials for non-expanded autologous stem cell therapies . Arguably, there is no known “drug” as safe as your own personal SVF or stem cell products which can never be considered a “drug” product.
Interestingly, human experience with isolated SVF has been described in the last 17 years but technically the clinical use of SVF goes back decades. We now know that every liposuction procedure mechanically dissociates the adipose cells so that every liposuction and cosmetic lipo-transfer procedure performed over the last 30 years has freely circulating SVF cells. This dilute SVF product has been serendipitously used in tens of thousands of procedures. Thus, this indirect clinical evidence of safety is actually quite compelling and it is important to remember that autologous SVF and SVF-like biological are not brand new and not risky to patients.
Our group has published safety data on over 1698 deployments in 1524 patients . This included regional and intravenous deployment of SVF. We have learned that intravenous infusions are safe with only one case of pulmonary embolism (in a wheelchair bound patient not directly related to cell therapy) after over 9500 procedures. We have also determined that IV infusions improve clinical outcomes since the cells “home” naturally to all parts of the body that are damaged based on cytokine and damage signal beacons. This is a natural targeting system and makes the cells “smart.” When you combine intravenous systemic injection with physician directed regional deployments, such as intra-articular or into an organ, efficacy outcomes appear to be optimized. We recommend that SVF be prepared in such a way that it is filtered through 100 µm filters to make intravenous infusion safe.
CLINICAL TRIALS OF SVF
The other fundamental issue regarding the study of SVF is that funding for well performed trials has been lacking. Although autologous point of care procedures generate revenue for the physician performing the procedure, there is no scaled up pharmacologic business model for SVF that is attractive to a pharmaceutical company seeking to develop a new drug since SVF as an autologous unique biologic could never be patented and then bottled and commercialized for distribution. This lack of business interest has trickled down into a lack of grants and funding and a requirement for most clinicians doing SVF research to rely on patient funding models and occasionally on charity.
REGULATION OF SVF
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Citation:Lander EB, Berman MH (2018) Autologous Stromal Vascular Fraction: A New Era of Personal Cell Therapy. J Stem Cell Res Dev Ther 4: 011.
Copyright: © 2018 Elliot B Lander, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.