Stem Cells Therapy

Balancing Safety & Efficiency

Stem Cells Therapy

Balancing Safety & Efficiency

Safety in the Use of Adipose-Derived Stem Cells- ADSCs

 The generalization of the term “Stem Cell” can lead to include useful treatments & therapies. The attitudes towards the use of stem cells for research or medical care vary from country to country,  in Germany, for example, the extraction of stem cells from human embryos is illegal while, in Britain is perfectly legal, but laws are strict. In many countries there is still no explicit laws designed to regulate research and treatment with human stem cells.

As most of arguments and controversies around the use of embryos is an ethical relation, scientists around the world are looking for other sources of stem cells.

The ideal source of stem cells used for regenerative medical applications should meet the following criteria:

  1. Can be found in large quantities (millions to billions of cells).
  2. Can be Easily obtainable, with minimal discomfort to the patients via a minimally invasive procedure
  3. Can be differentiated along multiple cell lineage pathways in a controllable and reproducible manner.
  4. Can be transplantable safely and effectively
  5. Can be manufactured in accordance with current Good Manufacturing Practice guidelines

The type of stem cells found in bone marrow of adults seems to be one possibility but, the adipose tissue-derived stem cells (ADSCs) can be considered to fulfill all these criteria. Today, ADSCs have come to be regarded as the ideal stem cell for regenerative clinical applications.

Ready-to-Use ADSC Pellet
(Non-cultured Adipose-derived Stem Cells-ADSCs)

     ADSCs today, regarded as the ideal stem cell for regenerative clinical applications since their yield upon isolation is so high that they do not require extensive manipulation before delivery. For this reason, Rasposio el al, concluded; there is no need for compliance with cell manufacturingin accordance with current Good Manufacturing Practice Guidelines. Restrictions are not applied in the case of non-substantial manipulation [Regulation (EC) No 1394/2007 of the European Parliament and of the Council]. ADSCs are considered as Advanced Therapy Medicinal Products.

 In 2015 the Committee for Advanced Therapies (CAT) are stated on the use of collagenase: ‘’Enzymatic release of cells from tissues & systemic administration have shown high accumulation of the cells into lungs, liver etc. Furthermore, there is growing evidence that cell surface proteins, their signalling etc. are impacted by the enzymatic treatments. However, the CAT retains the possibility for the Applicants to demonstrate, if the characteristics & structural & functional properties are not changed by the enzymatic dissociation, thus suggesting a non-substantial manipulation. Such a decision will be made on case by case basis and requires data from the Applicant.’’ So, the isolation of ASCs by means of collagenase digestion in a clinical setting is not regarded as extensive manipulation and hence it is not prohibited in Europe. 

Conversely, in the United States, enzymatically isolated ADSCs are regarded as more than just minimally manipulated and Cultured ADSCs are therefore classified as a drug. Consequently, their clinical application following enzymatic digestion is regulated by the Food and Drug Administration (CFR- Code of Federal Regulations Title Wq. Part 1271: Human Cells, Tissues and Cellular and Tissue-based Products, U.S. Food & Drug Administration, 2013). This implies the need for an Investigational New Drug application to be submitted by every surgeon who wishes to use enzymatically isolated ADSCs in clinical settings. However, the clinical application of ADSCs isolated using mechanical means during the same operative session falls under the jurisdiction of medical practice & is thus allowed. Therefore, the development of high-yield isolation processes for ADSCs with minimal handling would be highly desirable for clinical applications.

Further research and evaluation of the literature are mandatory, so that evidence of safety and effectiveness may inform clinical practice.

Cultured Adipose-derived Stem Cells- ADSC

ADSCs have been shown to be immune-privileged and more genetically stable in long-term culture, with a greater proliferative rate, than BmSCs. The discovery that ADSCs can readily be expanded and have the capacity to undergo adipogenic, osteogenic, chondrogenic, neurogenic and myogenic differentiation in vitro was a significant milestone in ADSC therapeutic applicability. To culture any stem cells for clinical applications, it should be;

  1. Easily obtainable.
  2. Yield sufficient numbers of cells for extensive cell culturing
  3. Be able to differentiate along multilineage pathways in a controlled and reproducible manner
  4. Be transplantable safely and effectively
  5. Be able to be manufactured in accordance with GMP guidelines (Misumi 2009).

Mesenchymal Stem Cells-MSCs whether BmSCs or ADSCs preparations should meet the criteria of MSCs preparation.  International Society for Cellular Therapy (ISCT) has proposed minimum criteria to define MSCs. These cells should:

  1. Exhibits plastic adherence
  2. Express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105& lack expression of CD14, CD34, CD45 and human leucocyte antigen-DR (HLA-DR) and
  3. Have the ability to differentiate in vitro into adipocyte (fat tissue), chondrocyte (cartilage tissue) and osteoblast (bone tissue).

These characteristics are valid for all MSCs, although few differences exist in MSCs isolated from various tissue origins. 

Cytometric analysis of adipose-derived stem cells (ASCs) has shown that these cells do not express CD31 and CD45, but do express CD34, CD73, CD105, and the mesenchymal stem cell marker CD90. ASCs have a differentiation potential similar to that of other mesenchymal stem cells as well as a higher yield upon isolation and a greater proliferative rate in culture than bone marrow-derived stem cells.

Today ADSCs considered the safest sources of stem cells therapy. The SVF which give us the ADSCs is expected to have an important role in medical healing and in dealing with chronic conditions and not only for plastic surgery applications because this treatment is simple to use, safe, and cost effective, it may provide many patients with a preferential alternative for treating conditions that would otherwise require more invasive and expensive procedures (e.g., total joint replacement). Stem cells from fat tissue are administered by a variety of techniques:

  1. Injected in a standard intravenous line
  2. Intra-articular placement
  3. Mixed with adipocytes for soft tissue augmentation (plastic surgery applications)
  4. Injected directly into the recipient bed (plastic surgery applications)

The last 2 methods of ADSCs methods of administration of SVF is used in plastic surgery indications and last 2 methodology is mostly safe and well tolerated.

The SVF isolation devices market is expanding for many years, and it is obviously important to check their efficacy before the transfer from bench to bedside. That what you need to check about it with your physician before considering the treatment. Also, you do need to check about authorization of the lab to work in your country and if the lab following any international standard role for preparation and banking of your ADSCs.

If you are considering stem-cell therapy in the United Arab Emirates, ask about the approval of the type of the treatment by local health authorities; MOH (Ministry of Health), DHA (Dubai Health Authority) or DHCC (Dubai Healthcare City), as there are many SVF therapy (Ready-to-Use) mechanical and enzymatic. For enzymatic SVF preparation, you need to ckeck about approval by local authority to use it in UAE.  

What about the cultured ADSCs, Is there a role to assure the safety of ADSCs that has been prepared in a lab before return it back into our body?

Cultured Mesenchymal Stem Cells-MSCs whether BmSCs or ADSCs preparations should meet the criteria of MSCs preparation.  International Society for Cellular Therapy (ISCT) has proposed minimum criteria to define MSCs. These cells should:

  1. Exhibits plastic adherence
  2. Express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 & lack expression of CD14, CD34, CD45 and human leucocyte antigen-DR (HLA-DR) 
  3. Have the ability to differentiate in vitro into adipocyte (fat tissue), chondrocyte (cartilage tissue) and osteoblast (bone tissue).

These characteristics are valid for all MSCs, although few differences exist in MSCs isolated from various tissue origins

Read More-References:

  1. A. Salibian, A.D. Widgerow, M. Abrouk, G.R. Evans, Stem cells in plastic surgery: a review of current clinical and translational applications, Arch. Plast. Surg. 40 (2013) 666675.
  2. ASPS & ASAPS. Joint ASPS & ASAPS position statement: stem cells and fat grafting. Click here for PDF
  3. The American Society of Plastic Surgery, ASPS Executive Committee May, 2011. Click Here for PDF
  4. Committee for Advanced Therapies (CAT), Overview of Comments Received on ‘Reflection Paper on Classification of Advanced Therapy Medicinal Products’ (EMA/CAT/600280/2010 rev. 1), 2015.
  5. Dominici, K. Le Blanc, I. Mueller et al., (2006) “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, Click Here for PDF
  6. A. Banyard, A.A. Salibian, A.D. Widgerow, G.R. Evans, Implications for human adipose-derived stem cells in plastic surgery, J. Cell Mol. Med. 19 (2015) 2130.
  7. Raposio, G. Caruana, S. Bonomini, G. Libondi, A novel and effective strategy for the isolation of adipose-derived stem cells: minimally manipulated adipose-derived stem cells for more rapid and safe stem cell therapy, Plast. Reconstr. Surg. 133 (2014) 14061409.
  8. Raposio, N. Bertozzi, S. Bonomini, et al., Adipose-derived stem cells added to platelet-rich plasma for chronic skin ulcer therapy, Wounds 28 (2016) 126131.
  9. Reoseti, M. Serra, D. Tigani, et al., M. Cell manipulation in autologous chondrocyte implantation: from research to cleanroom, Chir. Organi Mov. 91 (2008) 147151.
  10. Higuci A., C.W. Chuang, Q.D. Ling, et al., Differentiation ability of adiposederived stem cells separated from adipose tissue by a membrane filtration method, J. Memb. Sci. 366 (2011) 286294.
  11. Lander, E. B., Berman, M. H., & See, J. R. (2015). Safety of stromal vascular fraction cells applications in chronic pain. Techniques in Regional Anesthesia and Pain Management, 19 (1-2), 10-13. doi: 10.1053/j.trap.2016.09.002 Click Here for PDF
  12. Rodriguez, J., Pratta, A. S., Abbassi, N., Fabre, H., Rodriguez, F., Debard, C., . . . Mojallal, A. (2017). Evaluation of Three Devices for the Isolation of the Stromal Vascular Fraction from Adipose Tissue and for ASC Culture: A Comparative Study. Stem Cells Int, 2017, 9289213. doi: 10.1155/2017/9289213 Click Here for PDF
  13. S. Food and Drug Administration, CFR- Code of Federal Regulations Title wq. Part 1271: Human Cells, Tissues and Cellular and Tissue-based Products, U.S. Food & Drug Administration, 2013.
  14. A.A. Salibian, A.D. Widgerow, M. Abrouk, G.R. Evans, Stem cells in plastic surgery: a review of current clinical and translational applications, Arch. Plast. Surg. 40 (2013) 666e675.

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