Scientific Publications

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• Novel breast reconstruction procedure.

  Authors:

  Keizo Sugimachi, Kaoru Kitamura, Seiichi Teramoto, Masaki Mori

   

  Publication:

  Japanese Journal of Cosmetic Surgery. 2008 Sept. Vol. 30, No. 3 (p. 151-160) offprint / [Original in Japanese Language/English Language Translation]

   

  Abstract:

  Breast conservation surgery as the treatment for breast cancer typically results in postoperative breast asymmetry. Reconstructive surgery is problematic because whole breast irradiation commonly results in severe fibrosis and atrophy of the breast tissue and the underlying chest wall. Currently, there are no clinically relevant techniques to reconstruct these defects.
  We have tentatively tried a new reconstructive technique using a combination of autologous adipose tissue and concentrated autologous adipose tissue-derived stem and regenerative cells for patient who received partial mastectomy for breast cancer since May 24, 2006. There was no rejection nor infection, and also, fifteen patients out 19 (78.9%) were satisfied with the result of newly devised breast reconstruction after six months follow up.
  In this procedure, we have utilized the automated CelutionTM System (Cytori Therapeutics Inc., San Diego, CA, USA) for rapid extraction and concentration of adipose tissue-derived, stem and regenerative cells. As there were no adverse effects nor complications, our new technique is deemed to be safe and feasible. This treatment may have the potential to address a currently unmet clinical need in thousands of patients who received partial mastectomy for breast cancer. 
   

• Co-transplantation of Adipose tissue-derived Regenerative Cells Improves Long-term Retention of Fat Graft.

  Authors:

  Min Zhu, John K. Fraser, Zhengyu Zhou, Yan Chen, Ronda Schreiber, Marc H Hedrick, John T Ransom, Hai-Chien Kuo

  Publication: 

  Abstract 4072 presented at San Antonio Breast Cancer Symposium. Dec. 2007

  Poster:

  Background: Long-term persistence of large and small volume autologous fat grafts for soft tissue defects is hard to maintain. One of the potential mechanisms for graft loss may be a lack of adequate vascularization within the transplant. Adipose tissue-derived regenerative cells (ADRCs) contain a mix of cells, including vascular-related endothelial and smooth muscle cells and their progenitors, fibroblasts, preadipocytes, and primitive stem cells. Here we hypothesize ADRCs can improve the long-term retention of fat grafts by increasing the vascularization within the grafted tissue when co-transplanted.
  Methods: ADRCs were isolated by standard proteolytic digestion of the inguinal fat derived from ROSA26 mice, a transgenic strain expressing beta-galactosidase (LacZ). Adipose tissue was collected from wild-type syngeneic donor mice and finely minced. Minced adipose tissue was subsequently supplemented with either ADRCs or saline and transplanted into the subcutaneous tissue of the skull in syngeneic, wild-type recipients (n=24 per group) using a modified Coleman technique. At six and nine months after transplantation, grafts were harvested and weighed. Histological examinations and beta-gal staining were performed to track donor-derived cells in the grafts. In a second study human fat grafts (with and without supplementation of human ADRCs) were implanted into SCID mice that had been implanted with human breast cancer cells (either ER+ MCF-7 cells or ER- MDA-MB-231 cells). Tumor size was measured at eight weeks.
  Results: Most grafts were grossly evident at six months and nine months post transplantation in both experimental groups. The mean weight of the grafts supplemented with ADRCs was two times greater than that of the grafts without ADRCs (p=0.019 and p=0.034 at 6 and 9 months, respectively). Histological examinations revealed that the grafts supplemented with ADRCs contained less fibrous tissue than those without ADRCs, suggesting a better quality of the grafts with ADRCs. We also observed engraftment of donor cells in remodeled adipose tissue and incorporation of donor cells into blood vessels. ADRCs supplementation had no effect on the in vivo growth of the human breast cancer tumor lines.
  Conclusion: ADRCs can improve the long-term retention and the quality of subcutaneous fat grafts when co-transplanted. Direct incorporation or differentiation of ADRCs into vasculature is likely one of the contributing mechanisms. Other potential mechanisms by which ADRCs may improve the retention of fat grafts are currently under investigation in our laboratory. ADRCs supplementation does not appear to increase the risk of local relapse. Our study here demonstrates the ability of ADRCs to enhance the long-term retention of fat grafts and suggests utility of fat plus ADRCs as a therapy in indications like breast reconstruction in breast cancer patients with lumpectomy or partial mastectomy.
  
  

• Adipose-derived stem and progenitor cells as fillers in plastic and reconstructive surgery.

  Authors:

  Moseley TA, Zhu M, Hedrick MH

   

  Publication:

  Plast Reconstr Surg. 2006 Sep; 118 (3 Suppl): 121S-128S

   

  Abstract:

  Plastic surgeons are keenly aware of the principle "replace like with like." This principle underlies much of the rationale behind the clinical use of autologous fat transplantation, despite the procedure's drawbacks. Autologous fat transplantation is frequently used for a variety of cosmetic and reconstructive indications not limited to posttraumatic defects of the face and body, involutional disorders such as hemifacial atrophy, sequelae of radiation therapy, and many aesthetic uses such as lip and facial augmentation and wrinkle therapy. However, the limitations of fat transplantation are well known, particularly the long-term unpredictability of volume maintenance. Regenerative cell-based strategies such as those encompassing the use of stem cells hold tremendous promise for augmentation of the soft-tissue space. Preclinical studies and early clinical series show that adipose-derived stem cells offer the possibility of finally fulfilling the key principle of replacing like with like as an aesthetic filler, without the drawbacks of current technology.

• Autologous fat transfer for facial recontouring: is there science behind the art?

  Authors:

  Kaufman MR, Miller TA, Huang C, Roostaien J, Wasson KL, Ashley RK, Bradley JP

   

  Publication:

  Plast Reconstr Surg. 2007 Jun; 119(7): 2287-96.

   

  Abstract:

  BACKGROUND: Clinical use of autologous fat grafts for facial soft-tissue augmentation has grown in popularity in the plastic surgery community, despite a perceived drawback of unpredictable results. METHODS: The authors' review of the literature and their current techniques of autologous fat transfer focused on (1) the donor site, (2) aspiration methods, (3) local anesthesia, (4) centrifugation and washing, (5) exposure to cold and air, (6) addition of growth factors, (7) reinjection methods, and (8) longevity of fat grafts. RESULTS: Clinical experience and basic science data showed a slight preference for the following: harvesting abdominal fat with "nontraumatic," blunt cannula technique, preparation by means of centrifugation without washing or addition of growth factors, and immediate injection of small amounts of fat by means of multiple passes. Quantitative evidence of clinical fat survivability and predictability of volume restoration does not exist, yet reports of patient satisfaction with this procedure do. Clinicians report the need for revisionary procedures to optimize results. CONCLUSIONS: Although there is an increased trend in replacement of soft-tissue volume with autologous fat transfer, the literature fails to provide definitive evidence of fat survival. A large-scale clinical assessment using three-dimensional volumetric imaging would provide useful outcome data.

• Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells.

  Authors:

  Rigotti G, Marchi A, Galiè M, Baroni G, Benati D, Krampera M, Pasini A, Sbarbati A

   

  Publication:

  Plast Reconstr Surg. 2007 Apr 15; 119(5): 1409-22; discussion 1423-4
  
  Abstract:

  BACKGROUND: There is evidence that stem cells contribute to the restoration of tissue vascularization and organ function. The objective of this study was to assess the presence of adipose-derived adult stem cells left in their natural scaffold in the purified lipoaspirate and to assess the clinical effectiveness of lipoaspirate transplantation in the treatment of radiation side effects. METHODS: This study was designed beginning with surgical procedures in 2002 and envisaging a continuous patient follow-up to 31 months. Twenty consecutive patients undergoing therapy for side effects of radiation treatment with severe symptoms or irreversible function damage (LENT-SOMA scale grade 3 and 4) were enrolled. Purified autologous lipoaspirates (60 to 120 cc) taken from a healthy donor site were administered by repeated low-invasive computer-assisted injection. Therapy outcomes were assessed by symptoms classification according to the LENT-SOMA scale, cytofluorimetric characterization, and ultrastructural evaluation of targeted tissue. RESULTS: In the isolated stromal vascular fraction of 2 cc of human lipoaspirate, cells with mesenchymal stem cell physical properties and immunophenotype were in average 1.07 +/- 0.5 percent (n = 4), with a clonogenic fraction of 0.139 percent. At least 1.02 x 10(3) colony-forming units-fibroblast were present in each lipoaspirate. Ultrastructure of target tissue systematically exhibited progressive regeneration, including neovessel formation and improved hydration. Clinical outcomes led to a systematic improvement or remission of symptoms in all evaluated patients, including otherwise untreatable patients exhibiting initial irreversible functional damage. CONCLUSIONS: This surgical procedure is a low-invasive therapeutic approach for resolving the late side effects of radiotherapy. According to the proposed hypothesis of the ischemic nature of radiolesions, treatment with lipoaspirate transplantation is potentially extended to other forms of microangiopathies.

• Multilineage cells from human adipose tissue: implications for cell-based therapies.

  Authors:

  Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH

   

  Publication:

  Tissue Eng. 2001 Apr; 7(2): 211-28

   

  Abstract:

  Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.

• The growing importance of fat in regenerative medicine.

  Authors:

  Strem BM, Hedrick MH

   

  Publication:

  Trends Biotechnol. 2005 Feb; 23(2): 64-6

   

  Abstract:

  A recent publication by Michael Longaker and colleagues represents a landmark for the use of adipose tissue as a source of cells for tissue regeneration. The authors investigated the ability of adipose tissue-derived cells (ADCs) to regenerate critical size calvarial (superior portion of the skull) defects in mice by using a novel osteoconducive apatite-coated Poly-lactic-co-glycolic acid (PLGA) scaffold for cell delivery. Direct comparison of this osteogenic ability was performed with bone marrow stromal cells and juvenile calvarial-derived osteoblasts.

• Adipose-derived cells.

  Authors:

  Meliga E, Strem BM, Duckers HJ, Serruys PW

   

  Publication:

  Cell Transplant. 2007; 16(9): 963-70

   

  Abstract:

  Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 10(6) stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebo-controlled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI.

• Improved viability of random pattern skin flaps through the use of adipose-derived stem cells.

  Authors:

  Lu F, Mizuno H, Uysal CA, Cai X, Ogawa R, Hyakusoku H

   

  Publication:

  Plast Reconstr Surg. 2008 Jan; 121(1): 50-8

   

  Abstract:

  BACKGROUND: Flap necrosis caused by inadequate blood supply is a common postoperative complication in reconstructive surgery. Because a putative stem cell population within the adipose tissue has been found to possess angiogenic potential, the authors sought to determine whether these cells might selectively induce neovascularization and increase the viability of random pattern skin flaps. METHODS: Adipose-derived stem cells were isolated from the inguinal fat pads of ICR mice and expanded ex vivo for three passages. After the elevation of cranially based random pattern skin flaps (3 cm long and 1 cm wide), 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI)-labeled adipose-derived stem cells were then injected into the pedicle base (group A) or 1.5 cm distal to the pedicle (group B). Medium containing no adipose-derived stem cells, mature adipocytes, or basic fibroblast growth factor were injected in three other control groups separately (n = 10 for each group). Millimetric measurements were taken at postoperative day 7 for evaluation of flap viability. Specimens were harvested for histologic analyses. RESULTS: Adipose-derived stem cells led to a statistically significant increase in flap viability in both group A and group B compared with the control and the adipocyte groups. Histologic examination also demonstrated a statistically significant increase in capillary density in both group A and group B. Moreover, some of the endothelial cells were stained positively for DiI. CONCLUSIONS: These findings suggest that adipose-derived stem cells have a potential for enhancing the blood supply of random pattern skin flaps. This mechanism might be both the direct differentiation of adipose-derived stem cells into endothelial cells and the indirect effect of angiogenic growth factor released from adipose-derived stem cells.

• Characterization of adipose tissue-derived cells isolated with the Celution system.

  Authors:

  Lin K, Matsubara Y, Masuda Y, Togashi K, Ohno T, Tamura T, Toyoshima Y, Sugimachi K, Toyoda M, Marc H, Douglas A

   

  Publication:

  Cytotherapy. 2008; 10(4): 417-26

   

  Abstract:

  BACKGROUND: The therapeutic potential of using stem cells is tremendous. Mesenchymal stromal cells (MSC) have now been isolated in various tissues including bone marrow (BM), muscle, skin and adipose tissue. Among them, adipose tissue could be one of the most suitable cell sources for cell therapy, because of its easy accessibility, minimal morbidity and abundance of stem cells. The large numbers of stem cells in adipose tissue means that clinically relevant stem cell numbers could be extracted from the tissue, potentially eliminating the need for in vitro expansion. To utilize these characteristics of adipose tissue fully, Cytori Therapeutics Inc. has developed a closed system called Celution to isolate and concentrate stem cells and regenerative cells automatically from adipose tissue. METHODS: Adipose tissue-derived cells were isolated using the Celution system. The output from the Celution was characterized using multicolor FACS analysis with CD31, CD34, CD45, CD90, CD105 and CD146. The multidifferentiation potential of the cells was analyzed using adipogenic and osteogenic media. RESULTS: Our results showed that cells from the Celution are composed of heterogeneous cell populations including adipose-derived stem cells (ASC) (CD31- CD34+ CD45- CD90+ CD105- CD146-), endothelial (progenitor) cells (CD31+ CD34+ CD45- CD90+ CD105- CD146+) and vascular smooth muscle cells (CD31- CD34+ CD45- CD90+ CD105- CD146+). We also confirmed the output contains cells able to differentiate into adipogenic and osteogenic phenotypes. Our results show that cells isolated with the Celution and manually are equivalent. DISCUSSION: Cells from adipose tissue can be processed by Celution within the time frame of a single surgical procedure. This system could provide a 'real-time' treatment setting that is cost-effective and safe.