الفهرس 
Acknowledgment
Inflammatory phaseOnly 14 pages are availabe for public view
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Abstract
Cell therapy was developed to overcome challenges in treatment of chronic ulcers, yet it has limitations including the cost of isolation and preparation of stem cells, patient non-compliance, difficulty of offloading and uncontrolled diabetes. Recently SVF and ADSCs, with or without the addition of fat grafts, PRP, growth factors, and/or hormones had gained popularity in different clinical applications. Fat grafting and stem cells have been commonly used in plastic surgery for regeneration and rejuvenation purposes.(179) Studies have published results obtained from using platelet-rich plasma (PRP) mixed with fat grafting in treating facial scars,(180) chronic lower-extremity ulcers,(181) and loss of substance on the lower limbs(182) and from applying SVF in post-traumatic lower extremity ulcers.(183, 184) PRP was observed to favor growth and restoration of fat volume when injected together as PRP enhances adipose tissue maintenance and survival.(185) Another application of ADSCs by new fat grafting method, named ‘nanofat grafting’, was proposed by Tonnard et al.(186) for skin rejuvenation and treating particular areas, such as eyelids, lips, or fine rhytids.(187) PRP and micrografts containing human follicle mesenchymal stem cells (MSCs) were used as a potential treatment for androgenetic alopecia with an evaluation of the biomolecular pathway.(188) Some authors have published studies employing fat grafts enhanced with SVF and ADSC, called in some cases ‘cell-assisted lipotransfer’ in aesthetic breast augmentation.(189, 190) Cervelli et al. used enhanced stromal vascular fraction (e-SVF) and fat grafting mixed with PRP in post-traumatic lower extremity ulcers. Studies documented that combined treatment with PRP, and insulin favors the chondrogenic and osteogenic differentiation of ADSCs.(191) In this study we used autologous adipose tissue to obtain SVF to use in treatment of different types of nonhealing ulcers. In the study group, 46 (92%) patients showed complete healing of the ulcer (12 (24%) after the first session, 27 (54%) after the second session, and seven (14%) after the third session), whereas in the control group, 30 (60%) patients showed complete healing (eight (16%) after the second debridement and 22 (44%) after the third debridement). In this study, we found that adipose tissue is a rich source of stem cells. This was shown by Kathrine et al. in 2007.(9) In addition, adipose tissue is an available source with minimal donor site morbidity and minimally invasive maneuver of harvesting, which was proven by Carbone et al. in 2017.(10) Furthermore, this study showed that stem cells can be isolated from adipose tissue in a laboratory with preservation of their viability to obtain stem cell suspension that can be injected into chronic ulcers of the same subject. Zuk et al. were the first to investigate whether human adipose could be an alternative source of MSCs. We obtained human adipose from liposuction aspirates and used collagenase to release stromal cells from the extracellular matrix by processing SVF, containing various types of cells, including ADSCs. Patients in whom we injected the autologous stem cells yielded from adipose tissue showed better healing rates in a shorter duration and better outcomes with fewer rates of infection. In the study group, 46 (92%) patients showed complete healing, whereas in the control group, only 30 (60%) patients showed complete healing. The improved healing in the study group was accompanied by high rates of stem cell viability (up to 92% with a mean of 75.43%).A significant reduction in healing duration was observed in the study group. The healing duration in the study group was 7.87 ± 2.50 weeks, whereas in the control group, it was 13.87 ± 2.84 weeks. A significant reduction in the infection rate was observed in the study group. Only three (6%) patients in the study group developed infection, whereas 14 (28%) patients in the control group developed infection (p = 0.000), which could be due to the biological pump activity of stem cells and enhancement of vascularity by angioneogenesis. We found that ADSCs can promote angiogenesis, secrete growth factors, regulate the inflammatory process, and differentiate into multiple cell types, making them a potential ideal therapy for chronic wounds (Figs. 1 and 2). Meng et al. and Tonchev et al. have agreed with this.(3, 192) The patients were followed up for 6 months after the end of treatment to assess the healing quality and recurrence. The source of adipose tissue in this study was abdominal subcutaneous fat. The same source was used by Lee at al., Marino et al., Bura et al., and Moon et al.(193-196) Concerning the method of delivery of stem cells to the ulcer, we used the injection of stem cell yield into the ulcer base and edges. Some studies have used intramuscular injection, including Lee et al. in 2012(193) and Bura et al. in 2014.(195) In 2019, Moon et al. have applied stem cells seeded in hydrogel.(196) In 2013, Marino et al. have used injection of isolated cells with the Celution System at the edges of the ulcer.(194) We recommend text that future studies in this area include analysis based on age. We also suggest the use of a Kaplan-Meier approach in longer follow-up studies. Healing in the control group greatly depended on the small surface area of the ulcer, unlike the study group in which no significant relationship was observed between healing and ulcer surface area. The study strengths include the large sample size of patients, variations in age of patients and ulcer etiology, high viability of obtained stem cells, and promising results.
We considered the use of adipose-derived stromal vascular fraction cells a successful method in treating chronic ulcers alongside off-loading during treatment and optimization of general condition. Adipose tissue is a rich source of stem cells with minimal donor site morbidity. Cell therapy was developed to overcome challenges in treating chronic ulcers, yet it has limitations, including the cost of isolation and preparation of stem cells, patient noncompliance, difficulty of off-loading, and uncontrolled diabetes. Adipose tissue is a rich source of stem cells. Proved to have good viability after harvesting and preparation for injection. Treatment of chronic ulcers using adipose-derived stromal vascular fraction cells resulted in acceleration of healing rates, improvement of skin quality after healing, improvement of re-epithelialization, granulation, inflammatory cells, and angiogenesis. The more the viability of stem cells obtained from lipoaspirate the more effective therapy and healing irrespective of ulcer surface area. Translational Perspective Our study represents a step in proving the important clinical applications of regenerative medicine as a substitute to traditional modalities of treatment specially in chronic medical problems. We investigated the efficacy of adipose-derived SVF in treatment of chronic nonhealing ulcers and proved the advantage of this modality over the traditional ones. Regenerative medicine solutions to chronic ulcers provide alternative to more invasive modalities carrying more morbidity to an already suffering patient. A lot of future work is to be done, including investigating the use of SVF or ADSCs, with or without fat grafting, PRP, growth factors, and hormones. Is there a need to separate the stem cell yield or it is enough to use the lipoaspirate directly? Is there a need to culture the stem cells or it is better to use fresh cells every time? Another question to be answered in future studies if there is a type of stem cells superior to the others to use in different applications of stem cells. Summary points chronic wounds represent a major problem in the medical field. New therapies should optimize wound healing, including cell therapies. Adult stem cells are the most used in regenerative medicine. Human fat obtained from human lipoaspirates contains multilineage stem cells, which could undergo adipogenesis, osteogenesis, chondrogenesis, and myogenesis in vitro and in vivo. Over the years, ADSC-based therapies have been tested and used in many clinical settings. Adipose-derived stem cells (ADSCs) are isolated as part of the aqueous fraction derived from enzymatic digestion of lipoaspirate known as the stromal vascular fraction (SVF). SVF is either used alone or in combination with fat grafts, PRP, growth factors, and/or hormones. This study was conducted to assess the efficacy of SVF in managing chronic nonhealing ulcers both clinically and histologically. A significant reduction in the infection rate was observed in the study group. Considering overall healing, in the study group, 46 (92%) patients showed complete healing of the ulcer, whereas in the control group, 30 (60%) patients showed complete healing. In the study group, healing was irrespective of the baseline surface area of the ulcer, unlike the control group where healing depended on the ulcer surface area. Histological examination of the biopsy samples obtained after treatment showed complete epithelization with maturation, collagen matrix maturation, little inflammation, and good angiogenesis. The patients with unhealed ulcers in the study group were associated with off-loading noncompliance or uncontrolled diabetes mellitus. Generally, cell therapy using autologous adipose-derived stromal vascular fraction cells is an effective method to use in patients with chronic non-healing ulcers. Alongside with optimization of patient’s general condition, offloading and good local wound care. The method has no morbidity and very simple for the patient.