Stromal Vascular Fraction Therapy Research Articles

Combined Stromal Vascular Fraction and Fractional CO2 Laser Therapy for Hypertrophic Scar Treatment: A Systematic Review and Meta-Analysis.

Hypertrophic scars (HTSs) result from aberrant wound healing processes, leading to raised, thickened tissue with functional discomfort and cosmetic concerns. Current treatments, including corticosteroid injections and laser therapy, have limitations. Stromal vascular fraction (SVF) therapy and CO2 laser treatment offer promising avenues, with SVF therapy showing regenerative potential and CO2 laser therapy promoting precise tissue removal and wound healing. This study aims to investigate the combined application of SVF therapy and CO2 laser treatment for HTS, aiming to enhance treatment efficacy, tissue remodeling, and aesthetic outcomes, ultimately improving patient satisfaction in HTS management. PubMed, Scopus, Embase, and Web of Science databases have been searched for relevant studies. The "R" software (version 4.3.1) along with the "tidyverse" and "meta" statistical packages utilized to analyze data related to the efficiency of this combined method. A random-effects model was fitted to the data. For each study, continuous outcomes were pooled by calculating the standardized mean difference, along with their 95% confidence intervals. The assessment of heterogeneity utilized the I2 and chi-squared tests, applying the random effect model. Six articles fulfilled our inclusion criteria and were included in our review. Results from the pooled analysis of Vancouver Scar Scale (VSS) scores across three included studies indicated a significant impact of the SVF+CO2 method on VSS scores post-treatment (SMD=-3.0144; 95% CI:-4.3706 to -1.6583, p<0.0001). However, analysis of transepidermal water loss levels before and after treatment showed no significant difference (SMD=-2.7603; 95% CI: -6.8729 to 1.3522; p=0.1883). Comparatively, in a pooled analysis of two studies, the combined SVF+CO2 method demonstrated superior efficacy in VSS scores compared to other methods (SMD= -1.3573; 95% CI: -2.2475 to -0.4672, p = 0.0028), with moderate heterogeneity across studies (I^2=23.0%, p = 0.2545). The combined application of SVF and CO2 laser treatment shows significant promise in improving hypertrophic scars' appearance and texture. The SVF+CO2 method demonstrates superior efficacy compared to other modalities, suggesting its potential as a valuable therapeutic approach for hypertrophic scar management. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ultrasound-Guided PRP and SVF Therapy Shows Sustained Improvement in Severe Knee Osteoarthritis: A 12-Month Retrospective Study.

BACKGROUND Knee osteoarthritis (OA) is a chronic disease caused by cartilage degeneration in the joint accompanied by joint deformities, pain, and stiffness. This study assessed the changes over time in the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and Visual Analog Scale (VAS) values of patients after the combined application of stromal vascular fraction (SVF) and platelet-rich plasma (PRP). MATERIAL AND METHODS A retrospective clinical study was designed. Thirty-four patients (8 males, 26 females, mean age 65.21±10.71, range 30-83 years) with pain due to knee osteoarthritis received SVF and PRP between 2019 and 2020. During and after the procedure, ultrasound-guided intra-articular spread was checked. RESULTS PRP+SVF injection provided significant improvement in the clinical symptoms of the patients measured according to their VAS and WOMAC scores, and this improvement continued until the twelfth month. The change in VAS scores of the patients was 1.76±1.18 (P=0.000) in the first month, 1.50±1.46 (P=0.000) in the sixth month, and 1.53±1.41 (P=0.000) in the twelfth month. VAS scores decreased 6.6 to 1.6 point at the end of the twelfth month. The WOMAC scores of the patients were 23.20±12.12 (P=0.000) in the first month, 19.48±12.0 (P=0.000) in the sixth month, and 20.01±10.48 (P=0.000) in the twelfth month. WOMAC scores decreased 51.99 to 20.48 point at the end of the twelfth month. CONCLUSIONS Applying ultrasound-guided PRP+SVF injection into the knee joint once in OA patients improved VAS and WOMAC scores.

Clinical phase I/II trial of SVF therapy for cartilage regeneration: A cellular therapy with novel 3D MRI imaging for evaluating chondral defect of knee osteoarthritis.

Background: The clinical applications of stromal vascular fraction (SVF) therapy for osteoarthritis (OA) have attracted academic and clinical attention. However, data of the effects of stromal vascular fraction therapy on regeneration of degenerated cartilage are limited in the literature. Meanwhile, there is a great need for a simple and non-invasive evaluation method to analyze the changes of joint cartilage qualitatively and quantitatively in clinical trials. This study entitled "stromal vascular fraction Therapy for Human Knee Osteoarthritis" was registered in ClinicalTrial.gov # NCT05019378. Materials and Methods: We designed and conducted a single center, open labeled clinical phase I/II study, and 6 osteoarthritis patients with both knee cartilage defect I-II were enrolled in this study. The two knees of each patient were randomly assigned to autologous stromal vascular fraction treatment group or non-treatment control group to evaluate the safety and therapeutic effect of stromal vascular fraction therapy for human knee osteoarthritis. We have also established a novel protocol to provide 3D MRI imaging for human knee cartilage enabling us to qualitatively and quantitatively evaluate cartilage degeneration and regeneration in this study. Results: The qualitative and quantitative evaluation of 3D Magnetic Resonance Imaging (MRI) imaging of knee cartilage demonstrated that the stromal vascular fraction therapy reduced the cartilage defects; and significant increase of cartilage value both in defect cartilage area and whole cartilage area of treated group and significant increase of thickness and area of both femoral and tibia cartilage in vertical sections of the stromal vascular fraction treated Group at 12 and 24W post treatment in cartilage defect I-II osteoarthritis patients. Conclusion: This clinical phase I/II study indicated that stromal vascular fraction therapy is a safe clinical procedure and provided evidence that the stromal vascular fraction therapy significantly facilitated cartilage regeneration, opening the opportunity to a phase III trial investigating authentic efficacy of the procedure. This study is the first qualitative and quantitative evaluation of the efficacy of autologous stromal vascular fraction cellular therapy on cartilage regeneration. Through early and definite diagnosis of knee osteoarthritis patients, and providing safe and efficient therapy to facilitate cartilage regeneration, we will be able to control or reverse cartilage degeneration and completely change the epidemiology of osteoarthritis worldwide.

Safety of Stromal Vascular Fraction Cell Therapy for Chronic Kidney Disease of Unknown Cause (Mesoamerican Nephropathy)

Chronic kidney disease of unknown cause (CKDu), also known as Mesoamerican nephropathy, typically presents as an ischemic nephropathy with chronic tubulointerstitial fibrosis in normotensive patients, rapidly progressing to kidney failure. In this first-in-human, open-label, safety study, we followed 18 patients with CKDu (stages 3-5) for 36 months after receiving a single infusion of angiogenic/anti-fibrotic autologous adipose-derived stromal vascular fraction (SVF) cells into their kidneys bilaterally via renal artery catheterization. SVF therapy was safe and well tolerated. There were no SVF-related serious adverse events and no procedural complications. Color Doppler evaluation at 2 months demonstrated increased perfusion to the interlobar and/or arcuate artery levels in each kidney evaluated (36/36) with a reduction in resistance index at the hilar artery (35/36) kidneys. Beyond 12 months, patients with initial eGFR <30 mL/minute/1.73 m2 deteriorated, whereas those ≥30 mL/minute/1.73 m2 further sustained their renal function, suggesting a possible renal protective effect in that group.

Stromal Vascular Fraction Reverses the Age-Related Impairment in Revascularization following Injury

Adipose-derived stromal vascular fraction (SVF) has emerged as a potential regenerative therapy, but few studies utilize SVF in a setting of advanced age. Additionally, the specific cell population in SVF providing therapeutic benefit is unknown. We hypothesized that aging would alter the composition of cell populations present in SVF and its ability to promote angiogenesis following injury, a mechanism that is T cell-mediated. SVF isolated from young and old Fischer 344 rats was examined with flow cytometry for cell composition. Mesenteric windows from old rats were isolated following exteriorization-induced (EI) hypoxic injury and intravenous injection of one of four cell therapies: (1) SVF from young or (2) old donors, (3) SVF from old donors depleted of or (4) enriched for T cells. Advancing age increased the SVF T-cell population but reduced revascularization following injury. Both young and aged SVF incorporated throughout the host mesenteric microvessels, but only young SVF significantly increased vascular area following EI. This study highlights the effect of donor age on SVF angiogenic efficacy and demonstrates how the ex vivo mesenteric-window model can be used in conjunction with SVF therapy to investigate its contribution to angiogenesis.

Adipose stromal vascular fraction reverses mitochondrial dysfunction and hyperfission in aging-induced coronary microvascular disease.

Aging is associated with blunted coronary microvascular vasodilatory function. Previously, systemically administered adipose stromal vascular fraction (SVF) therapy reversed aging-induced attenuation of β1-adrenergic- and flow-mediated dilation dependent on reducing mitochondrial reactive oxygen species. We hypothesized that SVF-mediated recovery of microvascular dilatory function is dependent on recovery of mitochondrial function, specifically by reducing mitochondrial hyperfission. Female Fischer-344 rats were allocated into young control, old control, and old + SVF therapy groups. Pressure myography, immunofluorescent staining, Western blot analysis, and RNA sequencing were performed to determine coronary microvascular mitochondrial dynamics and function. Gene and protein expression of fission-mediator DRP-1 was enhanced with aging but reversed by SVF therapy. SVF facilitated an increase in fusion-mediator MFN-1 gene and protein expression. Mitochondrial morphology was characterized as rod-like and densely networked in young controls, isolated circular and punctate with aging, and less circularity with partially restored mitochondrial branch density with SVF therapy. Decreased mitochondrial membrane potential and ATP bioavailability in aged animals at baseline and during flow-mediated dilation were reversed by SVF and accompanied with enhanced oxygen consumption. Dilation to norepinephrine and flow in young controls were dependent on uninhibited mitochondrial fusion, whereas inhibiting fission did not restore aged microvessel response to norepinephrine or flow. SVF-mediated recovery of β-adrenergic function was dependent on uninhibited mitochondrial fusion, whereas recovery of flow-mediated dilation was dependent on maintained mitochondrial fission. Impaired dilation in aging is mitigated by SVF therapy, which recovers mitochondrial function and fission/fusion balance.NEW & NOTEWORTHY We elucidated the consequences of aging on coronary microvascular mitochondrial health as well as SVF's ability to reverse these effects. Aging shifts gene/protein expression and mitochondrial morphology indicating hyperfission, alongside attenuated mitochondrial membrane potential and ATP bioavailability, all reversed using SVF therapy. Mitochondrial membrane potential and ATP levels correlated with vasodilatory efficiency. Mitochondrial dysfunction is a contributing pathological factor in aging that can be targeted by therapeutic SVF to preserve microvascular dilative function.

Adipose Stromal Vascular Fraction Reverses Mitochondrial Hyperfission in Coronary Microvessels in Aging

IntroductionIn aging post‐menopausal women, Coronary Microvascular Disease (CMD) leads to hyperconstricted tone, reduced perfusion and chronic micro‐ischemia with angina. We previously showed an age‐related increase in coronary microvascular ROS alongside increased prooxidant gene and protein expression associated with blunted vasodilation. Adipose Stromal Vascular Fraction (SVF) is a heterogenous cell population that reduces vascular ROS to improve vasodilation. Oxidative stress with aging may be mediated by mitochondrial dysfunction, including fission/fusion imbalance. Therefore, we hypothesize aging leads to mitochondrial hyperfission and reduced fusion gene and protein expression, reversed by SVF therapy.MethodsCoronary microvessels from young (YC, 4 months), old (OC, 24 months), or old + SVF (OSVF, tail vein injection 4 weeks prior to sacrifice) from female Fischer 344 rats were assessed via RNA sequencing (n=3) and immunofluorescence imaging of fission/fusion proteins Dynamin Related Protein 1 (DRP‐1) and Mitofusin 1 &amp; 2 (MFN1 &amp; 2). Morphometric analysis was accomplished using ImageJ and the MiNA Image‐J tool to analyze 60x confocal images of microvessels stained with antibodies against mitochondrial TOM20. Statistics were preformed using One‐Way ANOVA with Bonferroni post hoc analysis.ResultsGene expression of DRP‐1 was significantly reduced, and MFN‐1 significantly enhanced in OSVF vs. OC (p = 0.035, 0.019). There was no significant difference in gene expression of fission or fusion mediators Fis‐1, MFN‐2 or Opa‐1. Protein expression of DRP‐1 was enhanced with aging, reduced to youthful levels by SVF (p = 0.007, 0.033) (Fig.1a). There were no differences in MFN1 or MFN2 protein expression with aging, however, protein expression of MFN‐1 was significantly increased after SVF (YC vs. OSVF p = 0.003, OC vs. OSVF p &lt; .001). Mitochondrial aspect ratio and form factor were reduced in aging (p = 0.024, &lt; 0.001), restored to youthful levels by SVF (p = &lt; 0.001, &lt; 0.001) (Fig. 1b). Mitochondrial fission factor was elevated with aging (p = &lt; 0.001), reversed by SVF therapy (p = &lt; 0.001) (Fig. 1c). Mitochondrial area was reduced with aging (p = 0.002). Mitochondrial branch length and numbers of branches within a network were greatest in youth, significantly attenuated with aging (p &lt; 0.001, &lt; 0.001), and significantly increased (albeit not to youthful levels) with SVF therapy (OC vs. OSVF: p = 0.017, 0.011, YC vs. OSVF: p = 0.004, 0.003) (Fig. 1d).ConclusionsDuring youth, mitochondrial morphology is more rod‐like and interconnected, vs. punctate and isolated in aging. Injection of SVF reversed mitochondrial circularity and partially restored mitochondrial network density in aging. These findings were complimented by enhanced expression of DRP‐1 with aging with reduced DRP‐1 and enhanced MFN‐1 expression with SVF. SVF is a plausible therapy for CMD by reversing mitochondrial dysfunction including alleviating oxidative stress, attenuating mitochondrial fission, and rejuvenating mitochondrial fusion.

Rehabilitation of spinal cord injury with autogenous stromal vascular fraction in dogs

Background: Spinal cord injury (SCI) is an unexpected, traumatic event, its consequences often persist for the rest of life. The neurological deficit caused by spinal cord (SC) injury is permanent, and conservative treatment can not completely restore neurological functions in animals. Repeated autogenous adipose-derived stromal vascular fraction (SVF) has been used to deliver MSCs, growth factors such as brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 at the site of injury. Methods: In the present study, six dogs presented with SCI, were routinely examined based on standard neurological examination protocol and subjected to the survey radiography. Treatment plans differed as per the presentation of the case. Stable and physically responsive patients were selected for repeated autogenous SVF therapy for rehabilitation. Results: After conservative treatment in SCI, from the second week onwards, when patient supports or able to move affected area in relation to forequarter, the patients were administered repeated autogenous SVF therapy, which restored motor function in the form of intermittent weight-bearing on fetlock and/or posture change. Significance: Spinal cord damage either partial or complete is always an ailment related to neurological deficit of the affected body parts. The repeated administration of autogenous stromal vascular fraction therapy in combination of physiotherapy significantly reverse, the effects of neurological deficit and progressively restore posture and weight bearing on the affected hind quarter in dogs.

Therapeutic potential of the stromal vascular fraction in COVID-19

The new coronavirus infection (COVID-19) is already known to cause serious respiratory illnesses such as pneumonia and lung failure. COVID-19 has caused catastrophic damage to the public health, economic and social stability. As COVID-19 has resulted in enormous human toll and serious economic loss that poses a global threat, urgent understanding of the current situation and the development of strategies to mitigate the spread of the virus is required. Today, many studies are being carried out around the world to study the pathogenesis of COVID-19, where the development of a cytokine storm or pulmonary fibrosis is a serious complication that can lead to unfavorable outcomes. This leads to the fact that a deeper understanding of the nature of the virus will allow to develop new approaches in pathogenetic therapy. In this regard, the stromal vascular fraction has tremendous therapeutic potential in COVID-19. Stromal vascular fraction provides anti-inflammatory and immunomodulatory effects and promotes the restoration and regeneration of damaged tissues. The availability, the ability to obtain a significant volume of viable cells of the stromal vascular fraction population, such as adipose tissue stem / stromal cells, as well as their use by the intravenous route, has proven safe and effective in other forms of lung disease, including fibrotic diseases. In other words, the goal of this therapy for COVID-19 is to eliminate the inflammatory process, restore trophic and regenerate damaged tissues, and remodel fibrous and connective tissue. However, stromal vascular fraction is not currently approved for the prevention or treatment of COVID-19 cases. However, clinical trials are ongoing to ensure maximum understanding in terms of efficacy and safety. In this paper, we will discuss this new approach to the use of stromal vascular fraction therapy, which serves as a ray of hope in the fight against severe forms of COVID-19

Meta-Analysis of Adipose Tissue Derived Cell-Based Therapy for the Treatment of Knee Osteoarthritis

Osteoarthritis (OA) is a degenerative disorder associated with cartilage loss and is a leading cause of disability around the world. In old age, the capacity of cartilage to regenerate is diminished. With an aging population, the burden of OA is set to rise. Currently, there is no definitive treatment for OA. However, cell-based therapies derived from adipose tissue are promising. A PRISMA systematic review was conducted employing four databases (MEDLINE, EMBASE, Cochrane, Web of Science) to identify all clinical studies that utilized adipose tissue derived mesenchymal stem cells (AMSCs) or stromal vascular fraction (SVF) for the treatment of knee OA. Eighteen studies were included, which met the inclusion criteria. Meta-analyses were conducted on fourteen of these studies, which all documented WOMAC scores after the administration of AMSCs. Pooled analysis revealed that cell-based treatments definitively improve WOMAC scores, post treatment. These improvements increased with time. The studies in this meta-analysis have established the safety and efficacy of both AMSC therapy and SVF therapy for knee OA in old adults and show that they reduce pain and improve knee function in symptomatic knee OA suggesting that they may be effective therapies to improve mobility in an aging population.

Stromal vascular fraction (SVF) therapy for treatment of various diseases: delivering safety of the first patented svf technique in indonesia

Background & Aim To report the safety of SVF therapy done by the first patented processing technique in Indonesia for treating various diseases via various routes of administration. Methods, Results & Conclusion Stromal vascular fraction (SVF) therapy has been performed over the past seven years to treat 493 patients by our group in five clinical centers. SVF was isolated from the lipoaspirate collected from each respective patient through a simple manual liposuction procedure. For each patients, blood was drawn as well to isolate platelet-rich plasma (PRP). SVF and PRP were administered to all subjects by intravenous (IV) injection in an autologous manner, with minority group within the population received an additional spinal, intra-articular, or subcutaneous injections, or combination of several injection sites. The top 5 common diseases were diabetes mellitus, antiaging, degenerative musculoskeletal disease, cardiovascular disease, and autism. On 2016 we patented a new technique called H-Remedy and use it for 402 patients since, 224 males (55.7%) and 178 females (44.3%) aged 1 to 86 year old (median = 55). Lipoaspirate volume was from 10 ml to 415 ml (median = 95) and total number of SVF was ranged between 0.2 × 10^6 per 10 ml to 5.5 × 10^6 per 10 ml (median = 22.4 × 10^6 per 10 ml). The total of 87 patients (21.6%) received 4 times SVF treatments, 161 patients (40%) received 3 times SVF treatments, and 114 patients (28.4%) received 2 times SVF treatments, all during 2 month period. Only 40 patients (10%) received 1 time SVF treatment. It was determined that any complications observed during the treatments with H-Remedy had been identified as a result of spinal or intra-articular injections and not related with direct therapeutic effect from SVF or PRP. These minor side effects had been identified early and successfully treated. In conclusion, the technique and clinical protocol were considered as safe and feasible, and therefore can be used to the next phase of trial to evaluate the efficacy of SVF therapy.

Photobiomodulation associated to cellular therapy improve wound healing of experimental full thickness burn wounds in rats

Adipose derived stromal vascular fraction (SVF) is a method of cell therapy potentially applicable for treatment of full thickness burns. Here we investigated if the association of photobiomodulation (PBM) with SVF therapy could improve wound healing in experimentally induced full thickness burn wounds in rats compared to the topical agent 2% silver sulfadiazine in a dose-dependent manner. Sixty-six male Wistar rats were divided in 4 groups containing 5 animals each which received the following treatments: 2% sulfadiazine (SD), SVF, SVF plus PBM at 30 mW (SVFL30), and SVF plus PBM at 100 mW (SVFL100). Two donor animals were used for each experimental series with 3, 7 and 30 days. Digital photography, microscopic analysis with Hematoxilin and Eosin (H&E), quantification of collagen type I by picrosirius red staining analysis and wound contraction evaluation were performed in order to quantify the results. At day 3 SVF alone or combined with PBM promoted increased early inflammatory response compared to SD. At day 7 SVFL30 and SVFL100 enhanced inflammatory cells infiltration, angiogenesis and fibroblast content compared to SVF and SD groups. At day 30 collagen concentration and wound contraction were higher in SVFL30 when compared to the other groups. In conclusion PBM promotes a synergistic outcome with SVF therapy with a dose dependent effect potentializing wound healing of experimental full thickness burns in rats through amplification of early inflammatory response, enhanced angiogenesis, fibroblast content, accentuated wound contraction and collagen concentration.

Improved diastolic dysfunction and coronary blood flow in aging following stromal vascular fraction therapy

In aged female rats and humans, decreased coronary flow contributes to an increased risk of cardiovascular disease. Coronary microvascular disease, caused by damage to the endothelial lining of coronary vessels, significantly alters microcirculation and leads to coronary perfusion deficits. Our past research has shown that tail vein injection of adipose‐derived stromal vascular fractions (SVF) was effective at migrating to the walls of peripheral small vessels and resetting dysregulated vasomotor tone. We hypothesized that i.v. injection of SVF would reverse the coronary microvascular dysfunction caused by aging by incorporating into the coronary microvessels and improving perfusion.MethodsYoung (3 months, n=9) and old (22 months, n=38) female fisher‐344 rats received baseline cardiac vevo measurements. Old rats were then divided into 3 groups: control (no treatment, n=9), negative control (i.v. injection of 6×10(6) endothelial cells (ECs), n=12) and experimental group which received 6×10(6) green fluorescent protein (GFP+) SVF cells (n=9)). Cardiac –vevo measurements were evaluated again at four weeks post injection. The left anterior descending (LAD) coronary arterioles were isolated for microvessel reactivity studies. Immunohistochemistry staining was performed on a subset of hearts.Results(GFP+) SVF cells were engrafted into the myocardium and coronary vasculature four weeks after injection (5.0% +/− 0.9% of total nucleated cells, n=4). Fractional shortening was not different between groups, but left ventricular diastolic function (E/A ratio) was significantly decreased in aged rats compared to young. Importantly, this was rescued after SVF treatment, but not EC injection. Coronary Peak velocity and coronary flow reserve (CFR) of the LAD were improved in old rats receiving SVF therapy vs. old control group. Endothelium‐dependent flow‐mediated relaxation was rescued in all old rats after incubating coronary arterioles with conditioned media (supernatant of rat cardiomyocytes cultured with 5% SVF cells). Only arterioles from SVF treated rats increased myogenic response following conditioned media, suggesting SVF therapy primes the coronary microcirculation to increased dilation in aging. Measures of vasoconstriction (endothelin) were similar between groups. A subset of SVF animals with indwelling telemetry units did not exhibit increased arrhythmias or mortality.Conclusioni.v. injected SVF cells are capable of incorporating into the cardiac peri‐vascular tissue and were shown to transiently improve coronary blood flow (CFR and microvascular vasoreactivity) and diastolic function in a model of advanced age. Importantly this cell therapy did not result in increased rate of arrhythmias or increased mortality. SVF cells provide an autologous cell therapy option for treatment of coronary and cardiac dysfunction in aged population.Support or Funding InformationNIH RO1 AG053585Jewish Heritage Fund for Excellence and the Green's FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Transplantation of Noncultured Stromal Vascular Fraction Cells of Adipose Tissue Ameliorates Osteonecrosis of the Jaw-Like Lesions in Mice.

The precise pathoetiology and effective treatment strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ) remain unknown. Transplantation of noncultured stromal vascular fraction (SVF) cells has been shown to be a useful method for regenerative medicine in place of stem cell therapy. This study investigated the effects of noncultured SVF transplantation on tooth extraction socket healing in mice. Both chemotherapeutic/bisphosphonate combination therapy for 7 weeks and tooth extraction of maxillary first molars at 3 weeks after drug administration were performed using female C57BL/6J mice. Osseous and soft tissue wound healing were validated at 4 weeks postextraction using gross wound healing and histomorphometry. Here, we created a new animal model of high-prevalence ONJ-like lesions that mimic human progression, because human ONJ mainly occurs in female patients taking both chemotherapeutic and bisphosphonate following tooth extraction. Moreover, mice with chemotherapeutic and bisphosphonate combination therapy for 5 weeks received SVF transplantation just after tooth extraction at 3 weeks post-drug administration. Euthanasia was performed at 2 weeks postextraction to assess the transplantation effects on wound healing using gross wound healing, histomorphometry, immunohistomorphometry, quantitative real-time polymerase chain reaction, and microcomputed tomography. We showed that systemic transplantation of noncultured SVF cells ameliorates ONJ-like lesions by improving both osseous and soft tissue healing of tooth extraction sockets. SVF therapy significantly increased blood vessels and the ratio of M2/M1 macrophages. In addition, SVF transplantation reduced the increases in tartrate-resistant acid phosphatase-positive (TRAP+ ) mononuclear cells (MNCs) and nonattached osteoclasts from the bone surface, which were significantly detected in the connective tissue of tooth extraction sockets and bone marrow by chemotherapeutic/bisphosphonate combination therapy. Our findings suggest that transplantation of noncultured SVF cells is a suitable treatment for BRONJ. Abnormal TRAP+ MNCs and nonattached osteoclasts in systemic and local environments may contribute to the development of BRONJ. © 2017 American Society for Bone and Mineral Research.

A Prospective Safety Study of Autologous Adipose-Derived Stromal Vascular Fraction Using a Specialized Surgical Processing System

Autologous adipose-derived stromal vascular fraction (SVF) has been proposed as a remedy for a number of inflammatory, autoimmune, and degenerative conditions. This procedure had mainly been evaluated in veterinary medicine and outside the United States when this study was initiated. This study looks at adverse events to evaluate safety as its primary objective and secondarily follows efficacy of SVF as deployed through intra-articular injections and intravenous infusions for a variety of orthopedic and non-orthopedic conditions. We hypothesized that autologous SVF deployment using a specialized surgical processing system (the CSN Time Machine® system, trademark name for the MediKhan Lipokit/Maxstem system; MediKhan, Los Angeles, California) was safe (ie, minimally acceptable adverse events) and that clinical efficacy could be demonstrated. This was a prospective case series. After institutional review board approval, 1698 SVF deployment procedures were performed between 2011 and 2016 by us and other affiliates with our same system trained by us as a nearly closed sterile surgical lipotransfer procedure on 1524 patients with various degenerative, inflammatory, and autoimmune conditions with a majority involving the musculoskeletal system. All outcome test data were collected in an online database over a 5-year period. Our study shows a very low number of reported adverse events and a reduction in pain ratings after 6 months or more across a variety of musculoskeletal diseases and improvements in a variety of other degenerative conditions. Our system for producing adipose-derived SVF therapy for our patients was safe and benefits could be measured for a long time after SVF deployment. Further controlled long-term studies for specific disease conditions with large patient populations are necessary to further investigate the benefits observed.

34. Stromal Vascular Fraction as a Novel Stem Cell-Based Therapy for a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is the most common neurodegenerative disorder affecting young adults worldwide and remains an unmet clinical challenge. MS is caused by an autoimmune reaction against constituents of the central nervous system (CNS). Subsequent immune cell infiltration into CNS tissues lead to widespread inflammation, demyelination, and pathological lesions causing debilities such as tremors, fatigue, and progressive loss of motor functions. These pathological hallmarks are reproducible in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS. Several clinical trials have demonstrated the safety and efficacy of adipose-derived stem cell (ASC)-based therapies in treating various disorders. ASC-based therapies are considered favorable due to their abundance in adult human adipose depots, less invasive harvest protocol, and potent immune-modulatory capabilities. However, due to the requisite for ex vivo culture isolation and expansion, alternative therapies are necessary. As such, the stromal vascular fraction (SVF) of adipose tissue has been considered a potential alternative to ASC-based therapies. The SVF consists of ASCs, adipocytes, and numerous leukocytes. The combination of cell types is believed to provide enhanced effectiveness by reducing inflammation and repairing damage. Currently, the SVF has advanced to clinical trials as a promising therapy for various medical indications including neurodegenerative diseases. Nevertheless, the efficacy of SVF therapy for MS patients or EAE mice has not been investigated. In this study, 1×106 SVF cells or ASCs were administered by intraperitoneal injected into EAE mice during the progression of disease, i.e. early, mid-stage, and chronic phases. Immune-modulatory activities of injected SVF and ASCs were analyzed using flow cytometry and qRT-PCR of lymphoid and CNS tissues and blood at the endpoint of the study. Both SVF and ASC treatments reduced pathological infiltrates and levels of inflammatory cytokines. Results show greater efficacy for reducing disease severity, recovery of motor functions, and improvement in histological examinations from EAE mice injected with SVF than ASCs, regardless of the timing. Together, SVF cells are more comprehensive at treating the immunopathogenesis of EAE by producing robust immune-modulatory effects. The translational aspects of this study support the use of SVF over ASCs as a prospective therapy for MS due to these promising results.

Stem cell therapy of osteoarthritis using stromal vascular fraction cells

Therapy of osteoarthritis relies on non-steroid analgesics, chondroprotectives and in late stages total joint replacement is considered a standard of care. We performed a pilot study using novel stem cell therapy approach that was performed during one surgical procedure. It relies on abdominal lipoaspiration and processing of connective tissue to stromal vascular fraction (SVF) cells that typically contain relatively large amounts of mesenchymal stromal and stem cells. SVF cells are injected immediately to the target joint or to the connective tissue of the target joint. Since 2011, total of 205 patients have been recruited and followed for up to 24 months to demonstrate the therapeutical potential of freshly isolated SVF cells. At the same time, one to four joints (knees and hips) were injected with SVF cells per patient. A total number of 319 joints were treated. Semiquantitative clinical scale evaluation and non-steroid analgesics dependence was used as measurement of the clinical effect, all patients were diagnosed with stage II–IV osteoarthritis using X-ray and ultrasound, in some cases MRI was also performed to monitor the changes before and after stem cell therapy. After 3 months from SVF therapy, at least 50% clinical improvement was recognized in 95%, at least 75% clinical improvement in 82%, and complete remission in 73% of patients, respectively. Within 1–2 weeks from SVF therapy 85% of patients were off the non-steroid analgesics and remain such for at least 6 months. No serious side effects, infection or cancer was associated with SVF cell therapy. In conclusion, here we report a novel and promising therapeutical approach that is safe, cost effective, and relying only on autologous cells.

Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety

Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach.