Effects of radiation and chemotherapy on adipose stem cells: Implications for use in fat grafting in cancer patients

Autologous fat transplantation is a versatile tool in reconstructive surgery.Adipose-derived stem cells(ASCs)increase survival of fat grafts and thus are increasingly used for breast reconstruction in breast cancer patients.However,radiation and/or chemotherapy have been proposed to inhibit soft tissue regeneration in wound healing thus suggesting alteration in stem cell pathways.Therefore,elucidating effects of radiation and chemotherapy on ASCs is critical if one desires to enhance the survival of fat grafts in patients.This review outlines our work evaluating the function and recoverability of ASCs from radiation or chemotherapy patients,focusing specifically on their availability as a source of autologous stem cells for fat grafting and breast reconstruction in cancer patients.Even though evidence suggests radiation and chemotherapy negatively influence ASCs at the cellular level,the efficiency of the isolation and differentiation capacity did not appear influenced in patients after receiving chemotherapy treatment,although fat from radiated patients exhibited significantly altered ASC differentiation into endothelial-like cells.Further,the in vitro growth rates of patient’s ASCs do not differ significantly before or after treatment.Taken together,these studies suggest ASCs as an important new tool for grafting and reconstruction even when radiation and chemotherapy treatment are involved.

Augmentation mammoplasty with autologous fat grafting

Considering the issues that can accompany prosthetic breast implants,augmentation mammoplasty(AM)with autologous fat grafting(AFG)has attracted growing interest globally,especially in the last two decades,as breast implant-associated anaplastic large cell lymphoma has been increasing in incidence over time.Here,we review the detailed processes of AFG to the breast and the pertinent complications associated with this procedure.This study aims to elucidate the critical points and technique improvements in AM with AFG in recent years,as well as discuss how to decrease complications related to this procedure.Attention was focused on the specific AFG steps,clinical outcomes,and complications to highlight the advantages and disadvantages of the available protocols.

Current state and exploration of fat grafting

Fat grafting has become one of the most frequently used techniques in plastic and reconstructive surgery.Many studies have focused on optimizing procedures,such as donor site selection,harvesting,processing,and grafting.Representative basic techniques include Coleman’s and“3L3M”techniques.A new technique called compartment-based targeted fat grafting(CTFG)has gradually been established based on anatomical findings of the facial and hand compartments.CTFG achieved precise restoration of the fat volume in the anatomical state.Cell-based fat grafting has introduced new fields involving tissue repair and regeneration,including facial rejuvenation and scar improvement,among others.In this review,we summarize the timeline for the development of fat grafting.

Fat Grafting for Rejuvenation and Regeneration with Stromal Vascular Fraction Gel

Lipotransfer has become a powerful regenerative tool,largely because of its cellular components,the stromal vascular fraction(SVF).However,the clinical separation of cells with collagenase is strictly legislated.In 2017,Yao et al.postulated a novel fat-derived product mechanically concentrating SVF cells and an extracellular matrix(ECM)and named it stromal vascular fraction gel(SVF-gel).This review discussed the protocol of SVF-gel and its component as well as its inner structure.The histologic examination and the retention rate after the transplantation of SVF-gel were also rendered.Moreover,we summed up the rejuvenating and regenerative use of SVF-gel and introduced its possible mechanism.

A Systemic Review of Autologous Fat Grafting Survival Rate and Related Severe Complications

Objective：Clinical application ofautologous fat grafting （AFG） is quickly expanding.Despite the widely acceptance,long-term survival rate （SR） of AFG remains a question not yet solved.Meanwhile,although rare,severe complications related to AFG including vision loss,stroke even death could be seen in the literature.Data Sources：A comprehensive research of PubMed database to June 2013 was performed according to guidelines of the American Society of Plastic Surgeons Fat Graft Task Force Assessment Methodology.Articles were screened using predetermined inclusion and exclusion criteria.Study Selection：Data collected included patient characteristics,surgical technique,donor site,recipient site,graft amount,and quantified measurement methods.Patient cohorts were pooled,and SR was calculated.All the severe complications were also summarized according to the different clinical characteristics.Results：Of 550 articles,16 clinical articles and 10 animal studies met the inclusion criteria and provided quantified measurement methods.Totally,596 patients were included.SR varied from 34％ to 82％ in breast and 30-83％ in the facial area.Nude mice were applied to investigate human fat grafting SR （38.3-52.5％ after 15 weeks）.Rabbits were commonly used to study animal AFG SR （14.00-14.56％ after 1-year）.Totally,21 severe complications were reported,including death （2）,stroke （10）,vision loss （11,8 of which accompanied with stroke）,sepsis （3）,multiple abscess （1） and giant fat necrotic cyst （2）.Ten of these complications happened within 10 years.Conclusions：There is no unified measurement method to evaluate fat graft SR until now and no clinical evidence to show better SR according to different donor and recipient cite.Body mass index change between pre-and postoperation may be the bias factor in evaluating fat SR.Fat embolisms of the ophthalmic artery and the middle cerebral artery are the most severe complication of AFG and still lack of effective treatment.

Role of adipose tissue grafting and adipose-derived stem cells in peripheral nerve surgery

The application of autologous fat grafting in reconstructive surgery is commonly used to improve functional form.This review aims to provide an overview of the scientific evidence on the biology of adipose tissue,the role of adipose-derived stem cells,and the indications of adipose tissue grafting in peripheral nerve surgery.Adipose tissue is easily accessible through the lower abdomen and inner thighs.Non-vascularized adipose tissue grafting does not support oxidative and ischemic stress,resulting in variable survival of adipocytes within the first 24 hours.Enrichment of adipose tissue with a stromal vascular fraction is purported to increase the number of adipose-derived stem cells and is postulated to augment the long-term stability of adipose tissue grafts.Basic science nerve research suggests an increase in nerve regeneration and nerve revascularization,and a decrease in nerve fibrosis after the addition of adipose-derived stem cells or adipose tissue.In clinical studies,the use of autologous lipofilling is mostly applied to secondary carpal tunnel release revisions with promising results.Since the use of adipose-derived stem cells in peripheral nerve reconstruction is relatively new,more studies are needed to explore safety and long-term effects on peripheral nerve regeneration.The Food and Drug Administration stipulates that adipose-derived stem cell transplantation should be minimally manipulated,enzyme-free,and used in the same surgical procedure,e.g.adipose tissue grafts that contain native adipose-derived stem cells or stromal vascular fraction.Future research may be shifted towards the use of tissue-engineered adipose tissue to create a supportive microenvironment for autologous graft survival.Shelf-ready alternatives could be enhanced with adipose-derived stem cells or growth factors and eliminate the need for adipose tissue harvest.

Treatment of intractable orbital implant exposure with a large conjunctival defect by secondary insertion of the implant after preceding dermis fat graft

AIM: To report a procedure and results of a two-stage operation to manage intractable extensive orbital implant exposure with a large conjunctival defect which was difficult to treat with dermis fat grafts due to repeated graft necrosis. METHODS: A retrospective chart review of four patients who had extensive orbital implant exposures with large conjunctival defects and had past histories of repeated autologous or preserved dermis graft failures was done. As a first-stage operation, the problematic pre-existing orbital implants were removed and autologous dermis fat grafts alone were performed on the defect area. Four months later, new orbital implants were secondarily inserted after confirmation of graft survival. The size of the conjunctival defects and state of the extraocular muscles were checked preoperatively. Success of the operations and complications were investigated.RESULTS: The mean size of the conjuctival defects was 17.3mm×16.0mm, and the mean time from the initial diagnosis of orbital implant exposure to implant removal and autologous dermis fat graft was 20.8 months. After implant removal and autologous dermis fat graft, no graft necrosis was observed in any patients. Also, implant exposure or fornix shortening was not observed in any patients after new orbital implant insertion. CONCLUSION: The secondary insertion of a new orbital implant after pre-existing implant removal and preceding dermis fat graft is thought to be an another selective management of intractable orbital implant exposure in which dermis fat grafts persistently fail.

Current Status of ADSCs-Enriched Fat Grafts in Plastic Surgery

Autologous fat grafting is an increasingly popular technique in plastic surgery for volume augmentation and rejuvenation.However,the unpredictability of long-term volume retention limits its clinical application.Various animal studies have documented the positive effects of adipose tissue-derived stem cells(ADSCs)on the acceleration of lipofilling.However,the results have been inconsistent,and there is an insufficient number of high-quality clinical studies to formulate evidence-based recommendations for ADSC-enriched fat grafts.Moreover,related technical standards,such as the final count of harvested ADSCs and the enrichment ratio,have not yet been established.This systematic review included all clinical trials on ADSC-enriched fat grafts in plastic surgery from PubMed in the past 10 years,as well as all registered clinical trials on ClinicalTrials.Gov.To examine the current landscape of ADSCs harvest,we summarize the current applications of ADSCs in the field of plastic surgery and discuss the current barriers to universal clinical use.

A Novel Composite Skin Graft Technique with Fat Derivatives

Skin grafting,although a relatively classic and well-known technique,still has multiple disadvantages such as secondary contracture of the skin graft,sunken depression,poor elasticity,and color mismatch.Adding adipose tissues significantly improved the graft appearance compared to traditional skin grafting methods.Herein,we report two cases of modified skin graft procedures,both showing positive outcomes.In case 1,a mechanically processed fat-derived product was injected into the lower half of the skin graft area.In case 2,left upper eyelid blepharoplasty was performed,and the orbital fat strip was transferred and placed under the recipient area on the right side.Hair growth was observed only in case 1,whereas the extent of sunken depression was significantly reduced in both cases.Compared to traditional skin grafting methods,adding fat components to the skin graft recipient area improved the appearance and blood supply,together with enhancing the regenerative rate.

Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars

BACKGROUND Sustained injury,through radiotherapy,burns or surgical trauma,can result in fibrosis,displaying an excessive deposition of extracellular matrix(ECM),persisting inflammatory reaction,and reduced vascularization.The increasing recognition of fibrosis as a cause for disease and mortality,and increasing use of radiotherapy causing fibrosis,stresses the importance of a decent anti-fibrotic treatment.AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis,and more specifically,the potential mechanisms-of-action of adiposederived stomal cells(ADSCs)in realizing their anti-fibrotic effect.METHODS A systematic review of the literature using PubMed,Embase and Web of Science was performed by two independent reviewers.RESULTS The injection of fat grafts into fibrotic tissue,releases ADSC into the environment.ADSCs’capacity to directly differentiate into key cell types(e.g.,ECs,fibroblasts),as well as to secrete multiple paracrine factors(e.g.,hepatocyte growth factor,basis fibroblast growth factor,IL-10),allows them to alter different mechanisms underlying fibrosis in a combined approach.ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation,favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases,positively influencing collagen organization,and inhibiting the pro-fibrotic effects of transforming growth factor-β1.Furthermore,they impact elements of both the innate and adaptive immune response system,and stimulate angiogenesis on the site of injury(through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).CONCLUSION This review shows that understanding the complex interactions of ECM accumulation,immune response and vascularization,is vital to fibrosis treatments’effectiveness like fat grafting.It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction,without falling into extreme dilation or stimulation of a single aspect.Detailing this combined approach,has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.

Prospective application of poloxamer 188 in plastic surgery:A comprehensive review

An increasing number of researchers have demonstrated that poloxamer 188(P188)can be used as a pharmaceutical excipient for clinical applications.Its membrane-sealing effects and inherent biological activities make it an extremely promising agent for plastic surgery.In this review,we summarize the positive roles of P188 in autologous fat grafting,wound healing,and cartilage transplantation.These roles include improving the survival rate of fat grafts and chondrocytes,stimulating the metabolic activity of adipocytes,promoting wound healing,and contributing to cartilage formation.Although further research is still needed,it is clear that P188 has great potential and application value in the field of plastic surgery.

Translational products of adipose tissue-derived mesenchymal stem cells:Bench to bedside applications

With developments in the field of tissue engineering and regenerative medicine,the use of biological products for the treatment of various disorders has come into the limelight among researchers and clinicians.Among all the available biological tissues,research and exploration of adipose tissue have become more robust.Adipose tissue engineering aims to develop by-products and their substitutes for their regenerative and immunomodulatory potential.The use of biodegradable scaffolds along with adipose tissue products has a major role in cellular growth,proliferation,and differentiation.Adipose tissue,apart from being the powerhouse of energy storage,also functions as the largest endocrine organ,with the release of various adipokines.The progenitor cells among the heterogeneous population in the adipose tissue are of paramount importance as they determine the capacity of regeneration of these tissues.The results of adipose-derived stemcell assisted fat grafting to provide numerous growth factors and adipokines that improve vasculogenesis,fat graft integration,and survival within the recipient tissue and promote the regeneration of tissue are promising.Adipose tissue gives rise to various by-products upon processing.This article highlights the significance and the usage of various adipose tissue by-products,their individual characteristics,and their clinical applications.

Advances in Oncoplastic Breast Surgery

Evidence from six prospective,randomized trials has shown that breast-conserving surgery(BCS)is a safe alternative to mastectomy,and this led to a heightened interest in achieving and balancing local control and cosmetic outcome post-surgery.However,it is also becoming apparent that conventional BCS techniques may not produce cosmetically favorable results for patients who present with ill-defined or poorly situated breast tumors.Other factors that are commonly found in Chinese women,such as small-volume and denser breasts,also contribute to the difficulty in achieving an optimal cosmetic outcome post-surgery,thus necessitating the need for oncoplastic breast surgery techniques to be employed.This article serves as an overview of the recent advances and principles of oncoplastic breast surgery,as well as the use of autologous fat grafts to improve cosmetic results and eliminate remaining smaller deformities post-surgery.

Differential fat harvesting

Aim:Volume replacement with fi llers is regularly performed with the use of diverse volumetric materials to correct different structures around the face,depending on the volume enhancement required and the thickness of the soft tissue envelope.Differential fat harvesting and posterior grafting is performed to place the correct fat parcel size for each target area,expanding the potential applications of fat.Methods:Sixty patients consecutively recruited on a fi rst come basis undergone a facial fat grafting procedure,in private practice setting between March 2012 and October 2013.Fat grafting quantity and quality was predicted for each case.Differential harvesting was performed,with 2 fat parcels size.Processing was performed through washing.Fat infi ltration was carried out through small cannulas or needles depending on the treated area.Outcomes were analysed both by the physicians and the patients at 7 days,1 month,3 months and 6 months through a perceived satisfaction questionnaire.Parameters considered were downtime or discomfort,skin benefi ts,volume restoration,reabsorption rate estimated and overall improvement.Results:Full facial differential fat grafting procedure lasted an average of 1.5-2.5 h.Average downtime was 3-4 days.Follow-up was performed to a minimum of 6 months.Both patient and physician overall satisfaction rates were mostly excellent.Adverse events like lumps or irregularities were not encountered.Conclusion:Differential fat harvesting and posterior grafting is a valid alternative,to expand the repertoire of fat use,allow a more homogeneous effect,reduce the potential complications,speed up the process,improve graft survival,and to enhance overall aesthetic outcome.

Comparison of adipose particle size on autologous fat graft retention in a rodent model

Aim:Unpredictable retention outcomes remain a significant issue in autologous fat grafting procedures.Liposuction cannula variation leads to variability in fat particle size.Recent data suggest that the size of fat particles is closely related to graft healing outcomes;however,this remains a point of contention due to potential confounding variables such as tissue trauma with harvest.The aim of this study was to compare autologous fat grafting outcomes with variable fat particle sizes in an animal model which isolated fat particle size as the primary experimental variable.The overall goal of this work was to determine if reducing fat particle size is an effective method for enhancing graft retention in autologous fat grafting.Methods:The range of fat particle diameter harvested by four common liposuction cannulas was quantified to define relevant small and large particle target diameters.To determine if particle size impacted nutrient and oxygen permeability,small and large particles were incubated in vitro in a spinner flask with an abundance of culture media and vascular endothelial growth factor secretion was measured with enzyme-linked immunosorbent assay.Finally,small and large fat grafts were prepared from subcutaneous mouse fat pads and grafted in syngeneic Balb/CJ mice.Weight and volume retention were evaluated at 1,4,8,and 12 weeks.Histological analysis with Masson's trichrome and perilipin immunofluorescent staining was performed.Real-time quantitative polymerase chain reaction was performed foradipogenic,inflammatory and apoptotic genes.Results:The range of fat particle diameters harvested with four commonly used cannulas was 2-7 mm.In vitro studies showed that 5-7-mm particles had significantly increased VEGF secretion normalized to weight,indicating increased tissue hypoxia in these particles compared to 2-4-mm particles.Surprisingly,in vivo comparison in two unique studies showed 2-4-mm and 5-7-mm fat particles had comparable graft retention(P=0.5329).Masson's trichrome staining revealed increased extracellular matrix and fibrosis in the 5-7-mm particle group(P=0.0115).Adipocyte survival with perilipin demonstrated comparable viability.Gene expression showed large particles experienced increased inflammation and apoptosis at one week after grafting,but overall there were no significant differences between groups.Conclusion:The ideal fat particle size should be large enough to contain adequate mesenchyme while not so thick as to preclude imbibition.This study suggests that,despite changes in hypoxia and VEGF levels,differing fat particles(2-4-mm and 5-7-mm)can achieve similar graft retention.

Cryopreserved fat: our clinical experience and applications

Aim:Cryopreservation of fat is an effective method for repeat fat grafting,but there are few reports about the clinical use of cryopreserved fat.The aim of this study was to determine the effectiveness and safety of cryopreserved fat for clinical use.Methods:Between Aug 2015 and Dec 2018,we investigated 590 patients who underwent fat harvesting at our clinic.The harvested fat was cryopreserved at a temperature of-196°C at a cell processing center and injections were performed in our clinic.Results:Of the 590 patients studied,216(312 cases)have undergone fat injections so far.Volume augmentations using harvested fat,such as facial and breast augmentations,were performed on 180 patients.For 84 patients,harvested fat was utilized only for revitalization/fertilization purposes,such as to improve skin condition.There were no severe complications in any patients.However,volume maintenance was rarely observed.Skin rejuvenation effects were comparable to that in cases using fresh fat.Conclusion:The clinical use of cryopreserved fat is thought to be safe and effective.

Breast cancer-related lymphedema: focus on surgical treatment

Breast cancer-related lymphedema(BCRL)can affect breast cancer patients,especially after axillary surgery and radiation treatment,for life.First line treatment is conservative and involves physical therapy and compression.It requires absolute,life-long compliance with treatment by the patient and,in some cases,it is ineffective.In recent years,surgery has emerged as a possible alternative or even,complementary therapy for BCRL.The most commonly reported techniques are reconstructive or debulking procedures.Reconstructive procedures are aimed at restoring the lymphatic pathways and can be effective early in the disease process,when increased arm volumes are mostly due to the accumulation of protein-rich fluid in the interstitial space.In more advanced stages,where fibrotic and hypertrophic adipose tissues are dominant,debulking techniques such as liposuction can be recommended.A standard of care for the treatment of BCRL has not been established.Currently,different techniques can be combined to optimize clinical outcomes,and the surgical approach must be individualized for each patient,based on sound clinical and imaging assessment.BCRL surgical treatment remains a challenging topic that requires further study before it can be standardized.

Composite augmentation phalloplasty:personal experience after 275 patients

Aim:To report the author’s experience in augmentation phalloplasty by studying a retrospective series of patients who underwent fat grafting for girth enhancement or a composite technique based on suspensory ligament release plus fat grafting performed simultaneously.Methods:The author analyzed retrospectively the outcomes of 275 augmentation phalloplasty procedures performed in 259 patients until November 2013.Of these,127 correspond to girth augmentation with fat grafting and 148 to composite augmentation phalloplasty(girth augmentation with fat grafting and length improvement by suspensory ligament release).In 16 patients girth and length enhancement were performed in two separate procedures.Results:Of this 259 patients,87 underwent postoperative follow-up for at least 12 months and 160 patients underwent follow-up for at least 6 months.The average increase in circumference at 6 months was 1.7 cm(1.57 cm at 12 months)and the average increase in length of 3.2 cm(3.1 cm at 12 months).Twenty-two patients showed minor complications that were treated without sequelae and without influencing the final result.Conclusion:By judicious use of currently available techniques,it is possible to achieve stable increases in penis size.The use of composite techniques provides better final results than the use of individual techniques performed alone due to the increase of the actual volume of the penis.An adequate informed consent is essential in all patients due to the unrealistic expectations expressed by the majority of them.