Farnesol Emulsion as an Effective Broad-Spectrum Agent against ESKAPE Biofilms.

The family of ESKAPE pathogens is comprised of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter. Together they are the main contributors of nosocomial infections and are well established for their ability to "escape" antibiotics. Farnesol is an FDA-approved cosmetic and flavoring agent with significant anti-biofilm properties. In a proprietary emulsion, farnesol has been shown to be capable of disrupting S. aureus, P. aeruginosa, and A. baumannii biofilms. The current work demonstrates that this farnesol emulsion reduces the number of viable bacteria, while also leading to reductions in biomass, of the other three ESKAPE pathogens: Enterococcus faecium, Klebsiella pneumoniae, and Enterobacter, both in vitro and in an ex vivo human skin model. A concentration of 0.5 mg/mL was effective for impeding biofilm development of all three bacteria, while 1 mg/mL for E. faecium and K. pneumoniae, or 0.2 mg/mL for E. cloacae, was able to kill bacteria in established biofilms. Contrary to antibiotics, no resistance to farnesol was observed for E. faecium or K. pneumoniae. The results indicate that farnesol is effective for direct cell killing and also has the ability to induce biofilm detachment from surfaces, as confirmed using Live/Dead image analysis. Our findings confirm that farnesol emulsion is an effective broad-spectrum agent to impede ESKAPE biofilms.

Enlarged Breast Size (Macromastia) and Associated Neurologic Risks: A Scoping Review.

BACKGROUND AND OBJECTIVES: Symptomatic macromastia (enlarged breasts) is a syndrome of persistent headache, neck and shoulder pain, thoracic kyphosis, painful shoulder grooving from bra straps, inframammary rash, backache, and upper extremity paresthesias. Up to 89% of the 100,000 US women undergoing breast reduction surgery (reduction mammoplasty) annually report headache preoperatively with many endorsing postoperative headache improvement. Headache is one insurance indication to cover surgical reduction, and peak prevalence of migraine matches the average age of women with macromastia at time of surgery. Little is known about the influence of macromastia on headache. The goal of our narrative review is to understand the evidence for and potential mechanisms underlying macromastia-related headache. METHODS: A literature search was performed in PubMed Medline using concepts "breast hypertrophy," "macromastia," "headache," "migraine," "breast reduction," and "reduction mammoplasty" excluding limits on age, language, publication date, or study type. Supplemental literature searches were performed to provide a comprehensive understanding of potential mechanisms underlying macromastia-related headache. RESULTS: We identified 25 studies describing macromastia-associated headache in the setting of reduction mammoplasty, with 23 original research studies (retrospective, n = 12, prospective, n = 11) totaling 3,799 patients, 1 systematic review, and 1 meta-analysis. Most (24/25) were published in Plastic Surgery, one in Internal Medicine, and none in Neurology. Wide ranges were identified for preoperative headache prevalence (2%-89%) and postoperative headache improvement (34%-100%). Studies described headache as "myofascial" or "tension-type" without detailing headache definitions, chronicity, headache screening method, or neurologic examination. Potential pathophysiologic mechanisms of macromastia-associated headache include structural, mechanical, psychosocial, and hormonal. DISCUSSION: No studies on macromastia-associated headache and reduction mammoplasty are published in Neurology. This important women's health topic remains unexplored in fields outside Plastic Surgery. Many questions remain unanswered that are important for neurologists to understand, including which headache type(s) women with macromastia experience and which headache type(s) respond to surgical intervention.

Farnesol repurposing for prevention and treatment of Acinetobacter baumannii biofilms.

Acinetobacter baumannii has emerged as a multidrug-resistant (MDR) superbug by causing severe infections, with high mortality rates. The ability of A. baumannii to form biofilms significantly contributes to its persistence in diverse environmental and hospital settings. Here we report that farnesol, an FDA-approved commercial cosmetic and flavoring agent, demonstrates efficacy for both inhibition of biofilm formation, and disruption of established A. baumannii biofilms. Moreover, no resistance to farnesol was observed even after prolonged culture in the presence of sub-inhibitory farnesol doses. Farnesol combats A. baumannii biofilms by direct killing, while also facilitating biofilm detachment. Furthermore, farnesol was safe, and effective, for both prevention and treatment of A. baumannii biofilms in an ex vivo burned human skin model. Since current treatment options for A. baumannii biofilm infections were mainly counted on the combination therapy of last-resort antibiotics, and clearly non-sustainable due to robust MDR phenotype of A. baumannii, we propose that farnesol alone can be repurposed as a highly effective agent for both preventing and treating life-threating biofilm-associated infections of A. baumannii due to its proven safety, convenient topical delivery, and excellent efficiency, plus its superiority of evading resistance development.

Repurposing Farnesol for Combating Drug-Resistant and Persistent Single and Polymicrobial Biofilms.

Biofilm-associated infections caused by drug-resistant and persistent bacteria remain a significant clinical challenge. Here we report that farnesol, commercially available as a cosmetic and flavoring agent, shows significant anti-biofilm properties when dissolved in ethanol using a proprietary formulation emulsion technique. Farnesol in the new formulation inhibits biofilm formation and disrupts established biofilms for Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, including their polymicrobial biofilms, and, moreover, kills S. aureus persister cells that have developed tolerance to antibiotics. No resistance to farnesol was observed for S. aureus after twenty continuous passages. Farnesol combats biofilms by direct killing, while also facilitating biofilm detachment. Furthermore, farnesol was safe and effective for preventing and treating biofilm-associated infections of both types of bacteria in an ex vivo burned human skin model. These data suggest that farnesol in the new formulation is an effective broad-spectrum anti-biofilm agent with promising clinical potential. Due to its established safety, low-cost, versatility, and excellent efficacy-including ability to reduce persistent and resistant microbial populations-farnesol in the proprietary formulation represents a compelling transformative, translational, and commercial platform for addressing many unsolved clinical challenges.

The Impact of Postoperative Antibiotic and Duration After Implant-Based Breast Reconstruction on Resistance Among Cultured Species.

BACKGROUND: There is a growing presence of literature within plastic surgery that establishes best practice for postoperative antibiotics after implant-based breast reconstruction (IBBR), although it has not been widely adopted or translated into clinical practice. This study aims to determine how antibiotic and duration affects patient outcomes. We hypothesize that IBBR patients who receive a longer duration of postoperative antibiotics will demonstrate higher rates of antibiotic resistance as compared with the institutional antibiogram. METHODS: A retrospective chart review included patients who underwent IBBR between 2015 and 2020 at a single institution. Variables of interest included patient demographics, comorbidities, surgical techniques, infectious complications, and antibiograms. Groups were classified by antibiotic (cephalexin, clindamycin, or trimethoprim/sulfamethoxazole) and duration (≤7 days, 8-14 days, and >14 days). RESULTS: There were a total of 70 patients who experienced infections included in this study. Onset of infection did not differ based on antibiotic during either device implantation (postexpander P = 0.391; postimplant P = 0.234). Antibiotic and duration did not have an established relationship with explantation rate either (P = 0.154). In patients who had Staphylococcus aureus isolated, there was significantly increased resistance to clindamycin when compared with the institutional antibiogram (sensitivities of 43% and 68%, respectively). CONCLUSIONS: Neither antibiotic nor duration displayed a difference in overall patient outcomes, including explantation rates. In this cohort, S. aureus strains isolated in association with IBBR infections demonstrated a higher level of resistance to clindamycin compared with strains isolated and tested within the broader institution.

Realizations of vascularized tissues: From in vitro platforms to in vivo grafts.

Vascularization is essential for realizing thick and functional tissue constructs that can be utilized for in vitro study platforms and in vivo grafts. The vasculature enables the transport of nutrients, oxygen, and wastes and is also indispensable to organ functional units such as the nephron filtration unit, the blood-air barrier, and the blood-brain barrier. This review aims to discuss the latest progress of organ-like vascularized constructs with specific functionalities and realizations even though they are not yet ready to be used as organ substitutes. First, the human vascular system is briefly introduced and related design considerations for engineering vascularized tissues are discussed. Second, up-to-date creation technologies for vascularized tissues are summarized and classified into the engineering and cellular self-assembly approaches. Third, recent applications ranging from in vitro tissue models, including generic vessel models, tumor models, and different human organ models such as heart, kidneys, liver, lungs, and brain, to prevascularized in vivo grafts for implantation and anastomosis are discussed in detail. The specific design considerations for the aforementioned applications are summarized and future perspectives regarding future clinical applications and commercialization are provided.

Comparing Outcomes in the Therapeutic and Prophylactic Breast for Bilateral Mastectomy With Implant-Based Breast Reconstruction.

BACKGROUND: Increasingly patients with unilateral breast cancer elect to undergo bilateral mastectomy with subsequent reconstruction. Studies have aimed to better identify the risks associated with performing mastectomy on the noncancerous breast. Our study aims to identify differences in complications between therapeutic and prophylactic mastectomy in patients undergoing implant-based breast reconstruction. METHODS: A retrospective analysis of implant-based breast reconstruction from 2015 to 2020 at our institution was completed. Patients with less than 6-month follow-up after final implant placement had reconstruction using autologous flaps, expander or implant rupture, metastatic disease requiring device removal, or death before completion of reconstruction were excluded. McNemar test identified differences in incidence of complications for therapeutic and prophylactic breasts. RESULTS: After analysis of 215 patients, we observed no significant difference in incidence of infection, ischemia, or hematoma between the therapeutic and prophylactic sides. Therapeutic mastectomies had higher odds of seroma formation ( P = 0.03; odds ratio, 3.500; 95% confidence interval, 1.099-14.603). Radiation treatment status was analyzed for patients with seroma; 14% of patients unilateral seroma of the therapeutic side underwent radiation (2 of 14), compared with 25% patients with unilateral seroma of the prophylactic side (1 of 4). CONCLUSIONS: For patients undergoing mastectomy with implant-based reconstruction, the therapeutic mastectomy side has an increased risk of seroma formation.

The effects of prolonged intraoperative hypothermia on patient outcomes in immediate implant-based breast reconstruction.

BACKGROUND: The importance of thermoregulation in surgical procedures has become a recent focus for anesthesiologists and surgeons to improve patient outcomes. In breast surgery, maintenance of normothermia has been shown to reduce surgical-site infections. However, there is a paucity of information evaluating the relationship between intraoperative core body temperatures and reconstructive surgical outcomes. METHODS: A retrospective review of patients who underwent immediate breast reconstruction following mastectomy from 2015 to 2020 was performed. Patients were classified into a majority normothermic (NT) group if patients spent greater than half of the operative time ≥36 °C or a majority hypothermic (HT) group if patients spent greater than or equal to half of the operative time <36 °C. Patient demographics, comorbidities, surgical techniques, and postoperative complications were recorded. Complications were classified according to the Clavien-Dindo Classification. Univariate and multivariate statistics were used to assess significant relationships. RESULTS: A total of 329 patients met inclusion criteria, of which 174 were in the NT group and 155 were in the HT group, yielding 302 and 264 total breasts, respectively. There was no significant difference in rates of infection (p = 1.0), seroma (p = 0.27), hematoma (p = 0.61), or wound dehiscence (p = 1.0). However, patients in the HT group had significantly more overall ischemic complications (p = 0.009) and, specifically, grade IIIb ischemic complications (p = 0.04). After controlling for tobacco use, body mass index, mastectomy pattern, radiation, operating surgeon, and mastectomy weight, multivariate analysis showed increased ischemic complications in the HT group (p = 0.04). CONCLUSION: Prolonged intraoperative hypothermia can increase the risk for the development of ischemic wounds such as tissue necrosis or eschar formation that require operative intervention. This presents reconstructive complications that increase both patient and health system burdens that could be addressed through the maintenance of normothermia. Further studies using real-time flap temperature would provide more accurate insight into the relationship between temperature and implant-based breast reconstruction.

The Language of Implant-based Breast Reconstruction: Can We Do Better?

The management of breast cancer has experienced tremendous changes in the last half-century. In today's multimodal approach to breast cancer, patients have the prospect of achieving a sense of normalcy after mastectomy thanks to advancements in oncology and breast reconstruction. Although the oncologic management of breast cancer has evolved over multiple centuries, implant-based breast reconstruction (IBBR) has only been around since the 1960s. The last half century has seen the conception of multiple techniques, novel devices, and new possibilities in hopes of achieving outcomes that are similar to or even better than the patient's premorbid state. However, with all these changes, a new problem has arisen-inconsistencies in the literature on how IBBR is described. In this article, we will discuss potential sources of confusion in the IBBR literature and lexicon, highlighting specific terms that may have multiple meanings or interpretations depending on perspective, context, and/or intent. As a first step toward clarifying what we perceive as a muddied landscape, we propose a naming convention for IBBR that centers around four important variables especially pertinent to IBBR-the type of mastectomy performed, the timing of reconstruction, the type of device that is placed, and the pocket location for device placement. We believe that adoption of a more standardized, consistent, and descriptive lexicon for IBBR will help provide clearer communication and easier comparisons in the literature so that we may continue to deliver the best outcomes for our patients.

Recurrent Skin and Soft Tissue Infection following Breast Reduction Surgery Caused by Gordonia bronchialis: A Case Report.

The expanding knowledge of the breast microbiome and its constituents necessitates understanding of how it plays into human disease. Consideration of how to identify novel organisms in breast tissue is a topic of hot debate. We report a case of a 26-year-old woman with repeat incisional break-down and sanguinopurulent drainage who required repeat incision and drainage procedures after bilateral breast reduction. Cultures revealed no growth until 4 months postoperation when matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) revealed Gordonia bronchialis, a fastidious, slow-growing organism. To date, there are fewer than 30 reported cases of G. bronchialis infections and only one with breast involvement. Our patient required 6 weeks of amoxicillin-clavulanate therapy and frequent follow-up for symptom resolution. This case demonstrates the need for additional microbiologic data in patients with delayed, persistent infections after breast surgery.

Quantity of Acellular Dermal Matrix in Immediate Breast Reconstruction and Outcomes.

PURPOSE: This study aimed to determine the impact of the quantity of acellular dermal matrix (ADM), "ADM burden," used in implant-based breast reconstruction on infection, drain duration, and seroma formation. METHODS: A single-institution, retrospective review from 2015 to 2020 was conducted for patients who underwent immediate, implant-based breast reconstruction after mastectomy. Three cohorts were generated based on the amount of ADM used: (1) total ADM, (2) sling ADM, and (3) no ADM. RESULTS: In total, there were 374 patients who satisfied the inclusion criteria yielding 641 breasts with 143, 432, and 66 breasts in the total ADM, sling ADM, and no-ADM groups, respectively. The no-ADM group had higher mastectomy weights (788.4 g) than the sling (654.2 g) and total ADM (503.4 g) groups (F = 10.8, P < 0.001). Total ADM had higher rates of explantation secondary to infection compared with no ADM (P < 0.001). Linear regression analysis for drain duration was significant for body mass index (P < 0.0001) but not for ADM quantity (P = 0.52). Logistic regression analysis demonstrated a higher risk of infection in the total ADM group (odds ratio [OR], 5.4; P < 0.0001). Diabetes mellitus was a risk factor for both infection (OR, 3.6; P = 0.05) and seroma formation (OR, 0.04; P = 0.04). CONCLUSIONS: Higher ADM burden is associated with an increased risk of infections and device explantation secondary to those infections. Although ADM has created new avenues in breast reconstruction, these findings indicate a need to evolve the technique to minimize the ADM burden. By doing so, patients can minimize their risk of postoperative complications while reducing the financial impact on institutions.

Viewing stromal vascular fraction de novo vessel formation and association with host microvasculature using the rat mesentery culture model.

OBJECTIVE: The objective of the study is to demonstrate the innovation and utility of mesenteric tissue culture for discovering the microvascular growth dynamics associated with adipose-derived stromal vascular fraction (SVF) transplantation. Understanding how SVF cells contribute to de novo vessel growth (i.e., neovascularization) and host network angiogenesis motivates the need to make observations at single-cell and network levels within a tissue. METHODS: Stromal vascular fraction was isolated from the inguinal adipose of adult male Wistar rats, labeled with DiI, and seeded onto adult Wistar rat mesentery tissues. Tissues were then cultured in MEM + 10% FBS for 3 days and labeled for BSI-lectin to identify vessels. Alternatively, SVF and tissues from green fluorescent-positive (GFP) Sprague Dawley rats were used to track SVF derived versus host vasculature. RESULTS: Stromal vascular fraction-treated tissues displayed a dramatically increased vascularized area compared to untreated tissues. DiI and GFP+ tracking of SVF identified neovascularization involving initial segment formation, radial outgrowth from central hub-like structures, and connection of segments. Neovascularization was also supported by the formation of segments in previously avascular areas. New segments characteristic of SVF neovessels contained endothelial cells and pericytes. Additionally, a subset of SVF cells displayed the ability to associate with host vessels and the presence of SVF increased host network angiogenesis. CONCLUSIONS: The results showcase the use of the rat mesentery culture model as a novel tool for elucidating SVF cell transplant dynamics and highlight the impact of model selection for visualization.

An Ex Vivo Tissue Culture Method for Discovering Cell Dynamics Involved in Stromal Vascular Fraction Vasculogenesis Using the Mouse Mesentery.

Stromal vascular fraction (SVF), isolated from adipose tissue, identifies as a rich cell source comprised of endothelial cells, endothelial progenitor cells, pericytes, smooth muscle cells, fibroblasts, and immune cells. SVF represents a promising therapeutic heterogonous cell source for growing new blood microvessels due to its rich niche of cells. However, the spatiotemporal dynamics of SVF within living tissues remain largely unknown. The objective of this chapter is to describe a protocol for culturing SVF on mouse mesentery tissues in order to aid in the discovery of SVF dynamics and associated vessel growth over time. SVF was isolated from the inguinal adipose from adult mice and seeded onto mesentery tissues. Tissues were then cultured for up to 5 days and labeled with endothelial cell and pericyte markers. Representative results demonstrate the observation of SVF-derived vasculogenesis characterized by de novo vessel formation and subsequent vessel connection.

Differences of embedding adipose-derived stromal cells in natural and synthetic scaffolds for dermal and subcutaneous delivery.

BACKGROUND: In recent years, adipose-derived stromal cells (ASCs) have been heavily studied for soft tissue regeneration, augmentation, and dermal wound healing. METHODS: In this review, we investigated the trends in injectable scaffolds for ASC delivery in the dermis, and injectable or implantable scaffolds for ASC delivery in the subcutis. A total of 547 articles were screened across three databases; of these, 22 studies were found to be eligible and were included. The scaffolds were subdivided and analyzed based on their tissue placement (dermis or subcutis), delivery method (injected or implanted), and by the origin of the materials (natural, synthetic, and combinatory). RESULTS: ASCs embedded in scaffolds generally showed improved viability. Neovascularization in the transplanted tissue was greater when undifferentiated ASCs were embedded in a combinatory scaffold or if differentiated ASCs were embedded in a natural scaffold. ASCs embedded in natural materials underwent more adipogenic differentiation than ASCs embedded in synthetic scaffolds, indicating an etiologically unknown difference that has yet to be described. Increased mechanical strength of the scaffold material correlated with improved outcome measurements in the investigated studies. Wound healing studies reported reduced healing time in all except one article due to contraction of the control wounds. CONCLUSIONS: In future clinical trials, we recommend embedding ASCs in injectable and implantable scaffolds for enhanced protection, retained viability, and improved therapeutic effects. TRIAL REGISTRATION: This review was registered with PROSPERO: ID=CRD42020171534 . The use of scaffolds as a vehicle for ASC delivery generally improved cell viability, angiogenesis, and wound healing in vivo compared to utilizing ASCs alone. ASCs embedded in natural materials induced more adipogenesis than ASCs embedded in synthetic materials. Adipogenic-induced ASCs further increased this effect. The included studies indicate that the seeded scaffold material influences the differentiation of ASCs in vivo. All studies investigating the mechanical strength of ASC scaffolds reported improved outcome measurements with improved mechanical strength. The results suggest that scaffolds, in general, are favorable for ASC delivery. We recommend initiating clinical studies using scaffolds based on mechanical properties and tunability to improve ASC viability. For fat regeneration, natural scaffolds are recommended.

A clinical perspective on adipose-derived cell therapy for enhancing microvascular health and function: Implications and applications for reconstructive surgery.

Restoration of form and function requires apposition of tissues in the form of flaps to reconstitute local perfusion. Successful reconstruction relies on flap survival and its integration with the recipient bed. The flap's precariously perfused hypoxic areas undergo adaptive microvascular changes both internally and in connection with the recipient bed. A cell-mediated, coordinated response to hypoxia drives these adaptive processes, restoring a tissue's normoxic homeostasis via de novo vasculogenesis, sprouting angiogenesis, and stabilizing arterialization. As cells exert prolonged and coordinated effects on site, their use as biological agents merit translational consideration of sourcing angio-competent cells and delivering them to territories enduring microcirculatory acclimatization. Angio-competent cells abound in adipose tissue: a reliable, accessible, and expendable source of adipose-derived cells (ADC). When subject to enzymatic digestion and centrifugation, adipose tissue separates its various ADC: A subset of buoyant oil-dense adipocytes (the tissue's parenchymal component) accumulates on a supra-natant layer, whereas the mesenchymal component remains in the infra-natant sediment, containing the tissue's stromal vascular fraction (SVF), where angio-component cells abound. The SVF can be further manipulated, selected, or culture expanded into more specific stromal subsets (herein defined as adipose stromal cells, ASC). While promising clinical applications for ADC await clinical proof and regulatory authorization, basic science investigation is needed to elucidate the specific ADC mechanisms that influence microvascular growth, remodeling, and function following flap surgery. The objective of this article is to share the clinical perspectives of reconstructive plastic surgeons regarding the use of ADC-based therapies to help with flap tissue integration, revascularization, and wound healing. Specifically, the focus will be on considering the potential for ADC as therapeutic agents and how their clinical application motivates basic science opportunities.

Autologous Fat Transfer for Scar Prevention and Remodeling: A Randomized, Blinded, Placebo-controlled Trial.

Autologous fat transfer-also referred to as fat grafting-has been reported to provide beneficial effects to overlying scar and skin. Despite procedural frequency, there is a paucity of high-level evidence guiding the surgeon in technique, patient selection, and efficacy. METHODS: A multicenter, double-blinded, randomized, internally placebo-controlled trial was performed with an aim to qualitatively and quantitatively evaluate the impact of autologous fat transfer on the quality of overlying scar tissue. Fat-grafted scars were evaluated and compared with paired, saline-injected "control" scars. Subjective and objective metrics were evaluated in treated sites for 12 months after treatment. RESULTS: Blinded qualitative results demonstrated a statistically significant improvement in scar quality over time in fat-grafted scars. However, these improvements were not found to be statistically different from changes noted in scars treated with saline. In addition, objective metrics did not statistically differ between saline-injected and autologous fat-grafted scars. CONCLUSIONS: Our results demonstrate that autologous fat grafting can improve the qualitative profile of a scar from both the patient and observer perspectives. However, there was no difference in improvement when compared with scars that were treated with saline in a randomized and blinded fashion. These results demonstrate that any improvements in scar quality related to fat grafting are also achieved using saline and suggest that mechanisms other than cell activity may be at play. Additional randomized, blinded, placebo-controlled trials are required to either corroborate or contest the putative beneficial effect(s) of adipose tissue on scar remodeling.

Ex vivo-expanded autologous adipose tissue-derived stromal cells ensure enhanced fat graft retention in breast augmentation: A randomized controlled clinical trial.

Autologous fat grafting and implant surgery are used for volume restoration in plastic surgery. With the aim of producing a treatment superior to current solutions, we report a randomized, controlled, data assessor-blinded clinical trial comparing fat grafts enriched with ex vivo-expanded autologous adipose-derived stromal cells (ASCs) to nonenriched fat grafts in breast augmentation. The intervention group received ASC-enriched fat grafts (≥20 × 106 viable ex vivo-expanded ASCs per milliliter fat), and the control group received conventional nonenriched fat grafts. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken simultaneously for outcome evaluation. ASC-enriched fat grafts had significantly higher retention rates (mean = 80.2%) compared with conventional fat grafts (mean = 45.1%). Clinical photos showed statistically significant superior results in the intervention group, assessed by independent clinical experts. These results improve the prospects for using culture-expanded ASCs in both reconstructive and cosmetic volume restoration and make the procedure an attractive alternative to conventional fat grafting and implants. This study is registered at www.ClinicalTrials.gov, number H-16046960.

Safety and Efficacy of Human Adipose-Derived Stromal/Stem Cell Therapy in an Immunocompetent Murine Pressure Ulcer Model.

Pressure injuries/ulcers are frequent complications in elderly, paraplegic, and quadriplegic patients, which account for considerable cost to the international health care economy and remain refractory to current treatment options. Autologous or allogeneic adult stromal/stem cells represent an alternative therapeutic approach. The current study extends prior findings by exploring the safety and efficacy of human adipose-derived stromal/stem cell (ASC) therapy in an established immunocompetent murine skin pressure ulcer model where dermal fibroblast cells (DFCs) served as a control. Human adipose tissue was processed using a closed system device designed for point-of-care use in the operating room and on file with the Food and Drug Administration. Cell characterization was performed using colony-forming unit-fibroblast, differentiation, and immunophenotypic assays in vitro. Wound healing was assessed over a 20-day period based on photomicrographs, histology, and immunohistochemistry. The isolated human ASCs displayed significantly greater colony formation relative to DFCs while both populations exhibited comparable immunophenotype and differentiation potential. Both fresh and cryopreserved human ASCs significantly accelerated and enhanced wound healing in young (2 month) mice of both sexes relative to DFC controls based on tissue architecture and CD68+ cell infiltration. In contrast, while injection of either fresh or cryopreserved human ASCs was safe in older mice, the fresh ASCs significantly enhanced wound closure relative to the cryopreserved ASCs. Overall, these findings support the safety and efficacy of human ASCs isolated using a closed system device designed for clinical procedures in the future treatment of pressure injuries.

Safety of Human Adipose Stromal Vascular Fraction Cells Isolated with a Closed System Device in an Immunocompetent Murine Pressure Ulcer Model.

Pressure ulcers (PUs) result in part due to ischemia-reperfusion injury to the skin and present frequently in elderly or quadriplegic patients with reduced mobility. Despite the high economic and societal cost of this condition, PU therapy relies primarily on preventive strategies and invasive surgical intervention. A growing body of clinical literature suggests that localized injection of adipose-derived cells can accelerate and enhance the closure of PUs. The current study systematically evaluated the safety of human adipose stromal vascular fraction (SVF) cells isolated using a closed system device when injected into a murine PU injury model. The human SVF cells were characterized by colony-forming unit-fibroblast and differentiation assays before use. Young (2 months) immunocompetent C57BL/6 mice subjected to a magnet-induced ischemia-reperfusion injury were injected subcutaneously with human SVF cells at increasing doses (0.25-2 million cells). The size of the PU was monitored over a 20-day period. Both female and male mice tolerated the concentration-dependent injection of the SVF cells without complications. While male mice trended toward more rapid wound closure rates in response to lower SVF cell concentrations (0.25-0.5 million cells), female mice responded favorably to higher SVF cell concentrations (1-2 million cells); however, outcomes did not reach statistical significance in either sex. Overall, the study demonstrates that human SVF cells prepared with a closed system device designed for use at point of care can be safely administered for PU therapy in an immunocompetent host animal model.

Arguments for a Different Regulatory Categorization and Framework for Stromal Vascular Fraction.

Although adipose tissue and cells show considerable promise for clinical translation in the emerging field of regenerative medicine, they present a challenge to the regulatory community both nationally and internationally. This commentary evaluates the status of adipose-derived therapeutics and considers regulatory approaches designed to maximize patient safety while advancing clinical translation in accordance with evidence-based medical science.