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 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.

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.

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.

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.

Historical Roots of Modern Plastic Surgery: A Cited Reference Analysis.

BACKGROUND: Highly cited publications are referred to as citation classics and can signify important contributions to a discipline. Although citation classics in plastic surgery have been identified, none were published before 1960. Citation classics in earlier periods may contain the historical roots or intellectual origins of the field. We set out to identify such scholarly works and analyze their characteristics. METHODS: A novel technique of citation analysis, referred to as reference publication year spectroscopy, was used to analyze the literature. The spectrogram revealed distinct peaks before 1960, which corresponded to 20 citation classics. These 20 references were then analyzed with respect to historical context, topic of interest, anatomical region, originality, and if authors were named for their findings (eponyms). RESULTS: Twenty distinct citation classics (published from 1851 to 1959) were identified, accounting for 430 literature citations. Salmon's "Arteres de la Peau" was the most cited reference, followed by Gillies' "Principles of Plastic Surgery" and Neuber's "Fat Grafting." The theme of angiosomes was highly represented. Most citation classics dealt with reconstruction of acquired defects (37%) and primarily focused on the head and neck regions (45%). Thirty-five percent of clinical studies were noted for their originality, and 5 studies earned their authors' eponymous distinctions. CONCLUSION: The roots of modern plastic surgery began in the late 19th century with early efforts to describe cutaneous vasculature. Historical studies that either establish principles or lead to an advancement in our reconstructive methods have the best chance of achieving classical status.

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.

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.

Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT).

BACKGROUND AIMS: Adipose tissue is a rich and very convenient source of cells for regenerative medicine therapeutic approaches. However, a characterization of the population of adipose-derived stromal and stem cells (ASCs) with the greatest therapeutic potential remains unclear. Under the authority of International Federation of Adipose Therapeutics and International Society for Cellular Therapy, this paper sets out to establish minimal definitions of stromal cells both as uncultured stromal vascular fraction (SVF) and as an adherent stromal/stem cells population. METHODS: Phenotypic and functional criteria for the identification of adipose-derived cells were drawn from the literature. RESULTS: In the SVF, cells are identified phenotypically by the following markers: CD45-CD235a-CD31-CD34+. Added value may be provided by both a viability marker and the following surface antigens: CD13, CD73, CD90 and CD105. The fibroblastoid colony-forming unit assay permits the evaluation of progenitor frequency in the SVF population. In culture, ASCs retain markers in common with other mesenchymal stromal/stem cells (MSCs), including CD90, CD73, CD105, and CD44 and remain negative for CD45 and CD31. They can be distinguished from bone-marrow-derived MSCs by their positivity for CD36 and negativity for CD106. The CFU-F assay is recommended to calculate population doublings capacity of ASCs. The adipocytic, chondroblastic and osteoblastic differentiation assays serve to complete the cell identification and potency assessment in conjunction with a quantitative evaluation of the differentiation either biochemically or by reverse transcription polymerase chain reaction. CONCLUSIONS: The goal of this paper is to provide initial guidance for the scientific community working with adipose-derived cells and to facilitate development of international standards based on reproducible parameters.

Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells.

After more than a decade of extensive experimentation, the promise of stem cells to revolutionize the field of medicine has negotiated their entry into clinical trial. Adipose tissue specifically holds potential as an attainable and abundant source of stem cells. Currently undergoing investigation are adipose stem cell (ASC) therapies for diabetes and critical limb ischemia, among others. In the enthusiastic pursuit of regenerative therapies, however, questions remain regarding ASC persistence and migration, and, importantly, their safety and potential for neoplasia. To date, assays of in vivo ASC activity have been limited by early end points. We hypothesized that with time, ASCs injected subcutaneously undergo removal by normal tissue turnover and homeostasis, and by the host's immune system. In this study, a high dose of culture expanded ASCs was formulated and implanted as multicellular aggregates into immunocompromised mice, which were maintained for over one year. Animals were monitored for toxicity, and surviving cells quantified at study endpoint. No difference in growth/weight or lifespan was found between cell-treated and vehicle treated animals, and no malignancies were detected in treated animals. Moreover, real-time PCR for a human specific sequence, ERV-3, detected no persistent ASCs. With the advent of clinical application, clarification of currently enigmatic stem cell properties has become imperative. Our study represents the longest duration determination of stem cell activity in vivo, and contributes strong evidence in support of the safety of adipose derived stem cell applications.

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.

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.

Evaluation of host tissue integration, revascularization, and cellular infiltration within various dermal substrates.

Acellular dermal matrices are used in a variety of reconstructive and cosmetic procedures. There seems to be host tissue integration, revascularization, and recellularization into these products, but the exact timing and differences among these remain unknown. The purpose of this study is to determine and compare these properties of 4 different acellular dermal matrices (AlloDerm, DermACELL, DermaMatrix, and Integra) in an in vivo rat model. Tissue specimens were obtained at various time points. Histology and immunohistologic assays were used to quantify the extent of cellular infiltration and revascularization within the various matrices. A bimodal cellular response was observed in all products except for DermACELL. Cellular infiltration was highest in DermACELL and lowest in AlloDerm, and angiogenesis was evident by day 7. There were clear differences within the various products. It is undetermined whether these differences are advantageous or clinically significant. Future work is needed to define the specific roles for each.

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.

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.

Hypoxic culture and in vivo inflammatory environments affect the assumption of pericyte characteristics by human adipose and bone marrow progenitor cells.

Previous studies have shown that exposure to a hypoxic in vitro environment increases the secretion of pro-angiogenic growth factors by human adipose-derived stromal cells (hASCs) [Cao Y, et al., Biochem Biophys Res Commun 332: 370-379, 2005; Kokai LE, et al., Plast Reconstr Surg 116: 1453-1460, 2005; Park BS, et al., Biomed Res (Tokyo) 31: 27-34, 2010; Rasmussen JG, et al., Cytotherapy 13: 318-328, 2010; Rehman J, et al., Circulation 109: 1292-1298, 2004]. Previously, it has been demonstrated that hASCs can differentiate into pericytes and promote microvascular stability and maintenance during angiogenesis in vivo (Amos PJ, et al., Stem Cells 26: 2682-2690, 2008; Traktuev DO, et al., Circ Res 102: 77-85, 2008). In this study, we tested the hypotheses that angiogenic induction can be increased and pericyte differentiation decreased by pretreatment of hASCs with hypoxic culture and that hASCs are similar to human bone marrow-derived stromal cells (hBMSCs) in these regards. Our data confirms previous studies showing that hASCs: 1) secrete pro-angiogenic proteins, which are upregulated following culture in hypoxia, and 2) migrate up gradients of PDGF-BB in vitro, while showing for the first time that a rat mesenteric model of angiogenesis induced by 48/80 increases the propensity of both hASCs and hBMSCs to assume perivascular phenotypes following injection. Moreover, culture of both cell types in hypoxia before injection results in a biphasic vascular length density response in this model of inflammation-induced angiogenesis. The effects of hypoxia and inflammation on the phenotype of adult progenitor cells impacts both the therapeutic and the basic science applications of the cell types, as hypoxia and inflammation are common features of natural and pathological vascular compartments in vivo.

An update on wound healing and the nervous system.

Impaired wound healing is a significant clinical, economic, and social problem. There is a growing body of research over the past several decades that supports the importance of neuropeptides and neurotransmitters in wound healing, particularly in diabetic patients. The purpose of this article is to review current translational research that supports the role of the nervous system in normal wound physiology and the current state of clinical application.

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.