Nanofat Accelerates and Improves the Vascularization, Lymphatic Drainage and Healing of Full-Thickness Murine Skin Wounds.

The treatment of wounds using the body's own resources is a promising approach to support the physiological regenerative process. To advance this concept, we evaluated the effect of nanofat (NF) on wound healing. For this purpose, full-thickness skin defects were created in dorsal skinfold chambers of wild-type mice. These defects were filled with NF generated from the inguinal subcutaneous adipose tissue of green fluorescent protein (GFP)+ donor mice, which was stabilized using platelet-rich plasma (PRP). Empty wounds and wounds solely filled with PRP served as controls. Wound closure, vascularization and formation of granulation tissue were repeatedly analyzed using stereomicroscopy, intravital fluorescence microscopy, histology and immunohistochemistry over an observation period of 14 days. PRP + NF-treated wounds exhibited accelerated vascularization and wound closure when compared to controls. This was primarily due to the fact that the grafted NF contained a substantial fraction of viable GFP+ vascular and lymph vessel fragments, which interconnected with the GFP- vessels of the host tissue. Moreover, the switch from inflammatory M1- to regenerative M2-polarized macrophages was promoted in PRP + NF-treated wounds. These findings indicate that NF markedly accelerates and improves the wound healing process and, thus, represents a promising autologous product for future wound management.

Effects of negative pressure wound therapy with instillation and dwell time (NPWTi-d) versus NPWT or standard of care in orthoplastic surgery: A systematic review and meta-analysis.

Negative pressure wound therapy (NPWT) is a wound-dressing system that applies sub-atmospheric pressure on the surface of a wound to promote healing. An evolution of this technology, NPWT with solution instillation and dwell time (NPWTi-d), is increasingly being used to maximise wound closure and reduce failure rates. However, there is still a lack of evidence concerning its use in orthoplastic surgery. Therefore, the aim of this study is to compare NPWTi-d with NPWT and standard of care for wound management in orthoplastic surgery. A comprehensive literature search using PubMed, Web of Science, and Cochrane databases up to 15 March 2022 was performed, including studies describing the outcomes of NPWTi-d for traumatic/orthopaedic injuries. A meta-analysis on the number of surgical debridements, as well as the rate of complete wound closure and complications was carried out, although for other outcomes, a descriptive statistic was applied. Risk of bias and quality of evidence were assessed using the Downs& Black's Checklist for Measuring Quality. Thirteen studies with a total number of 871 patients were included, in which NPWTi-d demonstrated significantly higher primary wound closure and lower complication rates (P < .05). No difference in the number of surgical procedures required for final wound healing was observed. Moreover, five out of six studies showed better results for NPWTi-d when the change of the bioburden and bacterial count of the wound were analysed. A singular study investigating the length of the hospital stay of patients treated with NPWTi-d showed a reduction in the latter. The present meta-analysis proves that NPWTi-d is superior to NPTW or conventional dressings in orthoplastic wound care management, in terms of complete wound closure rate and the reduced number of complications. Still, the limited quality of the studies analysed shows that future randomised studies are needed to confirm the benefits and to identify the most appropriate recommendations for using NPWTi-d in orthoplastic surgery, as well as to investigate the cost-effectiveness of this wound-dressing system.

Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery: Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study.

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

Generation of Cross-Specialty Consensus Statements on Soft Tissue Management via a Modified Delphi Method.

BACKGROUND: Soft tissue management (STM) training programs for surgeons are largely tradition based, and substantial differences exist among different surgical specialties. The lack of comprehensive and systematic clinical evidence on how surgical techniques and implants affect soft tissue healing makes it difficult to develop evidence-based curricula. As a curriculum development group (CDG), we set out to find common grounds in the form of a set of consensus statements to serve as the basis for surgical soft tissue education. METHODS: Following a backward planning process and Kern's six-step approach, the group selected 13 topics to build a cross-specialty STM curriculum. A set of statements based on the curriculum topics were generated by the CDG through discussions and a literature review of three topics. A modified Delphi process including one round of pilot voting through a face-to-face CDG meeting and two rounds of web-based survey involving 22 panelists were utilized for the generation of consensus statements. RESULTS: Seventy-one statements were evaluated, and 56 statements reached the 80% consensus for "can be taught as is." CONCLUSIONS: Using a modified Delphi method, a set of cross-specialty consensus statements on soft tissue management were generated. These consensus statements can be used as a foundation for multi-specialty surgical education. Similar methods that combine expert experience and clinical evidence can be used to develop specialty-specific consensus on soft tissue handling.

The Impact of the COVID-19 Pandemic on Surgical Management of Breast Cancer: Global Trends and Future Perspectives.

INTRODUCTION: The rapid spread of COVID-19 across the globe is forcing surgical oncologists to change their daily practice. We sought to evaluate how breast surgeons are adapting their surgical activity to limit viral spread and spare hospital resources. METHODS: A panel of 12 breast surgeons from the most affected regions of the world convened a virtual meeting on April 7, 2020, to discuss the changes in their local surgical practice during the COVID-19 pandemic. Similarly, a Web-based poll based was created to evaluate changes in surgical practice among breast surgeons from several countries. RESULTS: The virtual meeting showed that distinct countries and regions were experiencing different phases of the pandemic. Surgical priority was given to patients with aggressive disease not candidate for primary systemic therapy, those with progressive disease under neoadjuvant systemic therapy, and patients who have finished neoadjuvant therapy. One hundred breast surgeons filled out the poll. The trend showed reductions in operating room schedules, indications for surgery, and consultations, with an increasingly restrictive approach to elective surgery with worsening of the pandemic. CONCLUSION: The COVID-19 emergency should not compromise treatment of a potentially lethal disease such as breast cancer. Our results reveal that physicians are instinctively reluctant to abandon conventional standards of care when possible. However, as the situation deteriorates, alternative strategies of de-escalation are being adopted. IMPLICATIONS FOR PRACTICE: This study aimed to characterize how the COVID-19 pandemic is affecting breast cancer surgery and which strategies are being adopted to cope with the situation.

Changes in skin-physiology after local heat application using two different methods in individuals with complete paraplegia: a feasibility and safety trial.

STUDY DESIGN: Interventional feasibility study. OBJECTIVES: To evaluate safety and effects of local heat preconditioning on skin physiology using water-filtered infrared-A radiation (wIRA) or warm water therapy (wWT) in individuals with spinal cord injury (SCI). SETTING: Acute and rehabilitation center, specialized in SCI. METHODS: A convenience sample of 15 individuals (3 women, 12 men) with complete paraplegia from thoracic levels ranging between T2 and T12 received local heat applications either with wIRA or wWT on the thigh (paralyzed area) and on the upper arm (non-paralyzed area). Local heat was applied during three 30-min cycles, each separated by 30 min rest; thus, the treatment lasted for 180 min. Temperature, blood perfusion, and skin redness were measured at baseline, before and after heat application and 24 h after the last application. RESULTS: Heat applications with wIRA and wWT were well-tolerated. No burns or any other side effects were detected. Skin temperature (p ≤ 0.008) and blood perfusion (p ≤ 0.013) significantly increased after heat application. Local skin temperature (arm p = 0.004/leg p < 0.001) and blood perfusion (arm p = 0.011/leg p = 0.001) after the first and the second application cycle, respectively, were significantly higher during heat application with wIRA than with wWT. However, skin redness did not change significantly (p = 0.1). No significant differences were observed between the paralyzed and non-paralyzed areas for all parameters immediately, as well as 24 h after the treatment. CONCLUSIONS: Although both heating methods have been confirmed as safe treatments in this study, further investigations with regard to their efficacy in the context of preconditioning are warranted. SPONSORSHIP: The use of the instruments Hydrosun® 750 Irradiator (Hydrosun Medizintechnik, Germany) and Hilotherm-Calido 6 (Hilotherm GmbH, Germany) was sponsored by the Dr. med. h. c. Erwin Braun Foundation and by Hilotherm GmbH, respectively.

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

PURPOSE: Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. METHODS: The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. RESULTS: Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. CONCLUSIONS: In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.

Common Rodent Flap Models in Experimental Surgery.

BACKGROUND: Flap procedures are widely used in clinical reconstructive surgery. Since ische-mia-associated complications, e.g., wound breakdown or tissue necrosis, are still a great challenge in flap surgery, experimental flap models are widely used to study flap physiology and to evaluate treatment strategies to prevent these complications. SUMMARY: Since rodents in general, and mice and rats in particular, are widely used in experimental flap models, we give an overview of the most common flap models in rodents, including the cremaster flap, the osteomyocutaneous flap, the McFarlane flap, the ear flap, and the dorsal skinfold chamber. Key Messages: Rodent flap models in experimental surgery are manifold and have a long history. These models play an important role in training surgical techniques, understanding flap physiology, defining flap anatomy and vascularity, and developing treatment regimens to prevent the necrosis of ischemically challenged tissue. However, it is important to be aware of the advantages and disadvantages of the single flap models concerning the possible time span of the experiment, the degree of difficulty, and the reproducibility and the translation of the results in humans.

First international consensus conference on standardization of oncoplastic breast conserving surgery.

PURPOSE: To obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology. METHODS: A total of 52 questions were addressed by electronic voting. The panel's recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained. RESULTS: The panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-Q™-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient. CONCLUSIONS: When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.

Gluteal Augmentation Techniques: A Comprehensive Literature Review.

Background: Many studies of gluteal augmentation techniques have been published in recent decades, including case reports, retrospective and prospective case series, and multicenter survey reviews. However, to date, there has been no study of the overall complications or satisfaction rates associated with the broad spectrum of techniques. Objectives: The authors performed a comprehensive literature review to determine outcomes and complications of gluteoplasty techniques, including patient satisfaction. Methods: A search on PubMed/Medline was performed for clinical studies involving gluteal augmentation techniques. A priori criteria were used to review the resulting articles. Results: Fifty-two studies, published from 1969 through 2015, were included - representing 7834 treated patients. Five gluteal augmentation techniques were identified from these studies: gluteal augmentation with implants (n = 4781), autologous fat grafting (n = 2609), local flaps (n = 369), hyaluronic acid gel injection (n = 69), and local tissue rearrangement (n = 6). The overall complication rates of the most commonly utilized techniques were: 30.5% for gluteal augmentation with implants, 10.5% for autologous fat grafting, and 22% for local flaps. Patients' satisfaction was reported as consistently high for all the five techniques. Conclusions: Implant-based gluteal augmentation is associated with high patients' satisfaction despite a high complication rate, while autologous fat grafting is associated with the lowest complication rate yet including serious major complications such as fat embolism. Local flaps and local tissue rearrangements are the ideal procedures in case of massive weight loss patients. A paucity of data is available for hyaluronic acid gel injections, which appear to be effective but temporary and expensive.

Recurrence of Hypertrophic Abductor Digiti Minimi Muscle of the Foot After Subtotal Resection.

Soft tissue tumors of the foot are rare, and the diagnosis is often difficult. Surgery is indicated if pain, discomfort, or functional impairment is present or to rule out malignancy. We present the case of a 14-year-old female with a painless swelling at the lateral aspect of her right foot. After radiologic imaging, including ultrasonography and magnetic resonance imaging (MRI), we performed a subtotal resection of the abductor digiti minimi muscle, preserving its motor nerve. Four months later, recurrence of the soft tissue mass was observed. MRI revealed hypertrophy of the small muscles of the foot, including the abductor digiti minimi, quadratus plantae, and flexor digiti minimi brevis. Functional impairment resulted in complete excision of the remnant abductor digiti minimi muscle and partial excision of the flexor digiti minimi brevis muscle another 7 months later. Twelve months after the secondary surgery, neither clinical nor radiologic signs of a second recurrence were found. At the last follow-up visit, the patient was satisfied with the contour of her foot and not hindered at all during sporting activities. Our findings demonstrate that subtotal resection of a bulky muscle, preserving its motor nerve, can result in reactive hypertrophy of the remnant muscle part. The patient must be informed that partial excision of an innervated muscle could result in reactive hypertrophy and must be contrasted with radical muscle excision that might be more likely to result in functional impairment.

Pyoderma gangrenosum following reduction mammoplasty: Systematic review of the literature and case report.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic dermatosis that can develop at a surgical site. Diagnosis can be challenging at its presentation causing delays in appropriate treatment. The aim of this study is to review the current literature as well as to describe the clinical presentation, diagnostic pathway, and treatment of PG after reduction mammaplasty in order to define a standardized multidisciplinary diagnostic and therapeutic approach. In the future, this may ease early identification and prompt treatment, and eventually minimize severe morbidity and long-term sequelae. METHODS: The entire PubMed/Medline database was screened following the PRISMA guidelines to identify studies describing PG that have occurred after reduction mammoplasty. RESULTS: Twenty-eight articles including 31 patients reported a PG after breast reduction surgery between January 1988 and March 2022. Twenty-one (68%) patients presented with skin ulcerations, 14 (45%) with erythema, and 5 (16%) with vesicles. Out of the 30 cases that underwent bilateral surgery, 18 (60%) developed PG bilaterally. In 12 out of 31 patients, nipple-areolar complex (NAC) involvement was evaluated, though in 10 patients (83%) the NAC was spared. Of the 20 patients (65%) who underwent skin biopsies for histopathological examination, 18 (90%) showed neutrophilic infiltration of the dermal layers. All 31 patients (100%) showed rapid clinical improvement after the introduction of immunosuppressive therapy. CONCLUSIONS: PG can result in devastating skin alterations also after reduction mammoplasty, if misdiagnosed. However, it presents with constant yet unspecific local and general signs and symptoms that can be recognized to early initiate an appropriate pharmacological treatment.

Complications Associated with Facial Autologous Fat Grafting for Aesthetic Purposes: A Systematic Review of the Literature.

Background: With the increasing demand for aesthetic procedures, autologous fat grafting (AFG) seems to be an attractive option for facial volumization and rejuvenation. The aim of this study was to assess the type and severity of associated complications after facial AFG for aesthetic purposes. Methods: The entire PubMed/Medline and Cochrane databases were screened to identify studies describing complications that occurred after the injection of autologous fat into the face. These complications have been reviewed and analyzed according to their occurrence and severity in the different anatomical regions of the face. Results: Twenty-two articles including 38 patients reported on a total of 58 complications. Thirty-two complications have been classified as severe or permanent, including hemiplegia (n = 11), loss of vision (n = 7), or skin necrosis (n = 3). The other 26 complications were classified as mild or transient, such as lipogranuloma (n = 12) or mycobacterial abscess (n = 2). The majority of complications were reported after injection to the forehead (n = 26) and the temporal region (n = 21). Interestingly, this location seems to be the area at risk because 53% of all severe complications occurred in this anatomical region. Conclusions: AFG to the face is associated with a low incidence of complications, but if they occur, they can be dramatic, particularly in the forehead and temporal region. Nevertheless, AFG can be used to correct age-related changes of the face and volume loss and may represent an alternative to synthetic fillers. Therefore, AFG to the face should be performed by qualified doctors under careful consideration of risks and facial anatomy.

The Influence of Inset and Shaping of Abdominal-Based Free Flap Breast Reconstruction on Patient-Reported Aesthetic Outcome Scores-A Systematic Review.

Background: Nowadays, multimodal cancer therapy results in very high survival rates of early-stage breast cancer and microsurgical flap-based breast reconstruction has become safe and reliable, with gradually increasing demand because of its durable and aesthetically pleasing results. This study aimed to explore the impact of different flap shaping and inset techniques on patient-reported outcome measures (PROMs) with regard to the aesthetic result in abdominal flap-based breast reconstruction. Methods: A systematic review was performed screening Pubmed, Cochrane Library and Web of Science for original articles reporting flap inset strategies, concomitantly providing PROMs on the aesthetic result. Results: Of 319 studies identified, six met the inclusion criteria. The studies described different flap rotation options according to the patient's morphology, different inset planes, and avoidance of the monitoring skin paddle, and suggested that a higher flap-to-mastectomy mass ratio was associated with better aesthetic results. In two comparative studies, according to the PROMs (BREAST-Q, Likert scale) and independent observer judgement, both higher patient satisfaction and superior aesthetic results were observed with the newly described techniques. Conclusions: Emphasis on the aesthetic outcome in terms of breast shape and symmetry, providing an individualized approach of flap inset, considering the contralateral breast's shape and volume, results in higher satisfaction scores.

Is free nipple grafting necessary in patients undergoing reduction mammoplasty for gigantomastia? A systematic review and meta-analysis.

BACKGROUND: Gigantomastia is a debilitating condition characterised by an excessive breast tissue growth impacting patients' quality of life. Surgically treatment options include the limited-length pedicle (LP) technique with free nipple grafting (FNG) and the elongated pedicle (EP) technique, which maintains continuity of the nipple-areola complex (NAC). Initially, despite the less satisfactory aesthetic outcome, FNG was preferred to treat hypertrophic breasts requiring resections over 1000 g of parenchymal and adipose tissue, due to concerns about NAC perfusion. Recently, many studies have questioned this indication. The aim of this study was therefore to evaluate the safety of the NAC-carrying EP technique in patients with gigantomastia eventually challenging the need for FNG. METHODS: A literature search using PubMed and Cochrane databases was performed, including studies describing the outcome of EP technique for resection exceeding 1000 g of breast tissue. Thereby, a meta-analysis was conducted to evaluate the rate of NAC necrosis, whereas a descriptive statistic was applied to assess all other surgery-associated complications. RESULTS: Twenty-five studies, encompassing 1355 patients (2656 breasts), were included. EP demonstrated an extremely low rate of NAC necrosis. Moreover, the analysis demonstrated a low rate of ischaemia-independent complications and a very high probability of maintaining NAC-sensation equal to the preoperative state. CONCLUSION: Current evidence indicates that the EP technique should be the preferred surgical method to treat gigantomastia with or without massive ptosis whenever indicated. It has proven to be safe. Furthermore, it yields superior aesthetic and functional outcomes, including breast feeding and preservation of NAC-sensation compared to the LP technique.

Short-Term Periodic Fasting Reduces Ischemia-Induced Necrosis in Musculocutaneous Flap Tissue.

Periodic fasting (PF) as a form of dietary restriction has been shown to induce tissue-protective effects against ischemic injury in several different tissues. Accordingly, in this study we analyzed whether a short-term 24 h fast is suitable to prevent necrosis of musculocutaneous flap tissue undergoing acute persistent ischemia. C57BL/6N mice were randomly divided into a PF group (n = 8) and a control group that was given unrestricted access to standard chow (n = 8). The PF animals underwent a 24 h fast immediately before flap elevation and had unrestricted access to food for the rest of the 10 day observation period. Musculocutaneous flaps with a random pattern design were dissected on the animals' backs and mounted into dorsal skinfold chambers. On days 1, 3, 5, 7 and 10 after surgery, nutritive tissue perfusion, angiogenesis and flap necrosis were evaluated using intravital fluorescence microscopy. Thereafter, the flap tissue was excised and fixed for histological and immunohistochemical analyses. The flaps of PF-treated animals exhibited a higher functional capillary density and more newly formed microvessels, resulting in a significantly increased flap survival rate. Moreover, they contained a lower number of myeloperoxidase (MPO)-positive neutrophilic granulocytes and cleaved caspase-3-positive apoptotic cells in the transition zone between vital and necrotic flap tissue. These findings indicate that short-term PF improves tissue survival in ischemically challenged musculocutaneous flaps by maintaining nutritive blood perfusion and dampening ischemia-induced inflammation.

Preconditioning Strategies for Improving the Outcome of Fat Grafting.

Autologous fat grafting is a common procedure in plastic, reconstructive, and aesthetic surgery. However, it is frequently associated with an unpredictable resorption rate of the graft depending on the engraftment kinetics. This, in turn, is determined by the interaction of the grafted adipose tissue with the tissue at the recipient site. Accordingly, preconditioning strategies have been developed following the principle of exposing these tissues in the pretransplantation phase to stimuli inducing endogenous protective and regenerative cellular adaptations, such as the upregulation of stress-response genes or the release of cytokines and growth factors. As summarized in the present review, these stimuli include hypoxia, dietary restriction, local mechanical stress, heat, and exposure to fractional carbon dioxide laser. Preclinical studies show that they promote cell viability, adipogenesis, and angiogenesis, while reducing inflammation, fibrosis, and cyst formation, resulting in a higher survival rate and quality of fat grafts in different experimental settings. Hence, preconditioning represents a promising approach to improve the outcome of fat grafting in future clinical practice. For this purpose, it is necessary to establish standardized preconditioning protocols for specific clinical applications that are efficient, safe, and easy to implement into routine procedures.

The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use.

Erythropoietin (EPO) is the main regulator of red blood cell production but there exists also a variety of nonhematopoietic properties. More recent data show that EPO is also associated with the protection of tissues suffering from ischemia and reperfusion injury as well as with improved regeneration in various organ systems, in particular the skin. This review highlights the mechanisms of EPO in the different stages of wound healing and the reparative processes in the skin emphasizing pathophysiological mechanisms and potential clinical applications. There is clear evidence that EPO effectively influences all wound-healing phases in a dose-dependent manner. This includes inflammation, tissue, and blood vessel formation as well as the remodeling of the wound. The molecular mechanism is predominantly based on an increased expression of the endothelial and inducible nitric oxide (NO) synthase with a consecutive rapid supply of NO as well as an increased content of vascular endothelial growth factor (VEGF) in the wound. The improved understanding of the functions and regulatory mechanisms of EPO in the context of wound-healing problems and ischemia/reperfusion injury, especially during flap surgery, may lead to new considerations of this growth hormone for its regular clinical application in patients.

Long-term preconditioning with erythropoietin reduces ischemia-induced skin necrosis.

OBJECTIVE: Recent findings have attested to EPO tissue-protective effects in ischemically challenged tissues. Therefore, the study aimed at elaborating the effect of systemic pre- and postconditioning using EPO in a mouse model of persistent ischemia of the skin. METHODS: Three groups of nine C57Bl/6-mice each were analyzed. The experimental groups consisted of untreated controls, EPO preconditioning, and EPO postconditioning (500 IU EPO/kg bw/day for 10 days). Critically perfused skin flaps undergoing necrosis, if kept untreated, were mounted into dorsal skinfold chambers. Intravital epi-fluorescence microscopy was performed for 10 days to assess tissue necrosis, microcirculation, inflammation, and angiogenesis. Protein expression analysis of eNOS was performed. Hematocrit analyses were carried out separately in eight animals. RESULTS: Only EPO preconditioning was able to significantly reduce necrosis, when compared with controls. This correlated with a significantly increased CD in the critically perfused tissue. Administration of EPO only slightly increased eNOS expression at day 10, when compared with controls. EPO induced angiogenesis and increased hematocrit. Finally, EPO significantly reduced leukocytic inflammation in arterioles in all EPO receiving mice. CONCLUSIONS: EPO preconditioning effectively reduces skin necrosis predominantly by capillary maintenance and reperfusion, as well as improved tissue regeneration. Thus, EPO preconditioning might represent a promising, non-invasive approach to reduce complications in ischemically challenged skin.

Secondary burn progression decreased by erythropoietin.

OBJECTIVE: To investigate whether systemic erythropoietin administration can prevent secondary burn progression in an experimental model and to elucidate the underlying mechanisms. DESIGN: Prospective study. SETTING: University-based laboratory research. SUBJECTS: Twenty-one male Wistar rats. INTERVENTIONS: The burn comb model creates four rectangular burned surfaces that are intercalated by three unburned zones (interspaces) prone to secondary necrosis. Twenty-one animals were randomized to three experimental groups: 1) Local cooling with water for 20 minutes (control, 17°C); 2) and 3) local cooling with water and intraperitoneal erythropoietin once a day for five days starting 45 minutes after burn injury (500 IU/kg body weight: EPO 500 or 2500 IU/kg body weight: EPO 2500). MEASUREMENTS AND MAIN RESULTS: Secondary burn progression-both in depth (histology) and in surface (planimetry)-as well as interspace perfusion (laser Doppler flowmetry) and hematocrit were analyzed. Further, dilatory response (inducible nitric oxide synthase expression), inflammation (leukocyte count), and angiogenesis (CD31 expression) were assessed. Finally, wound healing time and contracture rate were reported. Burn progression resulted in complete dermal destruction as well as in important interspace necrosis in control animals, whereas burn progression was significantly reduced in a dose-dependent manner in animals treated with erythropoietin. Tissue protection was associated with an increased interspace perfusion with EPO 500, but not with EPO 2500, and was paralleled by a significant increase in inducible nitric oxide synthase expression and decreased inflammation, independent of the erythropoietin dosage. EPO 2500 led to a significant increase of hematocrit at day 4. Finally, faster wound healing and less contracture were observed in animals treated with EPO 500 only. CONCLUSIONS: Erythropoietin represents an easy-to-use therapeutic approach to prevent secondary burn progression, i.e., to control damage after burn injury. It preserves microcirculatory perfusion within the endangered areas in a dose-dependent manner.