Publications by authors named "Norbert Pallua"

193 Publications

Proliferation of endothelial cells (HUVEC) on specific-modified collagen sponges loaded with different growth factors.

Int J Artif Organs 2021 Nov 8;44(11):880-886. Epub 2021 Sep 8.

Department of Plastic Surgery and Hand Surgery, Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.

In general, matrices for tissue engineering must maintain structural integrity during the process of tissue formation and promote vascularization of developing tissue. Therefore, collagen sponges, manufactured by an approach that offers the potential of unidirectional pore size, were seeded with human umbilical vein endothelial cells (HUVEC) to demonstrate a positive effect on cell proliferation. In addition, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been used to promote proliferation of HUVEC on optimized collagen sponges. Growth and viability of the cells were evaluated. Potential unidirectional pore structure demonstrated an improvement of both, endothelial cell growth and viability. Supplementation of growth factors showed an additional increase of endothelial cell growth on collagen sponges, which confirmed the high potential of combining this biomaterial with growth factors. The results suggest that a collagen sponge with a potential specific pore size could be a suitable scaffold for endothelial cells and might be a promising implantable biomaterial with enhanced angiogenic capabilities for future clinical applications.
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http://dx.doi.org/10.1177/03913988211043198DOI Listing
November 2021

The Role of Macrophage Migration Inhibitory Factor in Adipose-Derived Stem Cells Under Hypoxia.

Front Physiol 2021 21;12:638448. Epub 2021 Jul 21.

Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.

Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue. Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody. Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs. Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.
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http://dx.doi.org/10.3389/fphys.2021.638448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334873PMC
July 2021

Macrophage Migration Inhibitory Factor-An Innovative Indicator for Free Flap Ischemia after Microsurgical Reconstruction.

Healthcare (Basel) 2021 May 21;9(6). Epub 2021 May 21.

Department of Plastic Surgery and Hand Surgery, Gemeinschaftskrankenhaus Havelhoehe, Kladower Damm 221, 14089 Berlin, Germany.

(1) Background: Nowadays, the use of microsurgical free flaps is a standard operative procedure in reconstructive surgery. Still, thrombosis of the microanastomosis is one of the most fatal postoperative complications. Clinical evaluation, different technical devices and laboratory markers are used to monitor critical flap perfusion. Macrophage migration inhibitory factor (MIF), a structurally unique cytokine with chemokine-like characteristics, could play a role in predicting vascular problems and the failure of flap perfusion. (2) Methods: In this prospective observational study, 26 subjects that underwent microsurgical reconstruction were observed. Besides clinical data, the number of blood leukocytes, CRP and MIF were monitored. (3) Results: Blood levels of MIF, C-reactive protein (CRP) and leukocytes increased directly after surgery. Subjects that needed surgical revision due to thrombosis of the microanastomosis showed significantly higher blood levels of MIF than subjects without revision. (4) Conclusion: We conclude that MIF is a potential and innovative indicator for thrombosis of the microanastomosis after free flap surgery. Since it is easy to obtain diagnostically, MIF could be an additional tool to monitor flap perfusion besides clinical and technical assessments.
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http://dx.doi.org/10.3390/healthcare9060616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223971PMC
May 2021

The Effect of Hyperbaric Oxygen Therapy on Human Adipose-Derived Stem Cells.

Plast Reconstr Surg 2020 08;146(2):309-320

From the Department of Plastic Surgery and Hand Surgery-Burn Center and the Department of Anesthesiology, University Hospital RWTH Aachen; HBO-Center Euregio Aachen; and Aesthetic Elite International.

Background: Adipose-derived stem cells are considered as candidate cells for regenerative plastic surgery. Measures to influence cellular properties and thereby direct their regenerative potential remain elusive. Hyperbaric oxygen therapy-the exposure to 100% oxygen at an increased atmospheric pressure-has been propagated as a noninvasive treatment for a multitude of indications and presents a potential option to condition cells for tissue-engineering purposes. The present study evaluates the effect of hyperbaric oxygen therapy on human adipose-derived stem cells.

Methods: Human adipose-derived stem cells from healthy donors were treated with hyperbaric oxygen therapy at 2 and 3 atm. Viability before and after each hyperbaric oxygen therapy, proliferation, expression of surface markers and protein contents of transforming growth factor (TGF)-β, tumor necrosis factor-α, hepatocyte growth factor, and epithelial growth factor in the supernatants of treated adipose-derived stem cells were measured. Lastly, adipogenic, osteogenic, and chondrogenic differentiation with and without use of differentiation-inducing media (i.e., autodifferentiation) was examined.

Results: Hyperbaric oxygen therapy with 3 atm increased viability, proliferation, and CD34 expression and reduced the CD31/CD34/CD45 adipose-derived stem cell subset and endothelial progenitor cell population. TGF-β levels were significantly decreased after two hyperbaric oxygen therapy sessions in the 2-atm group and decreased after three hyperbaric oxygen therapy sessions in the 3-atm group. Hepatocyte growth factor secretion remained unaltered in all groups. Although the osteogenic and chondrogenic differentiation were not influenced, adipogenic differentiation and autodifferentiation were significantly enhanced, with osteogenic autodifferentiation significantly alleviated by hyperbaric oxygen therapy with 3 atm.

Conclusion: Hyperbaric oxygen therapy with 3 atm increases viability and proliferation of adipose-derived stem cells, alters marker expression and subpopulations, decreases TGF-β secretion, and skews adipose-derived stem cells toward adipogenic differentiation.

Clinical Question/level Of Evidence: Therapeutic, V.
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http://dx.doi.org/10.1097/PRS.0000000000007029DOI Listing
August 2020

Occult Pathologic Findings in Reduction Mammaplasty in 5781 Patients-An International Multicenter Study.

J Clin Med 2020 Jul 13;9(7). Epub 2020 Jul 13.

Unit of Plastic Surgery, SABES, South Tyrol, 39042 Brixen, Italy.

Breast cancer is among the most commonly diagnosed cancers in the world, affecting one in eight women in their lifetimes. The disease places a substantial burden on healthcare systems in developed countries and often requires surgical correction. In spite of this, much of the breast cancer pathophysiology remains unknown, allowing for the cancer to develop to later stages prior to detection. Many women undergo reduction mammaplasties (RM) to adjust breast size, with over 500,000 operations being performed annually. Tissue samples from such procedures have drawn interest recently, with studies attempting to garner a better understanding of breast cancer's development. A number of samples have revealed nascent cancer developments that were previously undetected and unexpected. Investigating these so-called "occult" findings of cancer in otherwise healthy patients may provide further insight regarding risk factors and countermeasures. Here, we detail occult findings of cancer in reduction mammaplasty samples provided from a cohort of over 5000 patients from 16 different institutions in Europe. Although the majority of our resected breast tissue specimens were benign, our findings indicate that there is a continued need for histopathological examination. As a result, our study suggests that preoperative imaging should be routinely performed in patients scheduled for RM, especially those with risk factors of breast cancer, to identify and enable a primary oncologic approach.
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http://dx.doi.org/10.3390/jcm9072223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408965PMC
July 2020

The short scar three-block L-wing technique.

J Plast Reconstr Aesthet Surg 2020 Jun 22;73(6):1075-1080. Epub 2020 Jan 22.

Department of Plastic Surgery, Reconstructive and Hand Surgery, Burn Center, Medical Faculty of the RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Center of Reconstructive Surgery of Female Gender Characteristics, Luisenhospital Aachen, Teaching Hospital of the RWTH Aachen University, Boxgraben 99, 52064 Aachen, Germany.

Introduction: Numerous techniques have been proposed for the plastic surgical treatment of hypertrophic breasts. Challenges of the procedure include the preservation of vascular supply and sensitivity of the nipple areola complex (NAC), breast feeding, and an esthetically pleasing result.

Objectives: In the present preliminary report, we introduce a new technique called the three-block L-wing reduction mammaplasty that addresses the aforementioned difficulties.

Materials And Methods: The three-block L-wing reduction mammaplasty with a thick hemispheric superiorly based NAC pedicle and a medial as well as lateral pillar was performed in a total of 60 patients.

Results: Our technique increases both, vascular safety and the sensory supply to the NAC, as it conceptually decreases the need for dissection of breast tissue and skin. The incidence of fat necrosis and wound healing disorders may be reduced with this technique. Because the ducts of the breast-gland underneath the NAC are not dissected, this technique also promises a higher probability of regular breast-feeding. Finally, our technique permits a cosmetically pleasing round-shaped mound of the breast.

Conclusion: The three-block modification simplifies the procedure of the superior pedicle L-wing mammaplasty markedly. It may increase the esthetic as well as the functional outcome and decrease postoperative complications.
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http://dx.doi.org/10.1016/j.bjps.2020.01.027DOI Listing
June 2020

Impact of growth factor content on proliferation of mesenchymal stromal cells derived from adipose tissue.

PLoS One 2020 16;15(4):e0230265. Epub 2020 Apr 16.

Department of Plastic and Reconstructive Surgery, Hand Surgery and Burn Centre, Medical Faculty, Pauwelsstrasse, Aachen, Germany.

Autologous adipose tissue (AT) transfer has gained widespread acceptance and is used for a broad variety of regenerative clinical indications. It is assumed that the successful outcome of AT transfer essentially depends on the amount of autocrine-generated growth factors (GF). It is supposed that several GF enhance and improve the anatomic and functional integration of the transplanted AT grafts at the site of implantation. In the present study we have investigated for the first time the correlation between the concentration of GF of freshly isolated AT and the proliferation and migration capacity of mesenchymal stroma cells (MSCs) derived from the respective AT sample. We here show that the proliferation and migration capacity of MSCs strongly depends on the GF content of the AT the cells were isolated from but in an inversely proportional manner. The lower the GF content of an AT sample was, the higher was the proliferation and migration capacity of the respective MSC population contained in the AT and vice versa. Furthermore, we found that supplementation with recombinant GFs only in the case of AT samples with low but not with higher growth factor contents led to a significant enhancement of proliferation and migration of the AT-resident MSCs. As we further show, this inefficiency of GFs to enhance MSC proliferation and migration in AT samples with high GF contents indicates a GF-mediated negative feedback mechanism leading to an impaired GF signaling in MSC obtained from those AT samples. Our results might explain why the successful use of AT grafting is frequently limited by low and unpredictable survival rates, and we suggest to use the knowledge of GF content of harvested AT as a predictive clinical parameter for risk assessment of the therapeutic outcome of autologous AT transfer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162516PMC
June 2020

The effect of the macrophage migration inhibitory factor (MIF) on excisional wound healing .

J Plast Surg Hand Surg 2020 Jun 11;54(3):137-144. Epub 2020 Apr 11.

Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, RWTH Aachen University Hospital, Aachen, Germany.

The macrophage migration inhibitory factor (MIF) has been determined as a cytokine exerting a multitude of effects in inflammation and angiogenesis. Earlier studies have indicated that MIF may also be involved in wound healing and flap surgery. We investigated the effect of MIF in an excisional wound model in wildtype, and recombinant MIF treated mice. Wound closure rates as well as the macrophage marker Mac-3, the pro-inflammatory cytokine tumor necrosis factor α (TNFα) and the pro-angiogenic factor von Willebrand factor (vWF) were measured. Finally, we used a flap model in and WT mice with an established perfusion gradient to identify MIF's contribution in flap perfusion. In the excision wound model, we found reduced wound healing after MIF injection, whereas deletion improved wound healing. Furthermore, a reduced expression of Mac-3, TNF and vWF in mice was seen when compared to WT mice. In the flap model, knockout mice showed mitigated flap perfusion with lower hemoglobin content and oxygen saturation as measured by OC measurements when compared to WT mice. Our data suggest an inhibiting effect of MIF in wound healing with increased inflammation and perfusion. In flaps, by contrast, MIF may contribute to flap vascularization.
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http://dx.doi.org/10.1080/2000656X.2019.1710710DOI Listing
June 2020

Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

FASEB J 2020 03 21;34(3):4219-4233. Epub 2020 Jan 21.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.

Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF-2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti-inflammatory phenotype while Mif-2 gene knockout drove ATMs toward a pro-inflammatory phenotype and Mif-deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF-2 expression during systemic inflammation, with the downregulation of MIF-2 in fat tissue potentially increasing pro-inflammatory macrophage polarization to further drive adipose inflammation.
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http://dx.doi.org/10.1096/fj.201901511RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060131PMC
March 2020

Microfat and Lipoconcentrate for the Treatment of Facial Scars.

Clin Plast Surg 2020 Jan 21;47(1):139-145. Epub 2019 Oct 21.

Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland.

Fat grafting is as a unique regenerative filler with soluble factors and progenitor cells that may remodel scar tissue in an easy yet effective way. A combination of microfat grafting, lipococoncentrate injection, scar subcision, and platelet-rich plasma supplementation may be used to treat the majority of facial scars. The lipoconcentrate technique condenses the lipoaspirate to a progenitor cell-rich fluid of low volume by a combination of centrifugation and emulsification steps. In this article, the authors' methods for scar treatment by fat grafting are discussed. Choice of technique for facial scars, precise indications, and contraindications are introduced.
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http://dx.doi.org/10.1016/j.cps.2019.08.010DOI Listing
January 2020

Concentration of Chondrogenic Soluble Factors in Freshly Harvested Lipoaspirate.

Ann Plast Surg 2019 09;83(3):344-351

From the Department of Plastic Surgery, Hand Surgery-Burn Center University Hospital RWTH Aachen, Aachen, Germany.

Background: Cartilage tissue has a limited capacity for healing with the consequence that patients are often treated symptomatically until they become candidates for osteotomy or total joint replacement. Alternative biological therapies, for example, application of platelet-rich plasma and implantation of chondrocytes and mesenchymal stem cells, have emerged as a new treatment modality to repair articular cartilage. In addition, autologous fat transfer is performed for treatment of cartilage defects, example given, in osteoarthrosis, but several questions regarding basic biochemical properties of the transplant remain unanswered. Bone morphogenetic protein 4 (BMP4), matrix metalloproteinase (MMP)-8, cartilage oligomeric matrix protein (COMP), and chitinase-3-like protein 1 (CHI3L1) have been shown to be involved in chondrogenic regeneration and represent potential therapeutic agents for cartilage repair. However, no study regarding naturally occurring levels of these soluble factors in transplanted adipose tissue has yet been performed.

Methods: To investigate the influence of age, body mass index, donor site, and sex on the concentration of BMP4, MMP-8, COMP, and CHI3L1 in freshly aspirated adipose tissue, their content was measured by means of enzyme-linked immunosorbent assay readings.

Results: There were significant quantities of BMP4, MMP-8, COMP, and CHI3L1 (23.6, 249.9, 298.0, and 540.6 pg/mg, respectively) in the lipoaspirate harvested for transplantation. There was no correlation between the content of soluble factors and the patients' age or body mass index. Furthermore, the sex did not affect the amount of the investigated factors. However, there were significantly lower contents of BMP4, COMP, and CHI3L1 found in lipoaspirates harvested from the abdomen compared with nonabdominal donor sites.

Conclusions: Naturally occurring differences in the concentrations of the investigated soluble factors will favor certain donor sites for autologous fat transfer in the field of cartilage repair. Thus, increasing knowledge will enable researchers and clinicians to make autologous fat transfer procedures more reliable and efficient for treatment of articular cartilage defects.
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http://dx.doi.org/10.1097/SAP.0000000000001936DOI Listing
September 2019

Reply: Enhancement of Progenitor Cells by Two-Step Centrifugation of Emulsified Lipoaspirates.

Plast Reconstr Surg 2019 04;143(4):894e-895e

Department of Plastic Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.

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http://dx.doi.org/10.1097/PRS.0000000000005465DOI Listing
April 2019

Porcine-derived biomaterials in tissue engineering and reconstructive surgery: Considerations and alternatives in Muslim patients.

J Tissue Eng Regen Med 2019 02 4;13(2):253-260. Epub 2019 Jan 4.

Department of Plastic Surgery, Hand Surgery and Burn Center, Faculty of Medicine, RWTH University Hospital, Aachen, Germany.

During the last three decades, tissue engineering and reconstructive surgery have become standard therapeutic options in the world of medicine. Several biomaterials, either alone or in combination with cultured cellular products, have been introduced to compensate for the scarcity of autologous donor tissue or to improve healing in a variety of surgical specialties, for example, abdominal/visceral surgery, plastic surgery, and cardiovascular surgery. Many of these biomaterials are of porcine origin. It is well known that Islam has prohibited the consumption of porcine or any of its products. With Muslims accounting for 23% (1.6 billion) of the global population, a thorough review of the implications of porcine-derived tissue-engineered products in surgery seems necessary. In life-threatening conditions as well as severe diseases, the use of porcine-derived products is permissible if similar non-porcine-derived materials are not available. In this case, the use of porcine-derived products represents a necessity and is allowed. Therefore, this distinction between sole need and necessity has great importance not only for the medical community but also for researchers in biotechnology and industry who may consider alternatives to porcine-derived materials.
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http://dx.doi.org/10.1002/term.2788DOI Listing
February 2019

Cell-enrichment with olfactory ensheathing cells has limited local extra beneficial effects on nerve regeneration supported by the nerve guide Perimaix.

J Tissue Eng Regen Med 2018 11 12;12(11):2125-2137. Epub 2018 Sep 12.

Department of Plastic Surgery, Reconstructive and Hand Surgery, Burn Center, University Hospital RWTH Aachen, Aachen, Germany.

The reconstruction of peripheral nerve injuries is clinically challenging, and today, the autologous nerve transplantation is still considered as the only gold standard remedy for nerve lesions where a direct nerve coaptation is not possible. Nevertheless, the functional merits of many biomaterials have been tested as potential substitutes for the autologous nerve transplant. One of the strategies that have been pursued is the combination of bioengineered nerve guides with cellular enrichment. In this present study, we combined the previously evaluated collagen-based and microstructured nerve guide Perimaix with olfactory ensheathing cell enrichment. Rat sciatic nerve defects of 20 mm were either bridged by a cell-seeded or nonseeded nerve guide or an autologous nerve transplant. Animals were monitored for 12 weeks for structural and functional parameters. Seeded cells survived on Perimaix, and following implantation aligned along the microstructured Perimaix framework. Axonal densities within the cell-seeded nerve guides were higher than in the nonseeded nerve guides and were comparable to the autograft. Additionally, cell-seeding had local beneficial effects on myelination within the nerve guide, as myelin sheath thickness was enhanced when compared with the empty scaffold. Nevertheless, for bridging the nerve gap of 20 mm, both the cell-seeded as well as nonseeded scaffolds were equally efficient regarding the functional outcome, which did not differ between the autograft, seeded or nonseeded groups. Our data demonstrate that olfactory ensheathing cell enrichment has local effects on nerve regeneration in combination with the Perimaix nerve guide. Surprisingly, for traversing the lesion gap, additional cell-seeding is not crucial.
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http://dx.doi.org/10.1002/term.2731DOI Listing
November 2018

Enhancement of Progenitor Cells by Two-Step Centrifugation of Emulsified Lipoaspirates.

Plast Reconstr Surg 2018 07;142(1):99-109

From the Department of Plastic Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University.

Background: Adipose-derived stem cells, endothelial progenitor cells, and soluble factors jointly contribute to the regenerative effect of fat grafts. Nanofat grafting emulsifies the lipoaspirate and increases the progenitor cell yield. In the present study, the authors evaluated their extended nanofat grafting method that includes two additional centrifugation steps and results in a lipoaspirate of low volume that they termed "lipoconcentrate." Furthermore, the authors investigated the oily fractions after centrifugation for their regenerative potential.

Methods: Lipoaspirates of 20 healthy patients were processed by emulsification and/or centrifugation. Six groups were created: native (not emulsified) fat, 1× centrifuged native fat, 2× centrifuged native fat, nanofat (emulsified), 1× centrifuged nanofat, and lipoconcentrate (i.e., 2× centrifuged nanofat). The oily phases after the centrifugation steps were collected. Progenitor cells and basic fibroblast growth factor, insulin-like growth factor 1, matrix metalloproteinase-9, platelet-derived growth factor-BB, and vascular endothelial growth factor-A levels were measured by flow cytometry and immunoassays.

Results: Lipoconcentrate contained significantly higher numbers of adipose-derived stem cells and endothelial progenitor cells per gram compared with all other fractions. No difference of all five soluble factors between groups was found. The oily phases after centrifugation showed no or very few adipose-derived stem cells and endothelial progenitor cells, and no or very low levels of soluble factors.

Conclusions: Centrifugation of emulsified lipoaspirates increases the progenitor cell count in the lipoaspirate. The oily phase after centrifugation of lipoaspirates may be disposable because of the minuscule content of progenitor cells and soluble factors.
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http://dx.doi.org/10.1097/PRS.0000000000004495DOI Listing
July 2018

Proliferation, Metabolic Activity, and Adipogenic Differentiation of Human Preadipocytes Exposed to 2 Surfactants In Vitro.

J Pharm Sci 2018 05 21;107(5):1408-1415. Epub 2017 Dec 21.

Department of Plastic Surgery, Hand Surgery, Burn Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Fat grafting is a pivotal technique for tissue repair. Adipose stromal cells, including preadipocytes, play a major role in the regenerative effects attributed to fat grafting. But the benefits are impaired by the low survival of the graft due to mechanical stress during harvesting, hypoxia, and nutrient deprivation. Nonionic surfactant molecules demonstrated their efficacy in preventing and repairing mechanical damage on the cellular membrane, but it is poorly understood if and how they affect cellular viability, proliferation, and differentiation. We investigated the influence of 2 nonionic surfactants, KolliphorP188 and KolliphorEL, on cultured human preadipocytes. We analyzed their effects on metabolic activity, cell number, adipogenic differentiation, and secretion of growth factors. KolliphorP188 increased metabolic activity, while it did not influence proliferation and differentiation as well as growth factors release. KolliphorEL confirmed its cytotoxic effect at the highest concentrations applied. Contrariwise, treatment with lower concentrations significantly raised metabolic activity, induced adipogenesis, and increased insulin-like growth factor-1 and vascular endothelial growth factor secretion. The effect on differentiation was inhibited by blocking peroxisome proliferator-activated receptor gamma. Our results revealed important effects of surfactants on preadipocytes' survival, proliferation, death, and the interplay with their environment. Particularly KolliphorEL provides modes of action, which could recommend it for novel treatment to improve fat graft viability.
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http://dx.doi.org/10.1016/j.xphs.2017.12.017DOI Listing
May 2018

A clinical evaluation of a transparent, absorbent, adhesive wound dressing.

Br J Nurs 2017 Nov;26(Sup20):S46-S53

Scientific Advisor, BSN medical GmbH amrei.

The performance of a transparent absorbent adhesive wound dressing (TAAWD) was observed over 7 days in five plastic surgery clinics across Germany. The study included 47 diverse postoperative linear wounds and donor sites with dry or minimal exudate levels. Data on ease of application and removal, adhesive strength, skin compatibility, conformability to the body, visual wound inspection and parameters of wound assessment were collected and analysed. At the end of the observation period, 100% of wounds were recorded as healing with no reported complications. Clinicians considered that the new dressing had predominantly met clinical needs in 89% of cases. The dressing was shown to be skin friendly, easy to apply, adhere and conform to the skin while protecting the wound and allowing the patient to shower. Due to its transparency, the dressing enabled direct wound surveillance without potential disruption to the wound and healing process.
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http://dx.doi.org/10.12968/bjon.2017.26.Sup20.S46DOI Listing
November 2017

Commentary on: Mechanical Supplementation With the Stromal Vascular Fraction Yields Improved Volume Retention in Facial Lipotransfer: A 1-Year Comparative Study.

Aesthet Surg J 2017 10;37(9):986-987

Department of Plastic Surgery, Hand Surgery - Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.

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http://dx.doi.org/10.1093/asj/sjx128DOI Listing
October 2017

Clinical and biometrical 12-month follow-up in patients after reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix.

Eur J Med Res 2017 Sep 22;22(1):34. Epub 2017 Sep 22.

Department of Plastic Surgery, Reconstructive and Hand Surgery, Burn Center, RWTH Aachen University Hospital, Aachen, Germany.

Many new strategies for the reconstruction of peripheral nerve injuries have been explored for their effectiveness in supporting nerve regeneration. However only a few of these materials were actually clinically evaluated and approved for human use. This open, mono-center, non-randomized clinical study summarizes the 12-month follow-up of patients receiving reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix. Neuromaix was implanted as a micro-structured, two-component scaffold bridging 20-40 mm nerve defects after sural nerve biopsy in twenty patients (eighteen evaluated, two lost in follow-up). Safety of the material was evaluated by clinical examination of wound healing. Performance was assessed by sensory testing of modalities, pain assessment, and palpation for the Hoffmann-Tinel's sign as well as demarcating the asensitive area at each follow-up visit. Every patient demonstrated uneventful wound healing during the complete 12-month time course of the study. Two patients reported complete return of sensation, whereas eleven out of eighteen patients reported a positive Hoffmann-Tinel's sign at the lower leg with simultaneous reduction of the asensitive area by 12 months. Our data show that Neuromaix can be implanted safely in humans to bridge sural nerve gaps. No procedure-related, adverse events, or severe adverse events were reported. These first clinical data on Neuromaix provide promising perspectives for the bridging of larger nerve gaps in combined nerves, which should be investigated more through extensive, multi-center clinical trials in the near future.
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http://dx.doi.org/10.1186/s40001-017-0279-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610476PMC
September 2017

Macrophage Migration Inhibitory Factor - A Favorable Marker in Inflammatory Diseases?

Curr Med Chem 2018 Feb;25(5):601-605

Department of Plastic Surgery and Hand Surgery, Burn Center, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.

Background: Macrophage migration inhibitory factor (MIF) was firstly described in the 1960s as a pleiotropic cytokine affecting a variety of immune cells. Different physiological functions mainly involving inflammatory reactions such as chemokine-like function and regulating systemic stress responses have been reported.

Objective: In several clinical studies the use of MIF as a biomarker has been investigated promising support for diseases with an inflammatory aspect such as sepsis, systemic infections and autoimmune diseases. This article in detail reviews clinical data and evaluates the function as biomarker focusing on inflammatory and autoimmune diseases.

Conclusion: Recent studies suggest MIF to be a marker for different inflammatory diseases and might serve as therapeutic target in the future.
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http://dx.doi.org/10.2174/0929867324666170714114200DOI Listing
February 2018

Interleukin-6 Serum Levels Correlate With Severity of Burn Injury but Not With Gender.

J Burn Care Res 2018 04;39(3):379-386

Department of Plastic Surgery, Hand Surgery, Burn Center, University Hospital RWTH Aachen, Germany.

Gender-specific differences in the outcome of patients with burn injury have been recognized in the past with female patients being at a higher risk of mortality. We hypothesized that early post-burn interleukin-6 (IL-6) cytokine levels may contribute to the different gender-specific outcome. We retrospectively examined 94 burned patients who were treated in the Burn Intensive Care Unit at the University Hospital Aachen. Age, gender, presence of inhalation injury, depth, TBSA, and clinical outcome were documented. Serum samples for IL-6 analysis were collected within 24 hours posttrauma. The relationship between IL-6 levels, gender, survival, and abbreviated burn severity index score was investigated. Male patients (64.9%; n = 61) presented a higher median TBSA (26%) than female patients (20%). The mortality rate of male patients (27.9%; n = 17) and female patients (21.2%; n = 7) was similar. Deceased patients had significant higher TBSA (P = 0.0005) and IL-6 levels (P = 0.0007) than burn survivors. A moderate correlation between IL-6 levels and abbreviated burn severity index score was observed (r = 0.554; P < 0.0001). While TBSA showed a significant influence on IL-6 levels (P = 0.0003), gender did not (P = 0.7395) and inhalation injury indicated a minor influence (P = 0.0780). Only TBSA and age presented a significant influence on mortality (P = 0.0028 and P = 0.0031, respectively). All patients with burn trauma were characterized by elevated IL-6 levels with higher TBSA values resulting in more pronounced levels. Deceased patients had higher initial IL-6 serum levels reflecting higher TBSA and severity. In contrast to other defined trauma mechanisms, gender had no significant influence on postburn IL-6 serum levels and mortality in our patient population.
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http://dx.doi.org/10.1097/BCR.0000000000000604DOI Listing
April 2018

The effect of lipoaspirates vs. dissected abdominal fat on breast cancer cells in vitro.

Eur J Med Res 2017 Mar 21;22(1):10. Epub 2017 Mar 21.

Department of Plastic Surgery, Hand Surgery and Burn Center, RWTH University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany.

Background: Cancer cells are typically surrounded by stromal cells and embedded in extracellular matrix (ECM). The stromal compartment interacts with cancer cells to promote growth and metastasis. For decades, autologous fasciocutaneous flaps have been safely applied for breast reconstruction after mastectomy. In contrast, the safety of fat grafting (lipofilling) procedure has been under debate regarding the risk of cancer recurrence.

Methods: Harvested fat tissue (lipoaspirates) and dissected abdominal fat (DAF) were co-cultured with MCF-7 breast cancer cells. The vitality of MCF-7 cells was measured using AlamarBlue consecutively for 5 days. ECM degradation was determined by detection of matrix metalloproteinase-1 (MMP-1) expression in MCF-7 cells. Integrin α2 was measured by Western blot to assess the degree of adhesion and motility of MFC-7 cells.

Results: The MCF-7 proliferation increased substantially when co-cultured with fat tissue. However, there was no significant difference between the proliferation stimulating effects of lipoaspirates and DAF. Similarly, MMP-1 protein expression was equally elevated in MCF-7 cells by both lipoaspirates and DAF. Importantly, MCF-7 cells showed an increased level of integrin α2 once co-cultured with either lipoaspirates or DAF.

Conclusion: Fat tissue increases the proliferation of MCF-7 cells in vitro. Our data suggest that lipoaspirates as well as DAF might possess a considerable potency to promote tumorigenic growth of breast cancer cells. Thus, clinical trials are needed to address the safety of lipofilling by breast reconstruction surgery after mastectomy.
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http://dx.doi.org/10.1186/s40001-017-0251-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361692PMC
March 2017

The Effect of Antiseptics on Adipose-Derived Stem Cells.

Plast Reconstr Surg 2017 Mar;139(3):625-637

Aachen and Munich, Germany; and New Haven, Conn.

Background: Although chemical antiseptics are the most basic measure to control wound infection and frequently come into contact with subcutaneous adipose tissue, no studies have evaluated their toxicity on adipose tissue and its cell fractions. In the present study, the effects of five different antiseptics on adipose-derived stem cells were evaluated.

Methods: Human adipose-derived stem cells were harvested from healthy donors. Adipose-derived stem cell viability was measured after treatment with different concentrations of antiseptics over 5 days. Furthermore, the effect on the proliferation, adipogenic differentiation, and apoptosis/necrosis of adipose-derived stem cells was analyzed. Finally, the mRNA expression of the stem cell markers CD29, CD34, CD73, CD90, and CD105 was detected.

Results: Octenisept and Betaisodona significantly reduced cell proliferation and differentiation and led to considerable adipose-derived stem cell necrosis. Octenisept decreased stem cell viability at the lowest concentrations tested, and all stem cell markers were down-regulated by Octeniseptr and Betaisodona. Lavasept and Prontosan both led to reduced stem cell viability, proliferation, and differentiation, and increased apoptosis/necrosis, although the effects were less pronounced compared with Octenisept and Betaisodona. Adipose-derived stem cells survived treatment with mafenide acetate even at high concentrations, and mafenide acetate showed minimal negative effects on their proliferation, adipogenic differentiation, cell death, and stem cell marker expression.

Conclusions: Mafenide acetate may be regarded as a feasible antiseptic for the treatment of wounds with exposed adipose tissue because of its low adipose-derived stem cell toxicity. Lavasept and Prontosan are possible alternatives to mafenide acetate. Octenisept and Betaisodona, by contrast, may be used only in highly diluted solutions.

Clinical Question/level Of Evidence: Therapeutic, V.
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http://dx.doi.org/10.1097/PRS.0000000000003125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572132PMC
March 2017

Compound Dorsal Dislocation of Lunate with Trapezoid Fracture.

Clin Pract 2016 Oct 13;6(4):879. Epub 2016 Dec 13.

Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, RWTH Aachen University , Aachen, Germany.

We report about a dorsal dislocation of the lunate accompanied by a trapezoid fracture in a 41-year old male patient after a motorcycle accident. The lunate dislocation with no dorsal or volar intercalated segment instability (DISI, VISI) was diagnosed by x-ray whereas the trapezoid fracture was only diagnosable by computed tomography. A closed reduction and internal fixation of the lunate by two Kirschner wires was performed, the trapezoid fracture was conservatively treated. Surgery was followed by immobilization, intense physiotherapy and close follow-up. Even though complaints such as swelling and pain subsided during the course of rehabilitation, partial loss of strength and range of motion remained even after 16 months. In conclusion, a conservative treatment of trapezoid fractures seems to be sufficient in most cases. Closed reduction with K-wire fixation led to an overall satisfactory result in our case. For dorsal lunate dislocations in general, open reduction should be performed when close reduction is unsuccessful or DISI/VISI are observed in radiographs after attempted close reduction.
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http://dx.doi.org/10.4081/cp.2016.879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294926PMC
October 2016

The effect of mechanical stress on the proliferation, adipogenic differentiation and gene expression of human adipose-derived stem cells.

J Tissue Eng Regen Med 2018 01 16;12(1):276-284. Epub 2017 Jul 16.

Department of Plastic Surgery and Hand Surgery - Burn Center, Uniklinik RWTH Aachen, Aachen, Germany.

To allow for a better implementation of external volume expansion to clinical applications for soft tissue regeneration, it is necessary to comprehensively understand the underlying mechanisms. As human adipose-derived stem cells (hASCs) play a crucial role in soft tissue enlargement, we investigated the impact of cyclic stretch on gene expression, proliferation rate and adipogenic differentiation of these cells. After cyclic stretching, RNA was extracted and subjected to DNA microarray analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Also, the expression of FABP4 mRNA was analysed by RT-qPCR to test whether mechanical stretch affected adipogenic differentiation of hASCs. The proliferation rate was assessed using the alamarBlue assay and Ki-67 staining. A cell cycle analysis was performed with flow cytometry and Western blot. We found that cyclic stretch significantly induced the expression of CYP1B1 mRNA. Furthermore, the adipogenic differentiation of hASCs was impaired, as was the proliferation. This was partly due to a decrease in extracellular signal-regulated kinase (ERK) 1/2 and histone H3 phosphorylation, suggesting a growth arrest in the G /M phase of the cell cycle. Enrichment analyses demonstrated that stretch-regulated genes were over-represented in pathways and biological processes involved in extracellular matrix organization, vascular remodelling and responses to cell stress. Taken together, mechanical stress impaired both proliferation and adipogenic differentiation, but led to a tissue-remodelling phenotype of hASCs. These data suggest that extracellular matrix remodelling and neoangiogenesis may play a more important role in external volume expansion than proliferation and adipogenesis of hASCs. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2411DOI Listing
January 2018

Characterization of adipose tissue macrophages and adipose-derived stem cells in critical wounds.

PeerJ 2017 4;5:e2824. Epub 2017 Jan 4.

Department of Medicine, Yale University, New Haven, United States.

Background: Subcutaneous adipose tissue is a rich source of adipose tissue macrophages and adipose-derived stem cells which both play a key role in wound repair. While macrophages can be divided into the classically-activated M1 and the alternatively-activated M2 phenotype, ASCs are characterized by the expression of specific stem cell markers.

Methods: In the present study, we have investigated the expression of common macrophage polarization and stem cell markers in acutely inflamed adipose tissue. Subcutaneous adipose tissue adjacent to acutely inflamed wounds of 20 patients and 20 healthy subjects were harvested and underwent qPCR and flow cytometry analysis.

Results: Expression levels of the M1-specific markers CD80, iNOS, and IL-1b were significantly elevated in inflammatory adipose tissue when compared to healthy adipose tissue, whereas the M2-specific markers CD163 and TGF- were decreased. By flow cytometry, a significant shift of adipose tissue macrophage populations towards the M1 phenotype was confirmed. Furthermore, a decrease in the mesenchymal stem cell markers CD29, CD34, and CD105 was observed whereas CD73 and CD90 remained unchanged.

Discussion: This is the first report describing the predominance of M1 adipose tissue macrophages and the reduction of stem cell marker expression in acutely inflamed, non-healing wounds.
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http://dx.doi.org/10.7717/peerj.2824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217526PMC
January 2017

Pre-expanded Supraclavicular Artery Perforator Flap.

Clin Plast Surg 2017 Jan 15;44(1):49-63. Epub 2016 Oct 15.

Department of Plastic and Reconstructive Surgery, Hand Surgery - Burn Center, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, Aachen 52074, Germany.

The supraclavicular artery perforator (SAP) flap is a versatile flap for the reconstruction of head and neck defects. Recently, the authors have modified the SAP flap by using an anterior branch of the transverse cervical artery. The anterior SAP flap allows the harvest of a tissue island in the deltopectoral fossa, which is even thinner, is more pliable, and shows a superior color match to the face and neck compared with the original SAP flap. Pre-expansion increases flap size considerably, enabling the coverage of extended defects without the need of microsurgery.
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http://dx.doi.org/10.1016/j.cps.2016.08.005DOI Listing
January 2017

D-dopachrome tautomerase in adipose tissue inflammation and wound repair.

J Cell Mol Med 2017 01 7;21(1):35-45. Epub 2016 Sep 7.

Section of Rheumatology, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

D-dopachrome tautomerase (D-DT/MIF-2) is a member of the macrophage migration inhibitory factor (MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D-DT have been reported to be involved in obesity, but there is little known about the regulation of D-DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D-DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D-DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D-DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF-CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D-DT to MIF in inflamed adipose tissue, and indicate that D-DT may be beneficial in wound repair by improving fibroblast survival and proliferation.
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http://dx.doi.org/10.1111/jcmm.12936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192814PMC
January 2017

Viability of human composite tissue model for experimental study of burns.

Discov Med 2016 08;22(119):19-28

Department of Plastic and Reconstructive Surgery, Hand Surgery and Burn Center, RWTH Aachen University Hospital, Aachen 52074, Germany.

Experimental studies of burns are primarily performed with animal models that have important anatomical and physiological differences relative to human systems. The aim of this study was to develop a human experimental burn model using composite tissue obtained from bariatric surgery. We established a new protocol to maintain viable sections of human cutaneous and subcutaneous (sub/cutaneous) tissue in vitro. Under the conditions selected, multiparametric flow cytometry and histological analysis confirmed the viability and integrity of the human sub/cutaneous tissue for at least 5 days. Furthermore, we utilized a precision McKenna burner to inflict burns on the human tissue model under well-defined thermal conditions in vitro. Our data showed a localized, temporally restricted polarization of the resident macrophages in the subcutaneous human tissue in response to specific thermal forces. Therefore, our model provides a useful alternative to animal studies for further detailed investigations of human responses to injuries and treatments.
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August 2016

Plastic Surgery Training Worldwide: Part 1. The United States and Europe.

Plast Reconstr Surg Glob Open 2016 Mar 17;4(3):e641. Epub 2016 Mar 17.

Division of Plastic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.; Division of Plastic and Reconstructive Surgery, Louisiana State University Health Sciences Center, New Orleans, La.; Division of Plastic Reconstructive and Hand Surgery, VU Medical Center, Amsterdam, Netherlands; Division of Plastic Surgery, Centre hospitalier régional universitaire de Lille, Lille, France; Division of Plastic and Reconstructive Surgery, Red Cross Hospital, Kassel, Germany; and Department of Plastic Surgery, Hand Surgery and Burn Center, University Hospital Aachen, Aachen, Germany.

Background: Major differences exist in residency training, and the structure and quality of residency programs differ between different countries and teaching centers. It is of vital importance that a better understanding of the similarities and differences in plastic surgery training be ascertained as a means of initiating constructive discussion and commentary among training programs worldwide. In this study, the authors provide an overview of plastic surgery training in the United States and Europe.

Methods: A survey was sent to select surgeons in 10 European countries that were deemed to be regular contributors to the plastic surgery literature. The questions focused on pathway to plastic surgery residency, length of training, required pretraining experience, training scheme, research opportunities, and examinations during and after plastic surgery residency.

Results: Plastic surgery residency training programs in the United States differ from the various (selected) countries in Europe and are described in detail.

Conclusions: Plastic surgery education is vastly different between the United States and Europe, and even within Europe, training programs remain heterogeneous. Standardization of curricula across the different countries would improve the interaction of different centers and facilitate the exchange of vital information for quality control and future improvements. The unique characteristics of the various training programs potentially provide a basis from which to learn and to gain from one another.
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http://dx.doi.org/10.1097/GOX.0000000000000627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874285PMC
March 2016
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