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1.  Role of Lifeguard β-isoform in the development of breast cancer 
Oncology Reports  2014;32(4):1335-1340.
In the last century there has been great progress in the treatment of breast cancer by improving drug and radiation therapy as well as surgical techniques. Despite this development, breast cancer remains a major cause of death among women in Europe and the US. The cause of breast cancer at the cellular level is still not fully understood. In the present study, we investigated the expression of the Lifeguard β-isoform in breast cancer tissues. In contrast to Lifeguard, the β-isoform has one transmembrane domain less, which is the last of seven (99 bp), and due to this we suspect that the Lifeguard β-isoform exhibits a different function. We determined the expression and function of the β-isoform of Lifeguard in breast cancer cell lines (MCF-7 and MDA-MB-231), a human breast epithelial cell line (MCF10A) and in breast tumour tissue sections. Western blotting, PCR arrays and immunofluorescence were used to investigate the expression of Lifeguard and its β-isoform. Moreover, we investigated the ability of Lifeguard β-isoform expression to inhibit apoptosis induced by Fas. Our results indicated that Lifeguard β-isoform is strongly expressed in breast tumour tissues. More notably, we demonstrated that Fas sensitivity was reduced in the MCF10A breast cells expressing the Lifeguard β-isoform. Taken together, our findings indicate the role of the Lifeguard β-isoform as an anti-apoptotic protein and provide further evidence of the potential of the Lifeguard β-isoform as a target for the development of novel therapeutic strategies.
doi:10.3892/or.2014.3363
PMCID: PMC4148365  PMID: 25069766
Lifeguard; Lifeguard β-isoform; apoptosis; breast cancer
2.  Spider Silk as Guiding Biomaterial for Human Model Neurons 
BioMed Research International  2014;2014:906819.
Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neurons in vitro, we developed an in vitro crossed silk fiber array. Here, we describe in detail for the first time that human (NT2) model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arrays in vitro will allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies.
doi:10.1155/2014/906819
PMCID: PMC4052499  PMID: 24949480
3.  Intravenous Transplantation of Mesenchymal Stromal Cells to Enhance Peripheral Nerve Regeneration 
BioMed Research International  2013;2013:573169.
Peripheral nerve injury is a common and devastating complication after trauma and can cause irreversible impairment or even complete functional loss of the affected limb. While peripheral nerve repair results in some axonal regeneration and functional recovery, the clinical outcome is not optimal and research continues to optimize functional recovery after nerve repair. Cell transplantation approaches are being used experimentally to enhance regeneration. Intravenous infusion of mesenchymal stromal cells (MSCs) into spinal cord injury and stroke was shown to improve functional outcome. However, the repair potential of intravenously transplanted MSCs in peripheral nerve injury has not been addressed yet. Here we describe the impact of intravenously infused MSCs on functional outcome in a peripheral nerve injury model. Rat sciatic nerves were transected followed, by intravenous MSCs transplantation. Footprint analysis was carried out and 21 days after transplantation, the nerves were removed for histology. Labelled MSCs were found in the sciatic nerve lesion site after intravenous injection and regeneration was improved. Intravenously infused MSCs after acute peripheral nerve target the lesion site and survive within the nerve and the MSC treated group showed greater functional improvement. The results of study suggest that nerve repair with cell transplantation could lead to greater functional outcome.
doi:10.1155/2013/573169
PMCID: PMC3888686  PMID: 24459671
4.  Cellulite and Focused Extracorporeal Shockwave Therapy for Non-Invasive Body Contouring: a Randomized Trial 
Dermatology and Therapy  2013;3(2):143-155.
Introduction
Focused extracorporeal shockwave therapy (ESWT) has been demonstrated to improve wound healing and skin regeneration such as in burn wounds and scars. We hypothesized that the combination of focused ESWT and a daily gluteal muscle strength program is superior to SHAM-ESWT and gluteal muscle strength training in moderate to severe cellulite.
Methods
This was a single-center, double-blinded, randomized-controlled trial. For allocation of participants, a 1:1 ratio randomization was performed using opaque envelopes for the concealment of allocation. Eligible patients were females aged 18–65 years with cellulite. The primary outcome parameter was the photo-numeric Cellulite Severity Scale (CSS) determined by two blinded, independent assessors. The intervention group (group A) received six sessions of focused ESWT (2,000 impulses, 0.35 mJ/mm2, every 1–2 weeks) at both gluteal and thigh regions plus specific gluteal strength exercise training. The control group (group B) received six sessions of SHAM-ESWT plus specific gluteal strength exercise training.
Results
The CSS in group A was 10.9 ± 3.8 (mean ± SE) before intervention and 8.3 ± 4.1 after 12 weeks (P = 0.001, 2.53 improvement, 95% confidence interval (CI) 1.43–3.62). The CSS in group B was 10.0 ± 3.8 before intervention and 10.1 ± 3.8 after 12 weeks (P = 0.876, 95% CI 1.1–0.97). The change of the CSS in group A versus group B was significantly different (P = 0.001, −24.3 effect size, 95% CI −36.5 to −12.1).
Conclusion
The combination of non-invasive, focused ESWT (0.35 mJ/mm2, 2,000 impulses, 6 sessions) in combination with gluteal strength training was superior to gluteal strength training and SHAM-ESWT in moderate to severe cellulite in terms of the CSS in a 3-month perspective. Long-term results have to be evaluated in terms of the sustainability of these effects.
Electronic supplementary material
The online version of this article (doi:10.1007/s13555-013-0039-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s13555-013-0039-5
PMCID: PMC3889306  PMID: 24297647
Aesthetics; Body contouring; Cellulite; Dermatology; Extracorporeal shock wave therapy; Strength training
5.  Impact of Diabetes and Peripheral Arterial Occlusive Disease on the Functional Microcirculation at the Plantar Foot 
Background:
Plastic and reconstructive surgeons are commonly faced with chronic ulcerations and consecutive wound infections of the feet as complications in patients with diabetes and/or peripheral arterial occlusive disease (PAOD). Microcirculatory changes seem to play an important role. However, the evaluation of functional changes in the soft tissue microcirculation at the plantar foot using combined Laser-Doppler and Photospectrometry System has not yet been performed in patients with DM or PAOD.
Methods:
A prospective, controlled cohort study was designed consisting of a total of 107 subjects allocated to 1 of 3 groups—group A: healthy subjects (57% males, 63.3 y); group B: patients with diabetes mellitus (DM) (53% males, 59.4 y); and group C: patients with PAOD (81% males, 66.1 y). Microcirculatory data were assessed using a combined Laser-Doppler and Photospectrometry System.
Results:
Global cutaneous oxygen saturation microcirculation at the plantar foot of healthy individuals was 8.4% higher than in patients with DM and 8.1% higher than in patients with PAOD (both P = 0.033). Patients with diabetes did not show significant differences in global cutaneous blood flow when compared with either healthy subjects or patients suffering from PAOD.
Conclusions:
Functional microcirculation at the plantar foot differs between healthy subjects and patients suffering from diabetes or PAOD of the same age. Patients with either diabetes or PAOD demonstrate deteriorated cutaneous oxygen saturation with equivalent blood perfusion at the plantar foot. More clinical studies have to be conducted to evaluate therapeutical methods that might ameliorate cutaneous oxygen saturation within diabetic foot disease and PAOD.
doi:10.1097/GOX.0b013e3182a4b9cb
PMCID: PMC4174050  PMID: 25289243
6.  Cultivation of Keratinocytes and Fibroblasts in a Three-Dimensional Bovine Collagen-Elastin Matrix (Matriderm®) and Application for Full Thickness Wound Coverage in Vivo 
New skin substitutes for burn medicine or reconstructive surgery pose an important issue in plastic surgery. Matriderm® is a clinically approved three-dimensional bovine collagen-elastin matrix which is already used as a dermal substitute of full thickness burn wounds. The drawback of an avital matrix is the limited integration in full thickness skin defects, depending on the defect size. To further optimize this process, Matriderm® has also been studied as a matrix for tissue engineering of skin albeit long-term cultivation of the matrix with cells has been difficult. Cells have generally been seeded onto the matrix with high cell loss and minimal time-consuming migration. Here we developed a cell seeded skin equivalent after microtransfer of cells directly into the matrix. First, cells were cultured, and microinjected into Matriderm®. Then, cell viability in the matrix was determined by histology in vitro. As a next step, the skin substitute was applied in vivo into a full thickness rodent wound model. The wound coverage and healing was observed over a period of two weeks followed by histological examination assessing cell viability, proliferation and integration into the host. Viable and proliferating cells could be found throughout the entire matrix. The presented skin substitute resembles healthy skin in morphology and integrity. Based on this study, future investigations are planned to examine behaviour of epidermal stem cells injected into a collagen-elastin matrix under the aspects of establishment of stem cell niches and differentiation.
doi:10.3390/ijms140714460
PMCID: PMC3742254  PMID: 23852021
skin substitute; elastin-collagen bovine matrix; Matriderm®; epidermal stem cells; fibroblasts; keratinocytes
7.  Bundles of Spider Silk, Braided into Sutures, Resist Basic Cyclic Tests: Potential Use for Flexor Tendon Repair 
PLoS ONE  2013;8(4):e61100.
Repair success for injuries to the flexor tendon in the hand is often limited by the in vivo behaviour of the suture used for repair. Common problems associated with the choice of suture material include increased risk of infection, foreign body reactions, and inappropriate mechanical responses, particularly decreases in mechanical properties over time. Improved suture materials are therefore needed. As high-performance materials with excellent tensile strength, spider silk fibres are an extremely promising candidate for use in surgical sutures. However, the mechanical behaviour of sutures comprised of individual silk fibres braided together has not been thoroughly investigated. In the present study, we characterise the maximum tensile strength, stress, strain, elastic modulus, and fatigue response of silk sutures produced using different braiding methods to investigate the influence of braiding on the tensile properties of the sutures. The mechanical properties of conventional surgical sutures are also characterised to assess whether silk offers any advantages over conventional suture materials. The results demonstrate that braiding single spider silk fibres together produces strong sutures with excellent fatigue behaviour; the braided silk sutures exhibited tensile strengths comparable to those of conventional sutures and no loss of strength over 1000 fatigue cycles. In addition, the braiding technique had a significant influence on the tensile properties of the braided silk sutures. These results suggest that braided spider silk could be suitable for use as sutures in flexor tendon repair, providing similar tensile behaviour and improved fatigue properties compared with conventional suture materials.
doi:10.1371/journal.pone.0061100
PMCID: PMC3629086  PMID: 23613793
8.  Sclerosing therapy and eccentric training in flexor carpi radialis tendinopathy in a tennis player 
British Journal of Sports Medicine  2007;41(12):920-921.
Background
Tendinopathy of the flexor carpi ulnaris tendon is a rare entity. Recent research revealed the role of a neurovascular ingrowth at the point of pain in various tendinopathic locations, such as at the Achilles and patellar tendon, in plantar fasciitis as well as in supraspinatus and tennis elbow tendinopathy. However, beyond the elbow no such neovascularisation has been reported to date.
Methods
We present a 35‐year old tennis player suffering tremendous pain (visual analogue scale (VAS) rating of 9/10) at the flexor carpi ulnaris tendon with adjacent calcification in close proximity to the pisiform bone. The patient was assessed with power Doppler and laser Doppler quantification of neovascularisation at the point of pain.
Results
Power Doppler and laser Doppler quantification of neovascularisation at the point of pain identified higher capillary blood flow at three points over the painful vs the non‐painful tendon (146/240/232rU vs 93/74/70rU at the non‐affected side). Sclerosing therapy using polidocanol under power and laser Doppler guidance was initiated, with immediate decrease of capillary blood flow by 25% with resolution of the neovascularisation in power Doppler. Immediately following sclerosing, the patient's reported pain level on the VAS was reduced from 9/10 to 4/10. Following a short period of rest, eccentric training of the forearm muscle was initiated over 12 weeks with functional complete recovery and complete resolution of wrist pain.
Conclusion
Sclerosing therapy using polidocanol under power‐ and laser‐Doppler guidance can decrease capillary blood flow by 25% with resolution of the neovascularisation. Subsequent eccentric training of the forearm muscle over 12 weeks can result in complete resolution of wrist pain.
doi:10.1136/bjsm.2007.036558
PMCID: PMC2659004  PMID: 17496066
9.  Tissue Engineered Skin Substitutes Created by Laser-Assisted Bioprinting Form Skin-Like Structures in the Dorsal Skin Fold Chamber in Mice 
PLoS ONE  2013;8(3):e57741.
Tissue engineering plays an important role in the production of skin equivalents for the therapy of chronic and especially burn wounds. Actually, there exists no (cellularized) skin equivalent which might be able to satisfactorily mimic native skin. Here, we utilized a laser-assisted bioprinting (LaBP) technique to create a fully cellularized skin substitute. The unique feature of LaBP is the possibility to position different cell types in an exact three-dimensional (3D) spatial pattern. For the creation of the skin substitutes, we positioned fibroblasts and keratinocytes on top of a stabilizing matrix (Matriderm®). These skin constructs were subsequently tested in vivo, employing the dorsal skin fold chamber in nude mice. The transplants were placed into full-thickness skin wounds and were fully connected to the surrounding tissue when explanted after 11 days. The printed keratinocytes formed a multi-layered epidermis with beginning differentiation and stratum corneum. Proliferation of the keratinocytes was mainly detected in the suprabasal layers. In vitro controls, which were cultivated at the air-liquid-interface, also exhibited proliferative cells, but they were rather located in the whole epidermis. E-cadherin as a hint for adherens junctions and therefore tissue formation could be found in the epidermis in vivo as well as in vitro. In both conditions, the printed fibroblasts partly stayed on top of the underlying Matriderm® where they produced collagen, while part of them migrated into the Matriderm®. In the mice, some blood vessels could be found to grow from the wound bed and the wound edges in direction of the printed cells. In conclusion, we could show the successful 3D printing of a cell construct via LaBP and the subsequent tissue formation in vivo. These findings represent the prerequisite for the creation of a complex tissue like skin, consisting of different cell types in an intricate 3D pattern.
doi:10.1371/journal.pone.0057741
PMCID: PMC3587634  PMID: 23469227
10.  Intermittent KoldBlue cryotherapy of 3×10 min changes mid‐portion Achilles tendon microcirculation 
Background
Neovascularisation and microcirculatory changes have been reported in Achilles tendinopathy. Cryotherapy and compression, as part of a rest, ice, compression and elevation regimen, are shown to decrease pain and improve function. However, the microcirculatory changes following a given dosage of cryotherapy on mid‐portion Achilles tendon remain unclear.
Study design
Prospective clinical cohort study, level of evidence 2.
Methods
30 people (12 males, 33 (SD 12) years, body mass index 25.6 (5.3) kg/m2) were included in the cohort. 3×10 min KoldBlue ankle‐cooling bandages were applied and microcirculation of Achilles tendon mid‐portion was real‐time and continuously assessed using a laser‐Doppler‐spectrophotometry system (O2C, Germany).
Results
Superficial capillary blood flow was reduced from 42 to 6, 5 and 3 relative units (rU) in the first, second and third cryotherapy periods, respectively (−65%, p = 0.001), with no significant capillary hyperaemia. Deep capillary tendon blood flow was reduced from 180 to 82, 53 and 52 rU (−71%, p = 0.001) within 6–9 min of application without hyperaemia. Superficial tendon oxygen saturation dropped significantly from 43% to 26%, 18% and 11% (p = 0.001) after repetitive cryotherapy, with persisting increase of tendon oxygenation during rewarming (51%, 49% and 54%, p = 0.077) up to 27% of the baseline level. At 8 mm tendon depth, cryotherapy preserved local oxygenation. Relative postcapillary venous tendon filling pressures were favourably reduced from 41 (11) to 31, 28 and 26 rU (−36%, p = 0.001) superficially and from 56 (11) to 45, 46 and 48 rU (−18%, p = 0.001) in deep capillary blood flow during cryotherapy, facilitating capillary venous clearance.
Conclusion
Intermittent cryotherapy of 3×10 min significantly decreases local Achilles tendon mid‐portion capillary blood flow by 71%. Within 2 min of rewarming, tendon oxygen saturation is re‐established following cryotherapy. Postcapillary venous filling pressures are reduced during cryotherapy, favouring capillary venous outflow of the healthy Achilles tendon.
doi:10.1136/bjsm.2006.030957
PMCID: PMC2465323  PMID: 17138636
11.  Is tamoxifen associated with an increased risk for thromboembolic complications in patients undergoing microvascular breast reconstruction? 
GMS German Medical Science  2013;11:Doc05.
Introduction: Tamoxifen is associated with a twofold increased risk of thromboembolic events. Third generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane have therefore replaced tamoxifen in the adjuvant therapy of hormone receptor-positive breast cancer. A retrospective review was performed in patients who underwent delayed microvascular breast reconstruction and received tamoxifen at the time of surgery in order to assess the risk of both minor and major flap complications including thromboembolic events.
Patients and methods: Twenty-nine patients who underwent delayed microsurgical breast reconstruction with autologous tissue between 2006 and 2012 were included in the study. The overall complication rates were compared between patients who did versus those who did not receive tamoxifen at the time of microsurgical breast reconstruction.
Results: Breast reconstruction was performed with a DIEP flap in 25 patients and with a TRAM flap in 4 patients. Overall, the complication rate was 37.9% (n=11) consisting of 5 major (including one total flap loss) and 6 minor complications. In patients receiving tamoxifen (n=5), we observed one minor complication and one major complication with a total flap loss due to thrombus formation at the anastomosis site. In one patient pulmonary embolism occurred without association to tamoxifen. The number of thromboembolic events was equivalent in both groups (p=0.642). No increase of major (p=0.858) or minor (p=0.967) complications in the tamoxifen group could be observed. Taking the overall complication rate into account there was no statistically difference between the two groups (p=0.917).
Conclusion: In our study we could not observe an increased risk for thromobembolic events in patients receiving tamoxifen while undergoing autologous microvascular breast reconstruction.
doi:10.3205/000173
PMCID: PMC3575563  PMID: 23423877
Tamoxifen; breast cancer; adjuvant therapy; microvascular breast reconstruction
12.  Adhesion, Vitality and Osteogenic Differentiation Capacity of Adipose Derived Stem Cells Seeded on Nitinol Nanoparticle Coatings 
PLoS ONE  2013;8(1):e53309.
Autologous cells can be used for a bioactivation of osteoimplants to enhance osseointegration. In this regard, adipose derived stem cells (ASCs) offer interesting perspectives in implantology because they are fast and easy to isolate. However, not all materials licensed for bone implants are equally suited for cell adhesion. Surface modifications are under investigation to promote cytocompatibility and cell growth. The presented study focused on influences of a Nitinol-nanoparticle coating on ASCs. Possible toxic effects as well as influences on the osteogenic differentiation potential of ASCs were evaluated by viability assays, scanning electron microscopy, immunofluorescence and alizarin red staining. It was previously shown that Nitinol-nanoparticles exert no cell toxic effects to ASCs either in soluble form or as surface coating. Here we could demonstrate that a Nitinol-nanoparticle surface coating enhances cell adherence and growth on Nitinol-surfaces. No negative influence on the osteogenic differentiation was observed. Nitinol-nanoparticle coatings offer new possibilities in implantology research regarding bioactivation by autologous ASCs, respectively enhancement of surface attraction to cells.
doi:10.1371/journal.pone.0053309
PMCID: PMC3538760  PMID: 23308190
13.  Induction of Osteogenic Differentiation of Adipose Derived Stem Cells by Microstructured Nitinol Actuator-Mediated Mechanical Stress 
PLoS ONE  2012;7(12):e51264.
The development of large tissue engineered bone remains a challenge in vitro, therefore the use of hybrid-implants might offer a bridge between tissue engineering and dense metal or ceramic implants. Especially the combination of the pseudoelastic implant material Nitinol (NiTi) with adipose derived stem cells (ASCs) opens new opportunities, as ASCs are able to differentiate osteogenically and therefore enhance osseointegration of implants. Due to limited knowledge about the effects of NiTi-structures manufactured by selective laser melting (SLM) on ASCs the study started with an evaluation of cytocompatibility followed by the investigation of the use of SLM-generated 3-dimensional NiTi-structures preseeded with ASCs as osteoimplant model. In this study we could demonstrate for the first time that osteogenic differentiation of ASCs can be induced by implant-mediated mechanical stimulation without support of osteogenic cell culture media. By use of an innovative implant design and synthesis via SLM-technique we achieved high rates of vital cells, proper osteogenic differentiation and mechanically loadable NiTi-scaffolds could be achieved.
doi:10.1371/journal.pone.0051264
PMCID: PMC3517541  PMID: 23236461
14.  High-energy focussed extracorporeal shockwave therapy reduces pain in plantar fibromatosis (Ledderhose’s disease) 
BMC Research Notes  2012;5:542.
Background
Plantar fibromatosis is a benign disease creating nodules on the medial plantar side of affected patients. While surgical removal is regarded as the therapeutic mainstay, recurrence rates and impairment of daily activities remains substantial. High-energy focussed extracorporeal shockwave therapy has been suggested to be potentially effective in plantar fibromatosis in terms of pain reduction.
Hypothesis
High-energy focussed extracorporeal shockwave therapy reduces pain in plantar fibromatosis.
Findings
A total number of six patients (5 males, 58±4 years) were included with plantar fibromatosis (Ledderhose’s disease) associated with pain. Three patients were operated on previously, one had concomitant Dupuytren’s contracture. High-energy focussed ESWT was applied using a Storz Duolith SD1 (2000 impulses, 3 Hz, 1.24 mJ/mm2) in two sessions with 7 days between. Pain was 6±2 at baseline, 2±1 after 14 days and 1±1 after 3 months. Softening of the nodules was noted by all patients. No adverse effects were noted.
Conclusions
High-energy focussed extracorporeal shockwave energy reduces pain in painful plantar fibromatosis (Morbus Ledderhose). Further large-scale prospective trials are warranted to elucidate the value of high-energy focussed extracorporeal shockwave therapy (ESWT) in plantar fibromatosis in terms of recurrence and efficacy.
doi:10.1186/1756-0500-5-542
PMCID: PMC3637402  PMID: 23031080
Extracorporeal shockwave therapy (ESWT); Fibromatosis; Ledderhose; Pain
15.  A Differential Pressure Laminar Flow Reactor Supports Osteogenic Differentiation and Extracellular Matrix Formation from Adipose Mesenchymal Stem Cells in a Macroporous Ceramic Scaffold 
BioResearch Open Access  2012;1(3):145-156.
Abstract
We present a laminar flow reactor for bone tissue engineering that was developed based on a computational fluid dynamics model. The bioreactor design permits a laminar flow field through its specific internal shape. An integrated bypass system that prevents pressure build-up through bypass openings for pressure release allows for a constant pressure environment during the changing of permeability values that are caused by cellular growth within a porous scaffold. A macroporous ceramic scaffold, composed of zirconium dioxide, was used as a test biomaterial that studies adipose stem cell behavior within a controlled three-dimensional (3D) flow and pressure environment. The topographic structure of the material provided a basis for stem cell proliferation and differentiation toward the osteogenic lineage. Dynamic culture conditions in the bioreactor supported cell viability during long-term culture and induced cell cluster formation and extra-cellular matrix deposition within the porous scaffold, though no complete closure of the pores with new-formed tissue was observed. We postulate that our system is suitable for studying fluid shear stress effects on stem cell proliferation and differentiation toward bone formation in tissue-engineered 3D constructs.
doi:10.1089/biores.2012.9901
PMCID: PMC3559213  PMID: 23515420
bioreactor; bone tissue engineering; computer model; fluid dynamics; laminar flow; shear stress; 3D culture
16.  Anticoagulative strategies in reconstructive surgery – clinical significance and applicability 
GMS German Medical Science  2012;10:Doc01.
Advanced strategies in reconstructive microsurgery and especially free tissue transfer with advanced microvascular techniques have been routinely applied and continously refined for more than three decades in day-to-day clinical work. Bearing in mind the success rates of more than 95%, the value of these techniques in patient care and comfort (one-step reconstruction of even the most complex tissue defects) cannot be underestimated.
However, anticoagulative protocols and practices are far from general acceptance and – most importantly – lack the benchmark of evidence basis while the reconstructive and microsurgical methods are mostly standardized.
Therefore, the aim of our work was to review the actual literature and synoptically lay out the mechanisms of action of the plethora of anticoagulative substances.
The pharmacologic prevention and the surgical intervention of thrombembolic events represent an established and essential part of microsurgery. The high success rates of microvascular free tissue transfer as of today are due to treatment of patients in reconstructive centers where proper patient selection, excellent microsurgical technique, tissue transfer to adequate recipient vessels, and early anastomotic revision in case of thrombosis is provided. Whether the choice of antithrombotic agents is a factor of success remains still unclear. Undoubtedly however the lack of microsurgical experience and bad technique can never be compensated by any regimen of antithrombotic therapy. All the more, the development of consistent standards and algorithms in reconstructive microsurgery is absolutely essential to optimize clinical outcomes and increase multicentric and international comparability of postoperative results and complications.
doi:10.3205/000152
PMCID: PMC3263521  PMID: 22294976
anticoagulation; microsurgery; heparin-induced thrombocytopenia (HiT); thrombosis
17.  Schwann Cell Metabolic Activity in Various Short-Term Holding Conditions: Implications for Improved Nerve Graft Viability 
Strategies for improvement of nerve regeneration and optimal conditions to prevent Schwann cell (SC) loss within a nerve transplant procedure are critical. The purpose of this study was to examine SC viability, which plays an important role in peripheral nerve regeneration, under various incubation conditions up to three hours. To address this issue, Schwann cell metabolic activity was determined using different independent test methods. The following experimental conditions were compared: SCs prepared from nerves were incubated in (1) isotonic saline solution (2) Dulbecco's modified Eagles medium as used for cell culturing, (3) Hannover bioreactor medium, and (4) Leibovitz's medium. SC metabolic activity of excised rat sciatic nerve was determined at 4°C, 18°C, and 37°C over 3 hrs. The results indicate that SC activity was optimized by the usage of Leibovitz's medium or HBRM at 37°C. Greater SC viability at the time of surgical nerve grafting could contribute to improved axonal regeneration and remyelination after nerve transplantation, and thus more successful functional recovery.
doi:10.1155/2012/742183
PMCID: PMC3261467  PMID: 22272205
18.  Burn-induced Heart Failure: Lipopolysaccharide Binding Protein Improves Burn and Endotoxin-induced Cardiac Contractility Deficits 
The Journal of surgical research  2009;165(1):128-135.
Objective
Burn injury is frequently complicated by bacterial infection. Following burn injury, exposure to endotoxin produces a measurable decrease in cardiomyocyte sarcomere contractile function. Lipopolysaccharide-binding protein (LBP) is an acute phase protein that potentiates the recognition of lipopolysaccharide (LPS) by binding to the lipid A moiety of LPS. In this study we sought to determine the effect of recombinant rat LBP (rLBP) on cardiomyocyte sarcomere function after burn or sham injury in the presence or absence of bacterial endotoxin.
Methods
Rats underwent a full-thickness 30% total body surface area scald or sham burn. At 24 hours post injury, cardiomyocytes were isolated, plated at 50,000 cells/well and incubated with 50 μg/mL LPS and rLBP) or chloramphenicol acetyltransferase (BVCat, an irrelevant control protein produced using the same expression system as rLBP) at concentrations by volume of 1, 5, 10, and 30%. Subsets of cardiomyocytes were incubated with 5 % rat serum or 30% rLBP and blocking experiments were conducted using an LBP-like synthetic peptide (LBPK95A). In-vitro sarcomere function was measured using a variable rate video camera system with length detection software.
Results
Co-culture of burn and sham injury derived cardiomyocytes with high-dose rLBP in the presence of LPS resulted in a significant reduction to the functional impairment observed in peak sarcomere shortening following exposure to LPS alone. LBP-like peptide LBPK95A at a concentration of 20 μg/mL, in the presence of LPS, abolished the ability of 30 % rLBP and 5% rat serum to restore peak sarcomere shortening of cardiomyocytes isolated following burn injury to levels of function exhibited in the absence of endotoxin exposure.
Conclusions
In the setting of LPS challenge following burn injury, rLBP at high concentrations restores cardiomyocyte sarcomere contractile function in vitro. Rather than potentiating the recognition of LPS by the cellular LPS receptor complex, rLBP at high concentrations likely results in an inhibitory binding effect that minimizes the impact of endotoxin exposure on cardiomyocyte function following thermal injury.
doi:10.1016/j.jss.2009.06.012
PMCID: PMC2891338  PMID: 20085844
Burn trauma; Burn injury; Cardiac function; Endotoxin; Langendorff preparation; Sarcomere contraction and relaxation; Lipopolysaccharide-binding protein (LBP)
19.  Quality of reporting according to the CONSORT, STROBE and Timmer instrument at the American Burn Association (ABA) annual meetings 2000 and 2008 
Background
The quality of oral and poster conference presentations differ. We hypothesized that the quality of reporting is better in oral abstracts than in poster abstracts at the American Burn Association (ABA) conference meeting.
Methods
All 511 abstracts (2000: N = 259, 2008: N = 252) from the ABA annual meetings in year 2000 and 2008 were screened. RCT's and obervational studies were analyzed by two independent examiners regarding study design and quality of reporting for randomized-controlled trials (RCT) by CONSORT criteria, observational studies by the STROBE criteria and additionally the Timmer instrument.
Results
Overall, 13 RCT's in 2000 and 9 in 2008, 77 observational studies in 2000 and 98 in 2008 were identified. Of the presented abstracts, 5% (oral; 7%(n = 9) vs. poster; 3%(n = 4)) in 2000 and 4% ((oral; 5%(n = 7) vs. poster; 2%(n = 2)) in 2008 were randomized controlled trials. The amount of observational studies as well as experimental studies accepted for presentation was not significantly different between oral and poster in both years. Reporting quality of RCT was for oral vs. poster abstracts in 2000 (CONSORT; 7.2 ± 0.8 vs. 7 ± 0, p = 0.615, CI -0.72 to 1.16, Timmer; 7.8 ± 0.7 vs. 7.5 ± 0.6,) and 2008 (CONSORT; 7.2 ± 1.4 vs. 6.5 ± 1, Timmer; 9.7 ± 1.1 vs. 9.5 ± 0.7). While in 2000, oral and poster abstracts of observational studies were not significantly different for reporting quality according to STROBE (STROBE; 8.3 ± 1.7 vs. 8.9 ± 1.6, p = 0.977, CI -37.3 to 36.3, Timmer; 8.6 ± 1.5 vs. 8.5 ± 1.4, p = 0.712, CI -0.44 to 0.64), in 2008 oral observational abstracts were significantly better than posters (STROBE score; 9.4 ± 1.9 vs. 8.5 ± 2, p = 0.005, CI 0.28 to 1.54, Timmer; 9.4 ± 1.4 vs. 8.6 ± 1.7, p = 0.013, CI 0.32 to 1.28).
Conclusions
Poster abstract reporting quality at the American Burn Association annual meetings in 2000 and 2008 is not necessarily inferior to oral abstracts as far as study design and reporting quality of clinical trials are concerned. The primary hypothesis has to be rejected. However, endorsement for the comprehensive use of the CONSORT and STROBE criteria might further increase the quality of reporting ABA conference abstracts in the future.
doi:10.1186/1471-2288-11-161
PMCID: PMC3247193  PMID: 22126516
Burns; evidence; consort; strobe; timmer; reporting quality; abstract
20.  Acute effects of remote ischemic preconditioning on cutaneous microcirculation - a controlled prospective cohort study 
BMC Surgery  2011;11:32.
Background
Therapeutic strategies aiming to reduce ischemia/reperfusion injury by conditioning tissue tolerance against ischemia appear attractive not only from a scientific perspective, but also in clinics. Although previous studies indicate that remote ischemic intermittent preconditioning (RIPC) is a systemic phenomenon, only a few studies have focused on the elucidation of its mechanisms of action especially in the clinical setting. Therefore, the aim of this study is to evaluate the acute microcirculatory effects of remote ischemic preconditioning on a distinct cutaneous location at the lower extremity which is typically used as a harvesting site for free flap reconstructive surgery in a human in-vivo setting.
Methods
Microcirculatory data of 27 healthy subjects (25 males, age 24 ± 4 years, BMI 23.3) were evaluated continuously at the anterolateral aspect of the left thigh during RIPC using combined Laser-Doppler and photospectrometry (Oxygen-to-see, Lea Medizintechnik, Germany). After baseline microcirculatory measurement, remote ischemia was induced using a tourniquet on the contralateral upper arm for three cycles of 5 min.
Results
After RIPC, tissue oxygen saturation and capillary blood flow increased up to 29% and 35% during the third reperfusion phase versus baseline measurement, respectively (both p = 0.001). Postcapillary venous filling pressure decreased statistically significant by 16% during second reperfusion phase (p = 0.028).
Conclusion
Remote intermittent ischemic preconditioning affects cutaneous tissue oxygen saturation, arterial capillary blood flow and postcapillary venous filling pressure at a remote cutaneous location of the lower extremity. To what extent remote preconditioning might ameliorate reperfusion injury in soft tissue trauma or free flap transplantation further clinical trials have to evaluate.
Trial registration
ClinicalTrials.gov: NCT01235286
doi:10.1186/1471-2482-11-32
PMCID: PMC3231986  PMID: 22111972
Remote ischemic preconditioning; cutaneous microcirculation; free flap; soft tissue
21.  Artificial Skin – Culturing of Different Skin Cell Lines for Generating an Artificial Skin Substitute on Cross-Weaved Spider Silk Fibres 
PLoS ONE  2011;6(7):e21833.
Background
In the field of Plastic Reconstructive Surgery the development of new innovative matrices for skin repair is in urgent need. The ideal biomaterial should promote attachment, proliferation and growth of cells. Additionally, it should degrade in an appropriate time period without releasing harmful substances, but not exert a pathological immune response. Spider dragline silk from Nephila spp meets these demands to a large extent.
Methodology/Principal Findings
Native spider dragline silk, harvested directly out of Nephila spp spiders, was woven on steel frames. Constructs were sterilized and seeded with fibroblasts. After two weeks of cultivating single fibroblasts, keratinocytes were added to generate a bilayered skin model, consisting of dermis and epidermis equivalents. For the next three weeks, constructs in co-culture were lifted on an originally designed setup for air/liquid interface cultivation. After the culturing period, constructs were embedded in paraffin with an especially developed program for spidersilk to avoid supercontraction. Paraffin cross- sections were stained in Haematoxylin & Eosin (H&E) for microscopic analyses.
Conclusion/Significance
Native spider dragline silk woven on steel frames provides a suitable matrix for 3 dimensional skin cell culturing. Both fibroblasts and keratinocytes cell lines adhere to the spider silk fibres and proliferate. Guided by the spider silk fibres, they sprout into the meshes and reach confluence in at most one week. A well-balanced, bilayered cocultivation in two continuously separated strata can be achieved by serum reduction, changing the medium conditions and the cultivation period at the air/liquid interphase. Therefore spider silk appears to be a promising biomaterial for the enhancement of skin regeneration.
doi:10.1371/journal.pone.0021833
PMCID: PMC3144206  PMID: 21814557
22.  Silencing of anti-apoptotic transmembrane protein lifeguard sensitizes solid tumor cell lines MCF-7 and SW872 to perifosine-induced cell death activation 
Oncology Letters  2011;2(3):419-422.
Lifeguard (LFG), an anti-apoptotic protein with high expression rates in breast cancer cells, has been identified as a molecule that inhibits death mediated by Fas. The molecular function of LFG and its regulation in the carcinogenesis of human breast and sarcoma cells, however, remains to be elucidated. In the present study, we investigated the ability of LFG expression to inhibit apoptosis induced by the alkyl-phospholipid perifosine. Results showed that LFG was able to be downregulated in selected sarcoma and breast cancer cell lines characterized by high endogenous LFG expression. A decreased LFG expression led to enhanced sensitivity to treatment with an agonistic Fas antibody or treatment with perifosine. Taken together, our findings indicate the role of LFG as an anti-apoptotic protein and provide further evidence of the potential of LFG as a target for the development of novel therapeutic strategies.
doi:10.3892/ol.2011.285
PMCID: PMC3410496  PMID: 22866097
apoptosis; lifeguard; Fas; perifosine; cancer
23.  Spider Silk Constructs Enhance Axonal Regeneration and Remyelination in Long Nerve Defects in Sheep 
PLoS ONE  2011;6(2):e16990.
Background
Surgical reapposition of peripheral nerve results in some axonal regeneration and functional recovery, but the clinical outcome in long distance nerve defects is disappointing and research continues to utilize further interventional approaches to optimize functional recovery. We describe the use of nerve constructs consisting of decellularized vein grafts filled with spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect in adult sheep.
Methodology/Principal Findings
The nerve constructs were compared to autologous nerve grafts. Regeneration was evaluated for clinical, electrophysiological and histological outcome. Electrophysiological recordings were obtained at 6 months and 10 months post surgery in each group. Ten months later, the nerves were removed and prepared for immunostaining, electrophysiological and electron microscopy. Immunostaining for sodium channel (NaV 1.6) was used to define nodes of Ranvier on regenerated axons in combination with anti-S100 and neurofilament. Anti-S100 was used to identify Schwann cells. Axons regenerated through the constructs and were myelinated indicating migration of Schwann cells into the constructs. Nodes of Ranvier between myelin segments were observed and identified by intense sodium channel (NaV 1.6) staining on the regenerated axons. There was no significant difference in electrophysiological results between control autologous experimental and construct implantation indicating that our construct are an effective alternative to autologous nerve transplantation.
Conclusions/Significance
This study demonstrates that spider silk enhances Schwann cell migration, axonal regrowth and remyelination including electrophysiological recovery in a long-distance peripheral nerve gap model resulting in functional recovery. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery.
doi:10.1371/journal.pone.0016990
PMCID: PMC3045382  PMID: 21364921
24.  Neovascularisation in flexor carpi ulnaris tendinopathy: novel combined sclerosing therapy and eccentric training of the forearms in athletics’ wrist pain 
BMJ Case Reports  2009;2009:bcr08.2008.0714.
Tendinopathy of the flexor carpi ulnaris tendon is a rare entity. We present a 35-year old tennis player suffering tremendous pain (visual analogue scale (VAS) rating of 9/10) at the flexor carpi ulnaris tendon with adjacent calcification in close proximity to the pisiform bone. Sclerosing therapy using polidocanol under power and laser Doppler guidance was initiated, with immediate decrease of capillary blood flow by 25% with resolution of the neovascularisation in power Doppler. Immediately following sclerosing, the patient’s reported pain level on the VAS was reduced from 9/10 to 4/10. Following a short period of rest, eccentric training of the forearm muscle was initiated over 12 weeks with functional complete recovery and complete resolution of wrist pain.
doi:10.1136/bcr.08.2008.0714
PMCID: PMC3027360  PMID: 21686666
25.  Cellulite and extracorporeal Shockwave therapy (CelluShock-2009) - a Randomized Trial 
BMC Women's Health  2010;10:29.
Background
Cellulite is a widespread problem involving females' buttocks and thighs based on the female specific anatomy. Given the higher number of fat cells stored in female fatty tissue in contrast to males, and the aging process of connective tissue leads to an imbalance between lipogenesis and lipolysis with subsequent large fat cells bulging the skin. In addition, microcirculatory changes have been suggested, however remain largely unknown in a controlled clinical setting. We hypothesize that the combination of extracorporeal shockwave and a daily gluteal muscle strength program is superior to the gluteal muscle strength program alone in cellulite.
Methods/Design
Study design: Randomized-controlled trial. IRB approval was granted at Hannover Medical School, Germany on May 22, 2009. For allocation of participants, a 1:1 ratio randomization was performed using opaque envelopes for the concealment of allocation. Reporting: according to CONSORT 2010. Eligible patients were females aged 18 or over and 65 or younger with cellulite with documented cellulite 1°-4° according to the Nürnberger score. Exclusion criteria were suspected or evident pregnancy, no cellulite, no informed consent or age under 18 years or above 65 years. Patients were recruited by advertisements in local regional newspapers and via the Internet. Analysis: Intention-to-treat. Outcome parameters: a) Photonumeric severity scale, b) Nürnberger Score, c) circumference measurements, d) capillary blood flow, e) tissue oxygen saturation, f) postcapillary venous blood flow. Intervention group: Six sessions of extracorporeal focused shock wave for six sessions (2000 impulses, 0,25 mJ/m2 every 1-2 weeks) at both gluteal and thigh regions plus a specific gluteal strength exercise training. Control group: Six sessions of sham extracorporeal focused shock wave for six sessions (2000 impulses, 0,01 mJ/m2 every 1-2 weeks) at both gluteal and thigh regions plus a specific gluteal strength exercise training. Follow-up: 12 weeks. Blinding was achieved for all participants enrolled in the trial, the photograph taking the digital images for the primary outcome measure, the two assessors of the outcome measures, all additional health care providers and for the analyst from the biometrical department. Only one researcher (BJ) was aware of the group assignment performing the randomisation and the extracorporeal shock wave therapy.
Discussion
This randomised-controlled trial will provide much needed evidence on the clinical effectiveness of focused extracorporal shock wave therapy as an adjunct to gluteal strength training in females suffering cellulite.
ClinicalTrials.gov identifier
NCT00947414
doi:10.1186/1472-6874-10-29
PMCID: PMC2987889  PMID: 20977764

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