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

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.

Adipose tissue and the vascularization of biomaterials: Stem cells, microvascular fragments and nanofat-a review.

Tissue defects in the human body after trauma and injury require precise reconstruction to regain function. Hence, there is a great demand for clinically translatable approaches with materials that are both biocompatible and biodegradable. They should also be able to adequately integrate within the tissue through sufficient vascularization. Adipose tissue is abundant and easily accessible. It is a valuable tissue source in regenerative medicine and tissue engineering, especially with regard to its angiogenic potential. Derivatives of adipose tissue, such as microfat, nanofat, microvascular fragments, stromal vascular fraction and stem cells, are commonly used in research, but also clinically to enhance the vascularization of implants and grafts at defect sites. In plastic surgery, adipose tissue is harvested via liposuction and can be manipulated in three ways (macro-, micro- and nanofat) in the operating room, depending on its ultimate use. Whereas macro- and microfat are used as a filling material for soft tissue injuries, nanofat is an injectable viscous extract that primarily induces tissue remodeling because it is rich in growth factors and stem cells. In contrast to microfat that adds volume to a defect site, nanofat has the potential to be easily combined with scaffold materials due to its liquid and homogenous consistency and is particularly attractive for blood vessel formation. The same is true for microvascular fragments that are easily isolated from adipose tissue through collagenase digestion. In preclinical animal models, it has been convincingly shown that these vascular fragments inosculate with host vessels and subsequently accelerate scaffold perfusion and host tissue integration. Adipose tissue is also an ideal source of stem cells. It yields larger quantities of cells than any other source and is easier to access for both the patient and doctor compared with other sources such as bone marrow. They are often used for tissue regeneration in combination with biomaterials. Adipose-derived stem cells can be applied unmodified or as single cell suspensions. However, certain pretreatments, such as cultivation under hypoxic conditions or three-dimensional spheroids production, may provide substantial benefit with regard to subsequent vascularization in vivo due to induced growth factor production. In this narrative review, derivatives of adipose tissue and the vascularization of biomaterials are addressed in a comprehensive approach, including several sizes of derivatives, such as whole fat flaps for soft tissue engineering, nanofat or stem cells, their secretome and exosomes. Taken together, it can be concluded that adipose tissue and its fractions down to the molecular level promote, enhance and support vascularization of biomaterials. Therefore, there is a high potential of the individual fat component to be used in regenerative medicine.

Enoxaparin does not affect network formation of adipose tissue-derived microvascular fragments.

Dermal substitutes are frequently used for the initial coverage of extensive skin defects. The seeding of these implants with adipose tissue-derived microvascular fragments (ad-MVF) has recently been shown to accelerate their vascularization and incorporation. In the present study we analyzed whether these processes are affected by a thromboprophylactic therapy with the low molecular weight heparin (LMWH) enoxaparin (enox). Green fluorescent protein (GFP)+ ad-MVF were isolated from enox- (8 mg/kg s.c.) and vehicle-treated (0.9% NaCl s.c.) (C57BL/6-Tg(CAG-EGFP)1Osb/J mice and seeded onto Integra matrices. Subsequently, these were implanted into full-thickness skin defects within dorsal skinfold chambers of enox- and vehicle-treated C57BL/6 wild-type mice. Repetitive stereomicroscopy and intravital fluorescence microscopy over 2 weeks as well as histological and immunohistochemical analyses on day 14 revealed that enox does not inhibit the reassembly of ad-MVF into new microvascular networks. In addition, treatment with the anticoagulative compound did not promote implant-induced hemorrhage formation. Accordingly, Integra matrices in enox- and vehicle-treated animals exhibited a comparable final microvessel density, fraction of GFP+ blood vessels originating from seeded ad-MVF, collagen fiber content, and epithelialization. These novel findings demonstrate that the seeding of dermal substitutes with ad-MVF may be applied also during thromboprophylactic therapy without affecting implant vascularization and bleeding risk.

The Crucial Role of Vascularization and Lymphangiogenesis in Skin Reconstruction.

BACKGROUND: The treatment of extensive skin defects and bradytrophic wounds remains a challenge in clinical practice. Despite emerging tissue engineering approaches, skin grafts and dermal substitutes are still the routine procedure for the majority of skin defects. Here, we review the role of vascularization and lymphangiogenesis for skin grafting and dermal substitutes from the clinician's perspective. SUMMARY: Graft revascularization is a dynamic combination of inosculation, angiogenesis, and vasculogenesis. The majority of a graft's microvasculature regresses and is replaced by ingrowing microvessels from the wound bed, finally resulting in a chimeric microvascular network. After inosculation within 48-72 h, the graft is re-oxygenated. In contrast to skin grafts, the vascularization of dermal substitutes is slow and dependent on the ingrowth of vessel-forming angiogenic cells. Preclinical angiogenic strategies with adipose tissue-derived isolates are appealing for the treatment of difficult wounds and may markedly accelerate skin reconstruction in the future. However, their translation from bench to bedside is still restricted by major regulatory restrictions. Finally, the lymphatic system contributes to edema reduction and the removal of local wound debris. Therapeutic lymphangiogenesis is an emerging field of research in skin reconstruction. Key Messages: For the successful engraftment of skin grafts and dermal substitutes, the rapid formation of a microvascular network is of pivotal importance. Hence, to understand the biological processes behind revascularization of skin substitutes and to implement this knowledge into clinical practice is a prerequisite when treating skin defects. Furthermore, a functional lymphatic drainage crucially contributes to the engraftment of skin substitutes.

[Leg ulcers (ulcus cruris): The frequent macrovascular causes]. / Ulcus cruris: Die häufigen, makrovaskulären Ursachen.

Leg ulcers (ulcus cruris): The frequent macrovascular causes Abstract. Four pathologies make up the macrovascular etiologies of leg uclers: Venous leg ulcers (50 %), mixed venous-arterial leg ulcers (20 %), arterial leg ulcers (5 %), and Martorell hypertensive ischemic leg ulcer (5 %). The remaining 20 % concern a large array of other etiologies. Every leg ulcer requires vascular (arterial and venous) work-up, that can be completed with microbiology, biopsy, and more in-depth internal diagnostics, as indicated. Venous leg ulcers are treated with compression therapy. Incompetent saphenous veins and tributaries are abolished if the deep venous system is patent. Occluded iliac veins are recanalised and stented, as possible. Refractory venous leg ulcers are grafted with split skin or punch grafts, depending on their surface. Extensive dermatolipofasciosclerosis may be tangentially removed by shave therapy or fasciectomy, that can be combined with negative pressure wound treatment (NPWT). Skin equivalents are an alternative to treat superficial venous leg ulcers that fail to epithelialise. Their indication in the treatment of more complex leg ulcers still needs to be better investigated and understood. The use of dermal matrices leads to more stable scars. Mixed venous-arterial leg ulcers heal slower and recur more frequently. Compression needs to be reduced. Refractory cases require arterial revascularisation, to transform the mixed venous-arterial into a venous leg ulcer. Arterial leg ulcers require arterial revascularization and split skin graft. Martorell hypertensive ischemic leg ulcer is still underrecognised and often confounded with with pyoderma gangrenosum, which leads therapy into a wrong direction. Necrosectomy, antibiotic treatment in the presence of relevant bacterial superinfection, and repeated split skin grafts eventually heal the vast majority of these extremely painful and potentially mortal wounds.

Current and emerging vascularization strategies in skin tissue engineering.

Vascularization is a key process in skin tissue engineering, determining the biological function of artificial skin implants. Hence, efficient vascularization strategies are a major prerequisite for the safe application of these implants in clinical practice. Current approaches include (i) modification of structural and physicochemical properties of dermal scaffolds, (ii) biological scaffold activation with growth factor-releasing systems or gene vectors, and (iii) generation of prevascularized skin substitutes by seeding scaffolds with vessel-forming cells. These conventional approaches may be further supplemented by emerging strategies, such as transplantation of adipose tissue-derived microvascular fragments, 3D bioprinting and microfluidics, miRNA modulation, cell sheet engineering, and fabrication of photosynthetic scaffolds. The successful translation of these vascularization strategies from bench to bedside may pave the way for a broad clinical implementation of skin tissue engineering.

Magnetic Resonance Neurographic and Clinical Long-Term Results After Oberlin's Transfer for Adult Brachial Plexus Injuries.

The primary goal of the surgical treatment of upper brachial plexus injuries is to restore active elbow flexion. Accordingly, Oberlin's transfer has been frequently performed since 1994 and has influenced the development of other nerve transfers. However, the window of opportunity for nerve transfers remains a subject of controversy. The objective of this study was to assess magnetic resonance (MR) neurographic, clinical and electrophysiological long-term results after Oberlin's transfer. For this purpose, we performed a retrospective follow-up study. Six patients with upper brachial plexus or musculocutaneous nerve injuries were assessed; 2 were iatrogenic nerve injuries following shoulder arthroscopy or neurofibroma resection. Direct and indirect signs of neuropathy were objectified with MR neurography. Moreover, clinical and electrodiagnostic follow-up was performed and all patients completed the Disabilities of Arm, Shoulder and Hand score. Mean follow-up was 48 ± 21.9 (range, 20-73) months. Mean age was 40 ± 11.3 years and mean delay to surgery was 9 ± 3.2 months. All patients were satisfied with the functional results and the median Disabilities of Arm, Shoulder and Hand score was 21 (range, 1-57). Biceps strength was improved in 5 patients from Medical Research Council grade M0 to M4-5 and in one patient to M2-3. The donor nerve showed normal motor and sensory action potentials. Follow-up MR neurography demonstrated biceps reinnervation. Taken together, this study reports good long-term results after Oberlin's transfer. MR neurography represents an excellent, noninvasive preoperative planning tool and can be of high value in selected postoperative cases. The combined evaluation of nerves and muscles may help to indicate nerve transfers in delayed cases.

Animal models in surgical lymphedema research--a systematic review.

BACKGROUND: Chronic secondary lymphedema is a well-known complication in oncologic surgery. Autologous lymph node transplantation, lymphovenous anastomosis, and other lymphatic surgeries have been developed in the last decades with rising clinical application. Animal models to explore the pathophysiology of lymphedema and microsurgical interventions have reached great popularity, although the induction of stable lymphedema in animals is still challenging. The aim of this review was to systematically assess lymphedema animal models and their potential use to study surgical interventions. MATERIALS AND METHODS: A systematic review according to the PRISMA guidelines was performed without time or language restriction. Studies describing new or partially new models were included in chronological order. Models for primary and secondary lymphedema were assessed, and their potential for surgical procedures was evaluated. RESULTS: The systematic search yielded 8590 discrete articles. Of 180 articles included on basis of title, 84 were excluded after abstract review. Ninety-six were included in the final analysis with 24 key articles. CONCLUSIONS: No animal model is perfect, and many models show spontaneous lymphedema resolution. The rodent limb appears to be the most eligible animal model for experimental reconstruction of the lymphatic function as it is well accessible for vascularized tissue transfer. There is a need for standardized parameters in experimental lymphedema quantification. Also, more permanent models to study the effect of free vascularized lymph node transfer are needed.

Perforated sigmoid diverticulitis in a lumbar hernia after iliac crest bone graft--a case report.

BACKGROUND: The combination of perforated diverticulitis in a lumbar hernia constitutes an extremely rare condition. CASE PRESENTATION: We report a case of a 66 year old Caucasian woman presenting with perforated sigmoid diverticulitis localized in a lumbar hernia following iliac crest bone graft performed 18 years ago. Emergency treatment consisted of laparoscopic peritoneal lavage. Elective sigmoid resection was scheduled four months later. At the same time a laparoscopic hernia repair with a biologic mesh graft was performed. CONCLUSION: This case shows a very seldom clinical presentation of lumbar hernia. Secondary colonic resection and concurrent hernia repair with a biologic implant have proven useful in treating this rare condition.

10-Year single center experience in lower limb reconstruction with free muscle flaps - factors influencing complications in 266 consecutive cases.

The anatomy and technique of free muscle flaps - in particular gracilis flap and latissimus dorsi flap - in lower extremity reconstruction have been well described. There is a paucity of data on potential risk factors in larger patient series that affect the outcome. The objective of this study was to address this lack of knowledge by reporting outcomes and complications of free muscle flaps as a primary option in lower extremity reconstruction. From 2009 to 2020, a total of 253 consecutive patients with soft tissue defects of the lower limb from trauma, infection or malignancies underwent lower extremity reconstructive surgery with 266 free muscle flaps. Complications requiring revision surgery were noted in 36.1% of cases. Total flap loss occurred in 10.5% of cases. Patients requiring revision surgery were older, more likely to be female, more likely to be active smokers, and more likely to have a higher ASA score. Lower extremity reconstruction with free muscle flaps has a relevant complication rate that both patient and reconstructive surgeon need to be aware of. Prospective studies should try to further assess the factors affecting the outcome.

Basic science approaches to common hand surgery problems.

The field of hand surgery is constantly evolving to meet challenges of populations with increasing age and higher demands for active living. While our surgical care has improved over the last decades, it seems that future major improvement in outcomes of clinical treatment will come through advances in biologics and the translation of major discoveries in basic science. This article aims to provide an update on where basic science solutions may answer some of the most critical issues in hand surgery, with a focus on augmentation of tissue repair.

Intraneural fibrosis and loss of microvascular architecture - Key findings investigating failed human nerve allografts.

BACKGROUND: Processed nerve allografts are increasingly used in clinical nerve reconstruction with promising results. However, allograft failure has been reported, leading to chronic pain and persistent loss of function. In the present work, we performed a histological and immunohistochemical analysis of two failed allograft reconstructions of a sensory human nerve one year after primary surgery. METHODS: Two patients with a superficial radial nerve injury underwent nerve reconstruction with processed nerve allografts. The clinical follow-up was complicated by severe neuropathic pain and absent sensory reinnervation. Consequently, the failed allografts were excised with subsequent histological and immunohistochemical examinations. For that purpose, the collagen content and neurofilament network as well as the blood and lymphatic vasculature were analysed in the center of the specimens. RESULTS: Histology revealed increased fibrosis, fatty degeneration, and disorganised proliferation of nerve fibres. Moreover, the microvascular network within the allografts was characterised by increased numbers of microvessels, whereas no difference was found concerning the lymphatic vasculature. CONCLUSION: The herein presented histological and immunohistochemical findings indicate that the failure of human allografts is associated with loss of the physiological microvascular architecture. Future studies elucidating the complex interplay of angiogenesis, lymphangiogenesis and axonal regeneration are required to better understand the mechanisms of human allograft failure.

Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model.

Chronic lymphedema after cancer treatment is common and there is still no cure for this disease. We herein investigated the lymphangiogenic capacity of adipose tissue-derived microvascular fragments (MVF), which contain stem cells and lymphatic vessel fragments. Secondary lymphedema was induced in the hindlimbs of C57BL/6J mice. Green fluorescence protein (GFP)+ MVF were isolated from transgenic C57BL/6Tg (CAG-EGFP)1Osb/J mice, suspended in collagen hydrogel, and injected in the lymphadenectomy defect of wild-type animals. This crossover model allowed the detection of MVF-derived blood and lymphatic vessels after transplantation. The MVF group was compared with animals receiving collagen hydrogel only or a sham intervention. Lymphangiogenic effects were analyzed using volumetry, magnetic resonance (MR) lymphography, histology, and immunohistochemistry. MVF injection resulted in reduced hindlimb volumes when compared to non-treated controls. MR lymphography revealed lymphatic regeneration with reduced dermal backflow after MVF treatment. Finally, MVF transplantation promoted popliteal angiogenesis and lymphangiogenesis associated with a significantly increased microvessel and lymphatic vessel density. These findings indicate that MVF transplantation represents a promising approach to induce therapeutic lymphangiogenesis.

Fluorescence angiography-assisted debridement of critically perfused glabrous skin in degloving foot injuries: Two case reports.

RATIONALE: Degloving foot injuries are challenging to treat and associated with life-long sequelae for patients. An appropriate debridement of ischemic soft tissues with maximal preservation of glabrous skin is key during the reconstruction of these injuries. Indocyanine green (ICG) fluorescence angiography is an established technique for the intraoperative evaluation of tissue perfusion. PATIENT CONCERNS: Two patients sustained complex foot injuries in traffic accidents, including multiple fracture dislocations and extensive degloving of the plantar skin. DIAGNOSIS: Clinical inspection revealed significant degloving of the glabrous skin in both patients. INTERVENTIONS: After fracture fixation, ICG fluorescence angiography-assisted debridement with immediate latissimus dorsi free flap reconstruction was performed. OUTCOMES: In both cases, this technique allowed a precise debridement with maximal preservation of the glabrous skin. The healing of the remaining glabrous skin was uneventful and the 6-month follow-up was characterized by stable soft tissues and satisfying ambulation. LESSONS: ICG fluorescence angiography is a safe, user-friendly, and quick procedure with minimal risks, expanding the armamentarium of the reconstructive surgeon. It is highly useful for the debridement of extensive plantar degloving injuries and may also help to minimize the number of procedures and the risk of infection.

[Pain In the Thumb and Other Fingers]. / Schmerzen im Daumen und anderen Fingern.

Pain In the Thumb and Other Fingers Abstract. As the population ages, symptoms of osteoarthritis in the hand are seen with increasing frequency. It can lead to substantial pain, physical disability and impair the patient's capacity to work in a population with an increasing retirement age. This article gives an overview about the most prevalent forms of osteoarthritis in the hand, its diagnosis and current treatment options, stressing that the multimodal form of therapy is the most effective.

[Tendinopathies - Common Diagnoses in Hand Surgery]. / Tendinopathien ­ häufige Diagnosen in der Handchirurgie.

Tendinopathies - Common Diagnoses in Hand Surgery Abstract. Tendinopathies are among the most frequent reasons for consulting a hand surgeon. The diagnosis can usually be made clinically. A supplementary ultrasound examination helps to visualize the pathology. Most of these diseases respond to non-surgical treatment. If surgical treatment is necessary, it can usually be performed as an outpatient procedure under local anesthesia. This article provides an overview of the most common tendinopathies of the hand and wrist, their diagnosis and treatment.

[The Painful Wrist]. / Das schmerzhafte Handgelenk.

The Painful Wrist Abstract. Wrist pain is a problem that can significantly limit patients in their daily activities. The causes are manifold, and treatment is often challenging. A systematic approach is therefore helpful in working up the correct diagnosis. This article aims to demonstrate a straightforward approach to the evaluation of wrist pain in adults.

[Neuropathic Pain - Differential Diagnosis and Treatment from the Hand Surgeon's Perspective]. / Neuropathische Schmerzen ­ Handchirurgische Differenzialdiagnose und Therapie.

Neuropathic Pain - Differential Diagnosis and Treatment from the Hand Surgeon's Perspective Abstract. Neuropathic pain of the wrist and hand can be caused by a multitude of pathologies, such as trauma, iatrogenic damage, local peripheral nerve compression, nerve tumors and systemic diseases. Neuropathic pain can lead to chronification and disability, severely affecting the patients' quality of life and the ability to work. A precise diagnosis is the key to an adequate therapy with satisfactory functional results. An interdisciplinary and multimodal approach is a prerequisite when treating neuropathic pain. This review article provides an insight into the diagnosis and therapy of pathologies associated with neuropathic pain of the wrist and hand.

Improvement of islet transplantation by the fusion of islet cells with functional blood vessels.

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin-secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non-prevascularized islet organoids. This is caused by paracrine signaling between the ß-cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo, the prevascularized islet organoids are rapidly blood-perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation.

Intramedullary compression screw fixation of metacarpal and phalangeal fractures.

The intramedullary headless compression screw (IMCS) technique represents a reliable alternative to percutaneous Kirschner-wire and plate fixation with minimal complications.Transverse fractures of the metacarpal shaft represent a good indication for this technique. Non-comminuted subcapital and short oblique fractures can also be treated with IMCS.This technique should not be used in the presence of an open epiphysis, infection and, most of all, in subchondral fractures, because of the lack of purchase for the head of the screw.A double screw construct is recommended for comminuted subcapital fractures of the metacarpal to avoid metacarpal shortening. IMCS can even be applied for peri-articular fractures of the proximal third of the phalanx and in some multi-fragmentary proximal and middle phalangeal fractures.Usually the intramedullary screws are not removed. The main indications for screw removal are joint protrusion, infection and screw breakage after new fracture. Cite this article: EFORT Open Rev 2020;5:624-629. DOI: 10.1302/2058-5241.5.190068.