The Vascular Involvement in Soft Tissue Fibrosis-Lessons Learned from Pathological Scarring.

Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.

Changes in the Periodontium and Pulp in ISIAH Rats Caused by Stress Exposures in Different Modes.

It was shown that the intensity of morphological changes in the dental system tissues (periodontium and pulp) of ISIAH rats depends on the mode of stress exposure. Acute stress was associated with a significant increase in the area of periodontal and pulp vessels, a decrease in the area of connective tissue of these components, and an increase in the thickness of the vascular endothelium. Chronic stress in these animals induced an increase in the thickness of the endothelial layer of the periodontal and pulp vessels, fibromatosis (increase in the number of fibroblasts), and a sharp decrease in the level of odontoblasts.

Blood Flow Changes in Subsynovial Connective Tissue on Contrast-Enhanced Ultrasonography in Patients With Carpal Tunnel Syndrome Before and After Surgical Decompression.

OBJECTIVES: Although qualitative alteration of the subsynovial connective tissue in the carpal tunnel is considered to be one of the most important factors in the pathophysiologic mechanisms of carpal tunnel syndrome (CTS), little information is available about the microcirculation in the subsynovial connective tissue in patients with CTS. The aims of this study were to use contrast-enhanced ultrasonography (US) to evaluate blood flow in the subsynovial connective tissue proximal to the carpal tunnel in patients with CTS before and after carpal tunnel release. METHODS: The study included 15 volunteers and 12 patients with CTS. The blood flow in the subsynovial connective tissue and the median nerve was evaluated preoperatively and at 1, 2, and 3 months postoperatively using contrast-enhanced US. RESULTS: The blood flow in the subsynovial connective tissue was higher in the patients with CTS than in the volunteers. In the patients with CTS, there was a significant correlation between the blood flow in the subsynovial connective tissue and the median nerve (P = .01). The blood flow in both the subsynovial connective tissue and the median nerve increased markedly after carpal tunnel release. CONCLUSIONS: Our results suggest that increased blood flow in the subsynovial connective tissue may play a role in the alteration of the microcirculation within the median nerve related to the pathophysiologic mechanisms of CTS. The increase in the blood flow in the subsynovial connective tissue during the early postoperative period may contribute to the changes in intraneural circulation, and these changes may lead to neural recovery.

Bone Marrow Stroma and Vascular Contributions to Myeloma Bone Homing.

PURPOSE OF THE REVIEW: Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma. RECENT FINDINGS: The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow.

Interaction of stromal and microvascular components in keratocystic odontogenic tumors.

OBJECTIVE: Little is known about the interaction of stromal components in odontogenic tumors. Thus, the aim of this study was to investigate mast cells (MCs), myofibroblasts, macrophages, and their possible association with angiogenesis and lymphangiogenesis in keratocystic odontogenic tumors (KCOTs). MATERIAL AND METHODS: Thirty cases of KCOTs were included and analyzed by immunohistochemistry for mast cell tryptase, α-SMA, CD34, CD163, and D240. For comparative purpose, 15 radicular cysts (CRs) and 7 pericoronal follicles (PFs) were included. RESULTS: There was an increase in MCs for RCs and this difference was significant when they were compared to KCOTS and PFs. A significant increase in the density of MFs was observed for KCOTs when compared to RCs and PFs (P = 0.00). No significant difference in CD163-positive macrophages (P = 0.084) and CD34-positive vessels (P = 0.244) densities was observed between KCOTs, RCs, and PFs, although KCOTs showed a higher density of all proteins. Significant difference in lymphatic vessel density was observed for KCOTs when compared to RCs and PFs (P = 0.00). Positive correlation was observed between mast cell tryptase and CD34 in KCOTs (P = 0.025). CONCLUSIONS: A significant interaction between the MC population and CD34-positive vessels in KCOTs supported the hypothesis that MCs and blood vessels contribute to the stromal scaffold of KCOT.

The role of neoangiogenesis and vascular endothelial growth factor in the development of carpal tunnel syndrome in patients with diabetes.

OBJECTIVE: Carpal tunnel syndrome (CTS) is an entrapment neuropathy which is caused by the disruption of blood supply in the median nerve under transverse carpal ligament. Systemic factors facilitate the formation of the syndrome. In this study, neovascularization in the subsynovial tissue and proliferative activity in the stroma are analyzed within the cases of diabetic and idiopathic CTS. MATERIALS AND METHODS: Subsynovial connective tissue samples of 30 diabetes mellitus patients with CTS and 30 patients with idiopathic CTS were evaluated. Vascular endothelial growth factor (VEGF), CD31, CD34, Factor VIII-related antigen, and smooth muscle actin (SMA) was used to make a comparative study of neovascularization. Proliferative index was assessed using anti-Ki-67 antibody. RESULTS: As a result of the proliferation of endothelial elements, de novo blood vessel formations in the subsynovial tissue were assessed by vascular markers. Significant neovascularization was seen in diabetic group for VEGF, CD31, SMA (P < 0.01); and for CD34 (P < 0.05) when compared with idiopathic CTS group. In addition, more intense positive staining for CD34, SMA (P < 0.01); and for VEGF (P < 0.05) was found at isolated stromal cells of diabetic CTS group against idiopathic CTS group. Significantly high proliferative index in subsynovial connective tissue with Ki-67 was observed the diabetic group (P < 0.01). CONCLUSION: VEGF expression has an importance within CTS pathogenesis. Increased ischemia-reperfusion damage, neoangiogenesis, and VEGF expression has an important role frequently CTS occurrence in diabetic patients. Our study supports enhancement in VEGF expression similar to changes in diabetic nephropathy and retinopathy in the neovascularization within the subsynovial connective tissue in the cases of diabetes.

Response assessment to neoadjuvant therapy in soft tissue sarcomas: using CT texture analysis in comparison to tumor size, density, and perfusion.

PURPOSE: To evaluate the role of computed tomography (CT) texture analysis in assessing response of soft tissue sarcoma (STS) treated with neoadjuvant bevacizumab (BVZ) plus radiotherapy in comparison to tumor size, density, and perfusion. METHODS: In the phase II clinical trial, 20 patients with STSs received BVZ alone for 2 weeks followed by BVZ plus radiotherapy for 6 weeks prior to surgery. All patients received CT perfusion at baseline, 2 and 8 weeks after the therapy, and tumor blood flow (BF) was measured. In contrast enhanced CT image at the arterial peak enhancement time, mean of positive pixels (MPP) was measured as a texture parameter using texture analysis software, and tumor size and density were also measured. The percent changes of these parameters were compared with pathological response on surgical specimen. RESULTS: After 2 weeks of the therapy, MPP and BF decreased by 10.42% and 20.08%, while changes of tumor size and density were not obvious. After 8 weeks, MPP, BF, and density decreased by 29.2% (p = 0.03), 53.2% (p = 0.001), and 30.41% (p = 0.005), respectively, without a significant change in size. The percent change of MPP after 8 weeks had a significant correlation with tumor necrosis in surgical specimen (r = -0.801, p < 0.001), whereas those of size, density, and BF did not. The receiver-operating characteristic analysis demonstrated that the percent change of MPP < -35.36% was an optimal cut-off value to differentiate pathological responders. CONCLUSION: The change of MPP is the best biomarker for the treatment response in STS.

[Vascular Lesions of Vocal Folds - Part 2: Perpendicular Vascular Lesions]. / Gefäßveränderungen der Stimmlippen - Teil 2: Perpendikuläre Gefäßveränderungen.

The present work aims at a systematic pathogenetic description of perpendicular vascular changes in the vocal folds. Unlike longitudinal vascular changes, like ectasia and meander, perpendicular vascular changes can be observed in bening lesions. They predominantly occur as typical vascular loops in exophytic lesions, especially in recurrent respiratory papillomatosis (RRP), pre-cancerous and cancerous diseases of the larynx and vocal folds. Neoangiogenesis is caused by an epithelial growth stimulus in the early phase of cancerous genesis. In RRP the VVC impress by a single, long vessel loop with a narrow angle turning point in the each single papilla of the papilloma. In pre- and cancerous lesions the vascular loop is located directly underneath the epithelium. During progressive tumor growth, vascular loops develop an increasingly irregular, convoluted, spirally shape. The arrangement of the vascular loops is primarily still symmetrical. In the preliminary stage of tumor development occurs by neoangiogenesis to a microvascular compression. In advanced vocal fold carcinoma the regular vascular vocal fold structure is destroyed. The various stages of tumor growth are also characterized by typical primary epithelial and secondary connective tissue changes. The characteristic triad of vascular, epithelial and connective tissue changes therefore plays an important role in differential diagnosis.

[IN VIVO EVALUATION OF POLYCAPROLACTONE-HYDROXYAPATITE SCAFFOLD BIOCOMPATIBILITY].

Biocompatibility is one of the main and very important properties for scaffolds. The aim of the present study was to investigate cells population dynamics in vivo in the process of original polycaprolactone-hydroxyapatite scaffold colonization, as well as tissue reactions to the implantation to assess the biocompatibility of the matrix. It has been found that tissue reactive changes in white rats subside completely up to the 21st day after subcutaneous polycaprolactone-hydroxyapatite scaffold implantation. Matrix was actively colonized by connective tissue cells in the period from the 7th to the 21st day of the experiment. However, intensive scaffold vascularization started from the 14th day after implantation. These findings suggest a high degree of the polycaprolactone-hydroxyapatite scaffold biocompatiblilitye.

A multilevel hierarchical finite element model for capillary failure in soft tissue.

Bruising, the result of capillary failure due to trauma, is a common indication of abuse. However, the etiology of capillary failure has yet to be determined as the scale change from tissue to capillary represents several orders of magnitude. As a first step toward determining bruise etiology, we have developed a multilevel hierarchical finite element model (FEM) of a portion of the upper human arm using a commercial finite element tool and a series of three interconnected hierarchical submodels. The third and final submodel contains a portion of the muscle tissue in which a single capillary is embedded. Nonlinear, hyperelastic material properties were applied to skin, adipose, muscle, and capillary wall materials. A pseudostrain energy method was implemented to subtract rigid-body-like motion of the submodel volume experienced in the global model, and was critical for convergence and successful analyses in the submodels. The deformation and hoop stresses in the capillary wall were determined and compared with published capillary failure stress. For the dynamic load applied to the skin of the arm (physiologically simulating a punch), the model predicted that approximately 8% volume fraction of the capillary wall was above the reference capillary failure stress, indicating bruising would likely occur.

[Effect of cytokines and stromal cells of adipose tissue on integration of a two-component composite net imlant into biological tissues].

Morphological changes in biological tissues, surrounding the composite net-like implant, owing large pores "Ultrapro", and also its combination with adipose transplant, fibrin, enriched with thrombocytes, were studied in experiment on 36 adult male rats of a Wistar line. While application of such construction the processes of creation and organization of connective tissue, neoangiogenesis as well as development of a new adipose tissue are improved. As a consequence of increase of concentration of highly active biological substances and regenerative cytokines in combination of the net implant with adipose transplant, containing multipotent stem cells, proliferative activity of all cellular elements, surrounding the net implant, is raising, what predispose its optimal integration into surrounding tissues.

Ten frequently asked questions about MRI evaluation of soft-tissue vascular anomalies.

OBJECTIVE: The objective of this article was to address 10 frequently asked questions that radiologists face when planning, performing, and interpreting an MRI study in a patient with a soft-tissue vascular anomaly. CONCLUSION: MRI permits a comprehensive assessment of vascular anomalies. It is important for radiologists to be familiar with the classification and correct nomenclature of vascular anomalies as well as the MRI protocol and distinct imaging findings of the different vascular malformations and tumors.

Expression profile of macrophage migration-inhibitory factor in human gingiva and reconstituted human gingival epithelia stimulated by Porphyromonas gingivalis lipopolysaccharide.

BACKGROUND AND OBJECTIVE: Macrophage migration-inhibitory factor (MIF) plays crucial roles in the recruitment and activation of macrophages as well as in helping to kill bacteria. This study investigated the expression profile of MIF in human gingiva under different periodontal conditions and its expression patterns induced by Porphyromonas gingivalis lipopolysaccharide (LPS) in gingival epithelia. MATERIAL AND METHODS: Gingival tissue samples were collected from deep pockets and clinically healthy sites of 22 nonsmoking subjects with chronic periodontitis. The expression of MIF mRNA and protein was evaluated using real-time PCR and immunohistochemistry, respectively. The in vitro study analyzed the effects of P. gingivalis LPS on the expression of MIF in a reconstituted human gingival epithelia (RHGE) model. RESULTS: In gingival epithelia, MIF protein was diffusely expressed from the basal layer to the granular and spinous layers; whereas, in the underlying connective tissues, MIF was observed around the dilated blood vessels in the deep-pocket tissues. A significantly lower level of expression of MIF mRNA and an increased level of expression of MIF protein were found in deep-pocket tissues compared with clinically healthy tissues. Expression of MIF mRNA in the RHGE model was significantly down-regulated by P. gingivalis LPS. CONCLUSION: The present study suggests that MIF expression may be related to periodontal conditions and that its expression profile could be modulated by P. gingivalis LPS. MIF may play a role in periodontal pathogenesis.

Micro-CT observation of angiogenesis in bone regeneration.

OBJECTIVES: Restoration of an adequate blood supply is essential for the bone healing process and is key to the success of bone augmentation procedures. In this study, we evaluated angiogenesis in rat calvarial flat bone defects using in vivo microfocus computed tomography (micro-CT). MATERIALS AND METHODS: Twenty rats were used. The calvarium was exposed and calvarial bone defects of critical (5-mm diameter) and non-critical (2.7-mm diameter) sizes were prepared. Bone regeneration and angiogenesis were evaluated by image analysis using micro-CT and histological examination. RESULTS: Critical- and non-critical-sized calvarial bone defects showed bone regeneration and angiogenesis around the midsagittal suture. Critical-sized calvarial bone defects showed approximately 1.2% reossification of the original surgical defect, whereas the non-critical-sized defects showed approximately 43.3% reossification at day 28. Furthermore, angiogenesis was observed later in the critical-sized calvarial bone defects (about 38.2%), whereas angiogenesis was observed early in the non-critical-sized calvarial bone defects (about 75.5%) at day 28. New blood vessel networks were observed around defects of both sizes. CONCLUSIONS: Angiogenesis preceded bone regeneration around critical- and non-critical-sized calvarial bone defects. Angiogenesis led to full bone formation in non-critical-sized defects.

[Extended skin and soft tissue defects after vascular wounds: plastic surgical concepts]. / Ausgedehnte Gewebedefekte bei vaskulären Wunden--Möglichkeiten der plastischen Chirurgie.

INTRODUCTION: Skin and soft-tissue defects at the ischaemic lower extremity represent a challenging condition. Major amputations can be prevented by optimised surgical therapy. The aim of any intervention is the revascularisation and defect reconstruction of the extremity. METHODS: This article aims to provide a structured overview on up-to-date therapeutic strategies and differentiated indications for certain surgical flaps in combination with bypass surgery for the treatment of chronic "vascular" wounds. RESULTS: Optimised conservative wound therapy, skin grafts, pedicled or microsurgical free flaps in combination with vascular bypasses can be applied to salvage ischaemic extremities. These operations require an interdisciplinary cooperation between vascular surgeons and plastic surgeons. DISCUSSION: These procedures should accordingly only be performed in specialised high-volume centres with significant vascular surgical and microsurgical expertise.

The connective tissue changes of Crohn's disease.

Although the inflammatory pathology of Crohn's disease is manifestly its most important attribute, the connective tissue changes are important in the genesis of the more chronic features of the disease, and yet these have received little attention from clinicians, pathologists, and scientists. Fat-wrapping appears to be pathognomonic of Crohn's disease, and is an important marker of disease for surgeons. There is evidence of a complex interplay between the effector inflammatory cells of Crohn's disease and adipocytes, hyperplasia of which results in fat-wrapping. Pathologically, this is exhibited in the close relationship between the transmural inflammation that is so characteristic of Crohn's disease and fat-wrapping. Fibrosis and muscularization are also important components of the chronic changes of intestinal Crohn's disease. Neuronal and vascular changes make up the remaining connective tissue changes: these constitute a distinctive feature, and are even specific for Crohn's disease. For pathologists, the combination of these connective changes will allow a diagnosis of chronic 'burnt-out' Crohn's disease, even in the absence of its highly characteristic inflammatory features. The connective tissue changes of Crohn's disease form an important part of its long-term pathology. They deserve more attention from clinicians, diagnostic pathologists and researchers alike.

Analysis of inflammatory periimplant lesions during a 12-week period of undisturbed plaque accumulation--a comparison between flapless and flap surgery in the mini-pig.

This study's aim was to clarify the influence of soft tissue management on the development of periimplant infection. Four weeks after removal of all maxillary premolars in 12 mini-pigs, four BEGO Semados RI implants were inserted in each maxillary quadrant. Employing a split-mouth design, one quadrant was randomized to flapless insertion while the contralateral side was chosen for flap surgery. Following 1, 2, 4 and 12 weeks of transmucosal implant, healing biopsies were retrieved from the periimplant soft tissue and subjected to further analysis. Histomorphometrically, a significant reduction of transmigration of polymorphonuclear neutrophils (week 1, p = 0.007; week 2, p = 0.021; week 4, p = 0.023; week 12, p = 0.013) as well as the density of the subepithelial inflammatory infiltrates (week 1, p = 0.007; week 2, p = 0.046; week 4, p = 0.003; week 12, p = 0.032) was verified following flapless surgery. Quantification of inducible nitric oxide synthase showed significantly reduced expression in the flapless group 2 (p = 0.027), 4 (p = 0.005) and 12 (p = 0.004) weeks post-insertion. Analysis of CD31 and collagen I immunostained sections revealed more regular capillary distribution as well as higher vessel and collagen density in the flapless group. The data of the present study indicate that flapless placement reduces the incidence of inflammatory periimplant soft tissue lesions during a 12-week period. Considering the beneficial effects of flapless placement on early soft tissue healing and stability, the technique might be preferred in case of an uncomplicated locoregional anatomy with sufficient hard and soft tissue. However, this positive effect might disappear after manipulation of the implant and soft tissue during impression taking or try in of the prosthodontic supraconstruction.

Vascularisation of myringo-/tympanoplastic grafts in active and inactive chronic mucosal otitis media: a prospective cohort study.

OBJECTIVES: To evaluate the vascularisation process of the grafted fascia or perichondrium in active and inactive chronic mucosal otitis media. DESIGN: Prospective study. SETTING: University-based, secondary referral hospital. PARTICIPANTS: Two hundred thirty-two patients who underwent type 1 tympanoplasty or myringoplasty by one experienced surgeon. MAIN OUTCOME MEASURES: After postoperative days 5-7, the graft was inspected using a binocular operating microscope at least twice weekly until vascularisation was confirmed to have commenced. This point was defined as the time of vascularisation. An intact graft at 3 months postoperatively was considered a closure success. RESULTS: The mean time of vascularisation of 232 grafts was 14.2 ± 3.6 days (range 8-25). The vascularisation time differed according to the perforation size. The perforations involving 50% and less of the pars tensa were revascularised earlier than those involving 75% and more. There was no relationship between vascularisation time and closure success or failure. Age itself did not influence the vascularisation time or the risk of closure failure. Postoperative otorrhea was higher in patients with a preoperative wet middle ear mucosa than among those with a dry one. CONCLUSION: The vascularisation time was shorter in perforations of 50% and less than those of 75% and more but the rate of closure success was not different between two. The graft failure was not attributed to the failure of vascularisation. Age itself seemed not to be a contraindication for myringo-/tympanoplasty in otherwise healthy elderly patients.

Physiological measurements of tissue health; implications for clinical practice.

Pressure mapping alone insufficiently describes tissue health. Comprehensive, quantitative non invasive assessment is crucial. Interface pressures (IPs) and transcutaneous blood gas levels [transcutaneous tissue oxygen (T(c) PO(2) )] were simultaneously assessed over both ischia and the sacrum to investigate the hypotheses: (i) tissue oxygenation decreases with sustained applied pressure; (ii) tissue oxygen and IP are inversely correlated in loaded soft tissues; (iii) multisite assessments are unnecessary because healthy individuals are symmetrical. Measurements were taken at 5-minute intervals for 20 minutes in both sitting and supine lying for a cohort of 20 able-bodied adults. There were no statistically significant changes over time for either variable in 96% of timepoint comparisons. Specifically, no significant differences were seen between 10 and 20 minutes in either position. These findings imply that a 10-minute assessment can reliably indicate tissue health and that tissue may adapt to applied load over time. No statistically significant correlations between T(c) PO(2) and IP were observed. However, the left and right ischia were significantly different for both variables in supine lying (P < 0.001) and for sitting IP (P < 0.010). Thus, even in this healthy cohort, postural symmetry was not observed and should not be assumed for other populations with restricted mobility. If a multisite technique cannot be used, repeated tissue health assessments must use the same anatomic location.

Time-resolved detection enables standard two-photon fluorescence microscopy for in vivo label-free imaging of microvasculature in tissue.

We conducted a systematic study on two-photon excited fluorescence (TPEF) of hemoglobin using the near transform-limited and Gaussian-shaped femtosecond pulse sources. We found that the two-photon action cross section of hemoglobin drops over 2 orders of magnitude in the wavelength range from 550 to 800 nm, while the spectral and temporal characteristics of hemoglobin TPEF are insensitive to the change of excitation wavelength. In particular, our new findings showed that the hemoglobin fluorescence could be excited with sufficient efficiency using a conventional Ti:sapphire laser tuned at the wavelength close to 700 nm. With the employment of a time-resolved detection method, we demonstrated that the TPEF signals of hemoglobin excited by a Ti:sapphire laser could be clearly differentiated from other nonlinear signals presented within the living biological tissues, indicating that a standard TPEF microscope can become a routine tool for in vivo label-free microangiography imaging.