Local Vascular System Research Articles

Lipid nanoparticle-encapsulated VEGFa siRNA facilitates cartilage formation by suppressing angiogenesis

Cartilage is an important tissue that is widely found in joints, ears, nose and other organs. The limited capacity to regenerate makes cartilage reconstruction an urgent clinical demand. Due to the avascular nature of cartilage, we hypothesized that inhibition of vascularization contributes to cartilage formation. Here, we used VEGFa siRNA to inhibit the infiltration of the local vascular system. Optimized lipid nanoparticles were prepared by microfluidics for the delivery of siRNA. Then, we constructed a tissue engineering scaffold. Both seed cells and VEGFa siRNA-LNPs were loaded in a GELMA hydrogel. Subcutaneous implantation experiments in nude mice indicate that this is a promising strategy for cartilage reconstruction. The regenerated cartilage was superior, with significant upregulation of SOX9, COL-II and ACAN. This is attributed to an environment deficient in oxygen and nutrients, which facilitates cartilage formation by upregulating HIF-1α and FOXO transcription factors. In conclusion, a GelMA/Cells+VEGFa siRNA-LNPs scaffold was constructed to achieve superior cartilage regeneration.

New Insight on Pathophysiology, Diagnosis, and Treatment of Odontogenic Maxillary Sinusitis

Odontogenic maxillary sinusitis is often ignored by otolaryngologists, dentists, and imageological diagnosis doctors. Traditional treatments are often frustrating for refractory maxillary sinusitis and odontogenic maxillary sinusitis. In the last few years, new progress has been made in the diagnosis, pathophysiology, and treatment of odontogenic maxillary sinusitis. Periodontitis, polyposis, and iatrogenesis are regarded as causes of odontogenic maxillary sinusitis. Dental implant dislocation into the maxillary sinus and augmentation are the main cause of iatrogenesis compared to root canal full material. The symptoms are too similar to distinguish odontogenic maxillary sinusitis from chronic rhinosinusitis. Computed tomography is the gold standard for diagnosis, while it is difficult to rule out odontogenic maxillary sinusitis by conventional panoramic radiographs. Cone-beam computed tomography (CBCT) is currently the most broadly used to make diagnosis and differential diagnosis for maxillary sinus disease. The imaging diagnosis, clinical diagnosis, and pathological diagnosis are often not completely in accordance. Most researchers believe that odontogenic maxillary sinus infection results from the spread of apical pathogenic microbial infections: either through the local vascular system, lymphatic system, or the Haval system of the alveolar bone itself. DNA and RNA sequencing of mucosal tissues of maxillary sinus disease confirmed that the mechanisms of odontogenic maxillary sinusitis and nonodontogenic maxillary sinusitis are different. Microbial RNA sequencing of the maxillary sinus also verifies this conclusion. Clinical serum testing of chemical factors has not been widely exploited. It is unknown whether the thickening of the maxillary sinus membrane is the result of pathogen infection or inflammatory mediators. Many doctors have recommended a consensus on multidisciplinary cooperation management, but a global consensus has not yet been reached. Diagnosis methods for odontogenic maxillary sinus disease are diversified. Tissue DNA and RNA sequencing, chemical factor determination, and microbiological DNA and RNA sequencing have appeared, and the misdiagnosis rate has gradually decreased. The pathophysiology of odontogenic maxillary sinusitis and chronic rhinosinusitis is different. The molecular mechanism of the thickening of the Schneider membrane in odontogenic sinus is unknown.

Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts.

Hepatic fibrosis is characterized by the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying noxious trigger, tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. Genetic disorders, chronic viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, alterations in bile acid composition or concentration, venous obstruction, and parasite infections are well-established factors that predispose one to hepatic fibrosis. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and progression of hepatic fibrosis. Multidisciplinary panels of experts have developed practice guidelines, including recommendations of preferred therapeutic approaches to a specific cause of hepatic disease, stage of fibrosis, or occurring co-morbidities associated with ongoing loss of hepatic function. Here, we summarize the factors leading to liver fibrosis and the current concepts in anti-fibrotic therapies.

Inflammation: Extinguishing the Fires Within

The word “inflammation” is derived from the Latin word inflamacio, which means “to set a fire.” The fire of inflammation is a complex process that occurs in response to tissue or cell damage by pathogens, noxious stimuli, radiation, or physical injury. As one of the most deeply rooted cellular characteristics, inflammation plays a fundamental role in preserving the integrity of cells. Whether inflammation is beneficial or harmful is a question of balance. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial short-term response of the body to harmful stimuli, which under normal circumstances results in the process of healing. A cascade of biochemical events propagates and matures the inflammatory response. These processes involve the local vascular system, the immune system, and various cells within the injured tissue. This inflammatory response is basic, yet essential, for the removal of harmful stimuli and to initiate the healing process of the inflamed tissue. Without it, we would not be alive. If the cause of the inflammatory response is not eliminated or if mechanisms that terminate the inflammatory process fail, inflammation can become chronic. As a consequence, the balance between proinflammatory and anti-inflammatory mediators is not restored. Cells of the immune system liberate reactive oxygen species, chemokines, cytokines, and other small molecules that maintain and intensify the inflammatory response. Simultaneous degradation and regeneration of the affected tissue occurs—a precursor of a wide variety of pathologies. Thus, a persistent stimulus converts a normal and essential host defense mechanism into an injurious response. This issue of Clinical Pharmacology & Therapeutics highlights the emerging recognition of inflammation as a crucial factor in the development and course of chronic diseases and provides novel insights into current therapeutic modalities for the treatment of inflammation and the causes of the variable response to therapy in humans.

Effects of local injections of vasoactive drugs on eruption rate of incisor teeth in anaesthetized rats

Previous studies have suggested that the vasculature in the dental pulp and periodontal tissues plays an important role in producing the eruptive force in continuously erupting incisors. The aim of the present study was to investigate the effects of local injections of vasoactive drugs on regional blood flow within the socket in association with axial tooth movements to clarify the role of the local vascular system on tooth eruption. Twenty-two male Wistar rats, weighing 309+/-21 g (S.D.), were immobilized with halothane anaesthesia. We measured the regional blood flow within the socket using a laser Doppler flowmeter, and the axial movements of the mandibular incisor using a displacement detector. The local injections of the vasoactive drugs, adrenaline (0.001, 0.01, and 0.1 microg/kg body weight) and acetylcholine (0.05, 0.5, and 5 microg/kg), into the base of the incisor were performed by a microinjector at a rate of 1 microl/kg body weight. The injections of various doses of adrenaline decreased the mean regional blood flow and eruption rate dose-dependently, while those of acetylcholine increased the mean regional blood flow and eruption rate dose-dependently. The changes in the regional blood flow and eruption rate were transient. Significant correlations (p<0.001) were obtained between the maximum and minimum values in the regional blood flow and in the eruption rate following injections of various doses of adrenaline and acetylcholine. These results support the hypothesis that the eruptive force of the rat incisor is closely related to the vasculature within the socket.

Striated muscle microvascular response to implants with sol-gel calcium phosphate coating. A comparative in vivo study

Local microvascular perfusion plays an important role in reparative processes and the pathogenesis of infection. The impairment of skeletal muscle microcirculation by a biomaterial may therefore have profound consequences. The aim of our study was to determine whether the biological acceptance of the widely utilised implant material stainless steel can be improved by a coating of sol-gel calcium phosphate. Using the hamster dorsal skinfold chamber preparation and intravital microscopy, we quantified nutritive perfusion and leukocyte-endothelium interaction in skeletal muscle after implantation of sol-gel calcium phosphate-coated stainless steel- and commercial pure titanium implants, and compared these results to those obtained with uncoated stainless steel and titanium. Within the first 24 h after implantation, animals with calcium phosphate coated stainless steel showed a significantly lower inflammatory response than did those with an uncoated stainless steel implant. After 24 h the quantified microcirculatory parameters deteriorated for animals with a calcium phosphate-coated stainless steel plate, indicating that, for as yet unknown reasons, the shielding mechanism of the calcium phosphate seems to deteriorate. Although not as inert as pure titanium, we found a relatively low inflammatory response for calcium phosphate coated titanium over the whole observation period, suggesting that the coating as such is well tolerated by the skeletal muscle microcirculation. Our in vivo results suggest that the biological acceptance of a conventional stainless steel implant can be improved over a short term by a sol-gel coating of calcium phosphate. Concerning tolerance by the local vascular system, commercially pure titanium currently remains unsurpassed.

Control of Local Bacterial Soft Tissue Contamination by Adequate Microvascular Response is Critically Dependent on the Extent of Bacterial Challenge

Background: Local cellular and humoral defense mechanisms play a significant role in combating local bacterial infection. The effectiveness of these mechanisms is directly related to an intact vascular system. The objective of this study was to elucidate the effect of local bacterial challenge on the host tissue microvascular response and nutritive perfusion. Material and Methods: The hamster dorsal skin fold preparation and intravital microscopy allowed direct visualization of skeletal muscle microcirculation and quantification of microcirculatory and cellular parameters over an observation period of 24 h after bacterial exposition with doses of either 2 × 105 or 2 × 107 CFU (colony-forming units) Staphylococcus aureus Newman. Results: 2 × 105 bacteria led to a transient activation of leukocytes with an increase in endothelial cell interaction within the first 120 min. Here, the endothelial integrity remained intact, shown by a lack of venular macromolecular extravasation. In contrast, the challenge with 2 × 107 CFU resulted in a marked rise in leukocyte-endothelial cell interaction combined with macromolecular leakage. Dilation of the venular system as well as a drastic reduction in nutritive perfusion became evident. Whereas six of seven chambers in the 2 × 107-group were completely covered by bacteria within 48 h, the group confronted with 2 × 105 cells showed almost intact chambers within the observation period. Conclusions: The amount of bacteria has a considerable impact on the microvascular system and thus on the pathogenesis of infection. Our observations suggest that there may be a threshold level, whereby the host can tolerate a certain degree of bacterial exposition, but above which the fragile local vascular system collapses. Further dose-related experiments will be needed to clarify this hypothesis. This versatile skin fold model offers perspective in elucidating the pathogenesis of implant-related infection.

Impact of a nickel-reduced stainless steel implant on striated muscle microcirculation: a comparative in vivo study.

The impairment of skeletal muscle microcirculation by a biomaterial may have profound consequences. With moderately good physical and corrosion characteristics, implant-quality stainless steel is particularly popular in orthopedic surgery. However, due to the presence of a considerable amount of nickel in the alloy, concern has been voiced in respect to local tissue responses. More recently a stainless steel alloy with a significant reduction of nickel has become commercially available. We, therefore, studied in vivo nutritive perfusion and leukocytic response of striated muscle to this nickel-reduced alloy, and compared these results with those of the materials conventional stainless steel and titanium. Using the hamster dorsal skinfold chamber preparation and intravital microscopy, we could demonstrate that reduction of the nickel quantity in a stainless steel implant has a positive effect on local microvascular parameters. Although the implantation of a conventional stainless steel sample led to a distinct and persistent activation of leukocytes combined with disruption of the microvascular endothelial integrity, marked leukocyte extravasation, and considerable venular dilation, animals with a nickel-reduced stainless steel implant showed only a moderate increase of these parameters, with a clear tendency of recuperation. Titanium implants merely caused a transient increase of leukocyte-endothelial cell interaction within the first 120 min, and no significant change in macromolecular leakage, leukocyte extravasation, or venular diameter. Pending biomechanical and corrosion testing, nickel-reduced stainless steel may be a viable alternative to conventional implant-quality stainless steel for biomedical applications. Concerning tolerance by the local vascular system, titanium currently remains unsurpassed.

Striated muscle microvascular response to silver implants: A comparative in vivo study with titanium and stainless steel

Local microvascular perfusion is the primary line of defense of tissue against microorganisms and plays a considerable role in reparative processes. The impairment of the microcirculation by a biomaterial may therefore have profound consequences. Silver is known to have excellent antimicrobial activity and, although regional and systemic toxic effects have been described, silver is regularly discussed as an implant material in bone surgery. Because little is known about the influence of silver implants on the adjacent host tissue microvasculature, we studied in vivo nutritive perfusion and leukocytic response, and compared these results with those of the conventionally used materials titanium and stainless steel. Using the hamster dorsal skinfold chamber preparation and intravital microscopy, the implantation of a commercially pure silver sample led to a distinct and persistent activation of leukocytes combined with a marked disruption of the microvascular endothelial integrity, massive leukocyte extravasation, and considerable venular dilation. Whereas animals with stainless-steel implants showed a moderate increase in these parameters with a tendency to recuperate, titanium implants caused only a transient increase of leukocyte–endothelial cell interaction within the first 120 min and no significant change in macromolecular leakage, leukocyte extravasation and venular diameter. After 3 days, five of six preparations with silver samples showed severe inflammation and massive edema. Thus, the use of silver as an implant material should be critically judged despite its bactericidal properties. The implant material titanium seems to be well tolerated by the local vascular system and currently represents the golden standard.© 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 49, 192–199, 2000.

A physical-based model for the simulation of neoplastic growth and metastasis.

It is possible to formulate models capable of reproducing the main details of the physical processes involved in the evolution of biological systems. The complexity of the problem requires to begin with a simple and universal model for the description of the cellular growth, to be adapted successively to the local conditions found in clinically observed neoplastic growths. A model based on the Local Interaction Simulation Approach (LISA) has been formulated for the simulation of growth, diffusion, and metastasis of neoplasms. The vascularization is described by a blood vessel located on one edge of the specimen in which a constant and homogeneous flow is assumed. A nutrient density is defined to mimic the blood flow within the tissue. Photograms taken at proper times may identify the main characteristics of the tumor evolution and describe its volume variations in a transversal section. Furthermore, it is possible to monitor constantly the volume of the neoplasm and of the necrotic tissue as a function of time, as well as the portion of cells that have migrated in the blood vessel. In spite of strong simplifying assumptions, the model presents good qualitative agreement with clinical data, which may be further improved by more detailed information about cancer cells properties or local vascular system patterns.

Local transfer of hormones between blood vessels within the adrenal gland may explain the functional interaction between the adrenal cortex and medulla

The adrenal cortex has a local stimulatory action on synthesis and secretion of adrenaline by the adrenal medulla. This interaction may be based on nervous transmission and/or on glucocorticoids secreted trom the cortex either exerting paracrine effects or reaching the medulla through the local vascular system. The existence of a dual capillary network, a portal system, now seems unlikely. However, a new concept is postulated: the high demand for glucocorticoids in the medulla may be met by local transfer to blood vessels within the adrenal gland, particularly the medullary arteries.

Free vascularized groin fat flap in hypoplasia and hemiatrophy of the face: (A three years observation)

Two female patients with facial malformation are presented: one with microsomia (17 years old) and the other (35 years old) with a very severe form of Rhomberg-Parry facial hemiatrophy. The defect in one side of the face was augmented in both cases by means of a free inguinal fat flap connected to the local vascular system with microvascular anastomoses. After a follow up of three years (first patient) and 18 months (second patient) no sign of resorption could be observed and the fat shows a normal histological structure. The arterial flow is proved with the Doppler flowmeter and in one patient with arteriography. The operative technique is described, the advantages and disadvantages in contrast to other procedures are discussed.

Evaluation of fasciotomy and vasodilator for treatment of frostbite in the dog

Severe freezing injury was produced in the hind foot of 26 mongrel dogs. All dogs were given daily whirlpool treatment and protective bandaging for 14 days following injury. In addition, certain dogs received a vasodilator, fasciotomy, or both vasodilator and fasciotomy following injury. Deep foot temperatures, foot volumes, tissue pressures, and 14 day tissue loss-salvage scores were compared. Significant differences between fasciotomy and nonfasciotomy dogs were seen in foot temperature, volume, and tissue pressure immediately following fasciotomy. Though there was no significant difference in 14 day tissue loss, there was clinically apparent prolongation of integrity of the local vascular system for 2 to 5 days following fasciotomy, and total foot salvage in several dogs receiving fasciotomy.