Biocompatibility of a New Generation of Covered Metallic Biliary Stents in a Treatment of Malignant Causes Irreversibile Cholestasis A

Introduction: Overview of periprocedural and postprocedural (early and late) complication giving us access to determine the biological eff ects of treatment with covered versus uncovered metal stents in patients with irreversible jaundice malignant etiology. The Aim: The aim of study was to compare the clinical therapeutical eff ects of covered billiary stents versus uncovered billiary stents. Subjects and methods: We treated two groups of patients with irreversible cholestasis malignant etiology. In the fi rst group of patients were used metal covering stents (MCS), while in the other group used metal uncovered stents (MNS). Results: We observed periprocedural complications, technical complications, and the early-to 30-day and late-to 6 months post-procedural complications such as parameters of biocompatibility of inserted endoprosthesis, i.e. biological eff ects on surrounding tissues. We found statistically high diff erence in the occurrence of bleeding and periprocedural complications in total of MNS group. In the category of early postprocedural complications, we found a statistically signifi cant diff erence in the MNS groups for a hemobilia, post-stent cholangitis, stent occlusion, irritative symptoms and appetite loss, and also in the overall appearance of early postprocedural complications in MNS. In the category of late postprocedural complications statistically signifi cant diff erence we found in the MNS reobstructive cholangitis, reobstruktive jaundice, irritative symptoms, loss of appetite and in full. The cause of stent dysfunction-obliteration, biliary encrustation, ingrowth, overgrowth and mucosal hyperplasia, tells us in favor of the biological eff ects of the insertion, point applied prosthesis and the fi nal therapeutic eff ect achieved by them. Conclusions: According to our results, taking into account the parameters of biocompatibility under applicable defi nitions, authors can conclude that covered stents in contrast to the uncovered are meeting the criteria of almost ideal biological prostheses.


INTRODUCTION
Biocompatibility is a term that will surely mark the technical achievements and aspirations in medicine and biological systems of the 21 th century.Where the conventional pharmacology and surgery can give the therapeutic contribution, technology biocompatible device system is imposed as the only solution, and perhaps the best they can.Precondition that determines the success of any therapeutic device system is exactly biocompatibility.Th e extent to which the system will be suitable device specifi c biological systems is a key concept in many research,experimental and clinical.Th ere are many defi nitions of the term biocompatibility.It is defi ne as a the property of being biologically compatible and not producing a toxic, injurious, or immunological response in living tissue.As a result of its strength and biocompatibility, the material is oft en used in medical devices.Some other defi nitions are: the ability to coexist with living organisms without harming them; the quality of not having toxic or injurious eff ects on biological systems.Th e degree of biocompatibility depends on a material's chemical stability over time, tendency to cause infl ammation, incite disease, or become carcinogenic.
Biomaterials and its behavior in various contexts is related to biocompatibility.Th e term-biocompatibility may refer to specifi c properties of a material without specifying where or how the material is used (for example, that it elicits little or no immune response in a given organism, or is able to integrate with a particular cell type ortissue), or to more empirical clinical success of a whole device in which the material or materials feature.Quiddity of the term is laying in double meaning how biomaterials interact with thehuman bodyand, also, how those interactions determine the clinical success of a medical device.It is the main reason why modern medical devices and prostheses are oft en made of more than one material so it might not always be suffi cient to talk about the biocompatibility of a specifi c material [1].It is not adequate to determine the biocompatibility of single material in relation to a single cell type of tissue, because of the immune response and reparatory function of the body which are complicated.According to ISO 10993 or other similar standards, there are a lot of in vitro tests to determine if a certain material or biomedical products (such as pacemaker, hip replacement, stent etc.) is biocompatible, but not the biocompatibility of a material.Th ey towards the animal testing and fi nally clinical trials that will determine the biocompatibility of the material in a given application and thus medical devices such as implants or drug delivery devices.It is the most important step in medicotechnologically evolution of some device.
Th e biocompatibility as a term has been mentioned for the fi rst time in the peerreview journals and meetings in 1969/1970 [2,3], almost two decades before it began to be commonly used in scientifi c literature.Williams regarded factors which determine clinical success.Th e main thing for an implant, regarding to this author, is not to have to be positively bioactive but not to do any harm.Williams defi nition, which was defi ned in the European Society for Biomaterials Consensus Conference, and defi nition from "Th e Williams dictionary of Biomaterials" is "Th e ability of a material to perform with an appropriate host response in a specifi c application" [4,5].Th e other one from the same dictionary is "Th e quality of not having toxic or injurious eff ects on biological systems".Comparison of the tissue response produced through the close association of the implanted candidate material to its implant site within the host animal to that tissue response recognized and established as suitable with control materials -ASTM.Th e ASTM is not recommended according to Williams Dictionary since it only refers to local tissue responses, in animal models.Refers to the ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic eff ects in the recipient or benefi ciary of that therapy, but generating the most appropriate benefi cial cellular or tissue response in that specifi c situation, and optimizing the clinically relevant performance of that therapy [6].It is more precious version of the fi rst definition.One more defi nition is "Biocompatibility is the capability of a prosthesis implanted in the body to exist in harmony with tissue without causing deleterious changes" all these definitions claim that the material is the point of every device system.It is the reason why much of the preclinical testing of the material is not conducted on the devices but rather the material itself.Testing has to include the shape, geometry and surface treatment of the device will also aff ect its biocompability.In the litera-ture, one quite oft en stumbles upon the adjective form: biocompatible.However, according to Williams' defi nition, this does not make any sense because biocompatibility is contextual, i.e. much more than just the material itself will determine the clinical outcome of the medical device of which the biomaterial is a part.Th is also points to one of the weaknesses with the current defi nition because a medical device usually is made of more than one material.
Th e scope of the fi rst defi nition is so wide that Williams tried to fi nd suitable subgroups of applications in order to be able to make more narrow defi nitions [6].In this article, the chosen subgroups and their defi nitions were: 1. Biocompatibility of long -term implanted -Th e biocompatibility of a long-term implantable medical device refers to the ability of the device to perform its intended function, with the desired degree of incorporation in the host, without eliciting any undesirable local or systemic eff ects in that host; 2. Biocompatibility of short-term implantable devices -Th e biocompatibility of a medical device that is intentionally placed within the cardiovascular system for transient diagnostic or therapeutic purposes refers to the ability of the device to carry out its intended function within fl owing blood, with minimal interaction between device and blood that adversely aff ects device performance, and without inducing uncontrolled activation of cellular or plasma protein cascades; 3. Biocompatibility of tissue -engineeringproducts -Th e biocompatibility of a scaff old or matrix for a tissue -engineering products refers to the ability to perform as a substrate that will support the appropriate cellular activity, including the facilitation of molecular and mechanical signaling systems, in order to optimize tissue regeneration, without eliciting any undesirable eff ects in those cells, or inducing any undesirable local or systemic responses in the eventual host.
Medical grade siliconesaresiliconestested forbiocompatibilityand are appropriate to be used for medical applications.In the United States, the Food and Drug Administration (FDA) regulates materials implanted into the body [1].Medical grade silicones are generally grouped into three categories: nonimplantable, short term implantable and longterm implantable.Materials approved as USP Class V and VI can be considered medical grade [7].Most medical grade silicones are at least Class VI certifi ed.Silicone suppliers and 598 Volume 5 • Number 1 • January 2018 • HOPH some silicone prototyping companies provide guidelines for material use [8].
Polyethylene (abbreviated PE) or polythene [IUPAC name polyethene or poly (methylene)] is the most common plastic.Many kinds of polyethylene are known, with most having the chemical formula (C 2 H 4 ) n H 2 .Th us PE is usually a mixture of similar organic compoundsthat diff er in terms of the value of nit is biodegrading plastics.In May 2008, Daniel Burd, a 16-year-old Canadian, won the Canada-Wide Science Fair in Ottawa aft er discovering that Pseudomonas fl uorescens, with the help of Sphingomonas, can degrade over 40% of the weight of plastic bags in less than three months.
Application of metal alloys in the manufacture of prostheses for the use in medicine is defi ned in the International Standards Organization for Standardization in Medicine (ISO standards) and the decisions of the European Committee for Standardization in medicine (CEN standards).Th e most common metal alloy stent materials such as: ferum-chromium-nickel, cobalt-chrome, titanium and nitinol.In the period 1988-1991, metal stents were predominantly produced from surgical any steel (ISO 10993 -316L) which is the dominant element iron (65.6%) and chromium (17% responsible for corrosion resistance) and nickel (14% responsible for the stability metal alloys).Th e middle of the last decade of the last century, the expansion of the application had cobalt-chromium alloys (Palmatz stent, Cordis J & J) and alloys of titanium with 88.5% (Strecker stent, BS), which is composed not iron, nickel and chromium.In 1996, the largest application has had this type of stent.Today the dominant material for the metal stents has alloy nitinol.Nitinol stents dwelling build from about equal amounts of nickel and titanium with less 1% of the composition of the alloy participate iron, magnesium, cobalt and chromium.All biliary stents characterized by antimagnetizm, corrosion resistance and the capacity to reduce local aggregation of blood elements.Th ese characteristics constitute the notion biocompatibility prosthesis.In relation to the manner of insertion of stents used in hepatobiliary recanalization can be balloon expandible or selfexpandible.Incomparably greater usage in all indications has selfexpandable stents.Due to the passage through the soft tissue structures of the liver, as well as the way through parenchyma, and when changing the direction of penetration, the case of application of a stent balloon-expandable possible possibility of moving the catheter and the stent along its dislocation before insertion, as in the case of application selfexpandible stents not happen.
Metal stents in interventional radiology are applied almost twenty years.All the time we have witnessed continuous development expansion of this method of recanalization.Stent materials, corrosion resistance, design, insertion systems and all other aspects of importance for the therapeutic eff ectiveness continually refi ned through an extraordinary interdisciplinary scientifi c integration [9].A small number of other methodologies in clinical medicine that are so hyperactive unifi ed way superior technology of biocompatible materials and medical knowledge.It is appropriate that there is a continuous expansion of good therapeutic results, decreasing the number of relapses and a set of criteria which distinguish the ideal stent increased.Acquired numerous clinical experiences [10], and formed the impression that certain traditional qualifying runs for irreversible biliary strictures main choledoch or some of its branches now changing.Pushing the boundaries of medical biological relativity to omnipotence, metal stents have become one of diff erentiation specifi city of modern medicine at the end of this century.
Signifi cant contribution in metallic prostheses relations to the use of so-called covered stent for selective use of the biliary insertion 2003 rd years (Wallstent biliary endoprosthesis covering and Unistep and Ultrafl ex cover diamond biliary stent system -BS).In our hospital from March 2006, we used the covered biliary stents Allium length of 10 cm and a width of 8mm.Allium stents were selfexpandible nitinol covered with a biocompatible polyurethane and silicon.Placing stents in cancer patients is usually performed to treat advanced nonresectable tumors, but in some cases the stent is placed as a "bridge" to surgery.Th e main advantage of covered stents is that there is no option for ingrowing tissue reactive proliferation and progression of infi ltration.Clinical trials are aimed, in the context of assessment material, testing of materials and their behavior in biological tissue.Stents, as a metal prosthesis, covered and uncovered, and their biocompatibility may be discussed from the point of complicating (periprocedural, technical and postprocedural, early and late) as a reaction to the surrounding tissue and causes dysfunctional as the ultimate therapeutically eff ect realized in the particular circumstances.

THE AIM
Th e aim of study was to compare the clinical therapeutical eff ects of covered billiary stents versus uncovered billiary stents.

MATERIALS AND METHODS
Th is paper is academic, a phase IV study, done in accordance with the EU Directives and with current legislative and government regulations of the Republic of Serbia [11].Th e study has been approved by the Ethics Committee of the Faculty of Medicine, University of Belgrade, Serbia (No. 29/VI-2).All data and the personal information collected in this study are subject to medical confi dentiality and may only be brought together for processing and evaluation in an anonymous form.
Th e survey included patients treated at the department of interventional radiology and the department of digestive radiology Clinical Center of Serbia in the period from October 2006 to October 2011, who were diagnosed as biliary tract obstruction and propagation malignancies: cholangiocarcinoma, pancreatic carcinoma, gall bladder carcinoma, gastric cancer and metastases in the hilum of the liver.
Two groups of 29 patients with irreversible cholestasis malignant etiology, we applied the treatment with metal stents, uncovered Balton biliary stent® (Balton, Poland) or Wallstent® (Boston Scientifi c, USA), and covered Allium biliary stent® (Hedera, Israel).Th e Allium self-expandable, large caliber fully covered and easily removable biliary stents were designed to be used in chronic Common Bile Duct (CBD) obstructions for allowing intra-luminal fl ow duringits long indwelling period (up to 6 months).Th ey are made of a super-elastic alloy (nitinol) fully covered by a novel polymeric material for preventing tissue ingrowth and reduce occlusion by sludge.Th eir 8 mm or 10 mm diameterallows excellent intra-luminal fl ow.Th e specially designed proprietaryend elementsminimize reactive tissue proliferation.Th e anchored model has a low radial force sphincteric segment to prevent or minimize the refl ux which is the main cause of cholangitis seen with conventional stents.Th e deployment procedure can be performed using the standard ERCP procedure or percutaneously (depending on the deployment system used).Th e Allium Biliary Stents are designed to be removed easily and safely.Th e main stent characteristics areindicated for all strictures in the common bile duct, large caliber for intraluminal fl ow, long dwelling time, endoscopic or Trans-Hepatic insertion, easy insertion and stent positioning, available with or without an anchor, no tissue in-growth, anti-refl ux design, easy removal of the device.Complications may develop during positioning, usually being recognized immediately by the operator, or may be detected aft er placement by diagnostic imaging as early (fi rst 30 days aft er placement) or late (> 30 days) events.
Evaluation included radiographic, CT and exciting ultrasonic control to evaluate the position and patency of the stent functions.Subscriptions are periprocedural complications (TA fall, jump TA, over sedation, pain, bleeding, contrast artifacts, fever, irritability) and technical complications related to the technique of insertion (catheter dislocation, dislocation of the guide wires, repuncture, catapulting the stent, stent incomplete distension).Besides periprocedural were measured and postprocedural complications (early and late).Early procedural complica-tions (cholangitis, abscess, acute cholecystitis, biliary perforation, pleural emphysema, haemobilia, intraperitoneal pulse, subcutaneous metastases, poststent cholangitis, percutaneous fi stula,stent occlusion, irritative symptoms and loss of appetite), made up to a month aft er stent insertion.Late complications (reobstructive jaundice, reobstructive cholangitis, acute cholecystitis, chronic bleeding and melena, duodenal ulcer or perforation, stent migration path forward, pancreatitis, fi stula, percutaneous, irritative symptoms and loss of appetite) incurred in the periodfrom one month to six months aft er insertion.As predictors constant of dysfunctional accompanied by obliteration of the stent, ingrowth, overgrowth, mucosal hyperplasia and biliary encrustation.

Statistical analysis
Descriptive statistics were presented as mean values with standard deviation (SD) for numeric variables, or as absolute numbers with percentages for categorical variables.Diff erences in continuous variables between the groups were compared using the Students ttest or the Mann-Whitney U test (for skewed data).Diff erences between the categorical data were tested by the Chi-square test and/or Fisher's exact test where appropriate; p value <0, 05 were considered statistically signifi cant.

RESULTS
Patients were divided into two groups according to the type of intervention/dentures that were treated (MCS -metal covered stents, uncovered/noncovered stents -MNS).Th e distribution of patients by age, sex, diagnosis and state of mind at the time of intervention is shown in table 1. Th ere were signifi cantly more males but there was no diff erence in the distribution of poles per group.Patients were nearly identical states of consciousness in groups.Th e pathological substrate occurs in fi ve entities -cholangiocarcinoma, pancreatic cancer, stomach cancer, gallbladder and secondary deposits in the hilum of the liver -with no statistically signifi cant diff erences in distribution between groups.
Complications are parameter of implants biocompatibility in the broader context of the word.Th erefore, a good part of the research devoted to technical screening, periprocedural and postprocedural, early (30 days) and late (30 days to 6 months) complications.Periprocedural complications like bleeding fully exhibit highly statistically signifi cant diff erence between the groups (table 2).In a group of technical complications, were no statistical diff erences, except in incomplet stent distension (table 3).Technical success was achieved in 100% (29/29), so stent incomplete distension isn't occurred.
Table 4 presents the distribution of early postprocedural complications in groups.Our experience indicates conclusion that the new Allium biliary covered stent allows a minimally invasive, ambulatory approach to recurrent biliary strictures with very satisfactory results comparable with earlier generation of biliary stents, metal uncovered stents.In the category of early postprocedural complications (table 4).Postprocedural complications, early (table 4) haemobilia, poststent cholangitis, occlusion of the stent, irritative symptoms, loss of appetite and early post-procedural complications in its entirety are fully statistical signifi cantly diff erent distributed by groups.Late post-procedural complications reopstructive jaundice, reopstructive cholangitis, irritative symptoms, loss of weight and late post-procedural complications in their entirety are presented with statistically signifi cant diff erences in groups (table 5).
Cause of stent dysfunction-obliteration, biliary encrustration, ingrowth, overgrowth and mucosal hyperplasia, tells us in favor of the biological eff ects in insertion place applied prosthesis and the fi nal therapeutic effect achieved by them.All causes of stent dysfunctional (table 6) considered in two groups treated with covered and non-covered stents recorded a statistically signifi cant diff erence at all, except for biliary encrustations.Reintervention signifi cantly diff erently distributed in groups, showing both weekly.Lethal outcome is the same in groups and presented by weeks in that record.Since the early and late postprocedural complication to a lesser extent occur in MPS, and also records the signifi cantly smaller number of causes dysfunctional of stent in the same group and a smaller number of reintervention.

DISCUSSION
Th e results obtained in this study confi rm the hypothesis that the fi rst line therapy in the treatment of jaundice and irreversible malig- Low rate, technical and postprocedural complications, early and late, and low mortality rates, supports extraordinary therapeutic eff ects of a new generation of covered metallic stents, and diff erentiated polyurethane covered stents compared to uncovered stents as an almost ideal stretch.By all criteria, biocompatibility, this generation of stents proved to nititol stent mesh covered with silicone and polyurethane insert very successful, good in vivo tolerated without causing irritation and any complications, with very survival and durability of the therapeutic eff ects and preserving consistency within the tissue.
Th e research we have conducted on two groups, shown in table 1. demographic almost identical characteristics, diagnosis and general condition.Th is research has given us the opportunity to compare the therapeutic effects of two groups of stents to sample nearly identical groups of patients in virtually identical clinical conditions, monitoring of diff erent categories of complications and causes of stent dysfunctional as direct and indirect parameters of stent biocompatibility.Th is minimally invasive approach, carried out radiologically as well as endoscopically, allows the narrowed viscus lumen to be kept patient, decreasing the obstructive impairment of the hepatobiliary and gastrointestinal function, with consequent relief of patient symptoms and improvement in quality of life [14][15][16].However, complications may develop during positioning, usually being recognized immediately by the operator, or may be detected aft er placement by diagnostic imaging as early (fi rst 30 days aft er placement) or late (> 30 days) events [13,[17][18].
To the extent periprocedural complications, bleeding was the only complication that signifi cantly more frequent in uncovered stents illustrating the irritation uncovered versus covered metal stent to the surrounding tissue and therefore less conspicuous biocompatibidity.
As in most studies of biliary SEMS [19], technical placement success was almost universal.From the technical complications incomplete insertion is imposed by uncovered metal stents as signifi cantly greater hindrance biocompatibility or achieving the expected therapeutic eff ect riched by technically correct insertion.In addition, noninserted on the proper way and the full diameter, the stent becomes a foreign body that can cause weight side eff ects and complications of the surrounding tissues and the body as a whole.Complications of this type are considered in the category of early and late postprocedural complication.As postprocedural early complications occurred up to one month aft er the intervention-hemobilia, poststent cholangitis, stent occlusion, irritative siptoms and loss of appetite are indicators statistically signifi cant consequences of uncovered stents unbiocompatibility.
Superinfection is an important potential complication for patients with biliary stents.Superinfection includes cases of cholangitis and liver abscess [20] and according to literature; early infectious complications are less frequent with covered stents and in subjects with a stent in a transpapillary position [20,21].From those studies, liver abscess appeared in 0.3-0.5% cases; adequate is our result for MCS 0%, but little bit higher in a case of MNS 3.4%.Cholangitis described on a level of 0.3%-22%, appears in almost the same level in our study -MCS 20.7%, and higher in MNS 41.4% (table 4).Cholecystitis described 1.9-12% in theliterature [19,20], in our study is 3.4% for MCS, and 6.9% for MNS,as early complication and 0% for MCS, 8% for MNS as late postprocedural complication.
Reobstructive jundice, Reobstructive cholangitis, irritativ symptoms and weith loss from the fi ld of late postprocedural complication gave us the same conclusion.Although usually spontaneous, stent migration may sometime be caused by surgical, endoscopic, or percutaneous maneuvers [22].Migration seems to occur more frequently with covered stents, probably because of their weaker anchorage, than with uncovered stents [14].Stent migretion we evaluate in this complication category, and we found 7.1% in a case of covered stents (table 5).Our results is higher than results presented by some multicentric studies on the fi ld of stent migration; Kullman and coauthors reported 3% migration rate in covered stent verus uncovered and also no patient with migration in uncoverd stent group as we considered during the period of 6 months [21].Stent migration may cause obstruction, hemorrhage, and perforation [23] or may have no consequence.Haemobilia, in early complication group, and chronic bleeding and melena, in late complication group, are complication that can be associated with stent migration or irritation by the stent.Perforation can be free or covered and, depending on the anatomic site, may cause free peritoneal air and eff usion, retroperitoneal gas spread, or fi stula formation with other hollow organs and structures.In our study are described perforation as early complication (MPS 0%, MNS 6.9%) and duodenal ulcer and perforation, as late complication (MPS 0%, MNS 12%).Pancreatitis in our patients with MCS isn't appeared (0%), but in MNS 8%; information from literature is 2%.
Stent obstruction can result from several causes including tumor regrowth through the mesh of an uncovered stent (i.e., ingrowth) or at its extremities (i.e., outgrowth), tissue hyperplasia (granulation tissue), luminal impaction, stent collapse or angulations, insuffi cient stent diameter, stent fracture, and stent migration [24].In our study almost all of causses of stent aff unction are in favor biocomatability of covered stents.We have no patient with obliteration, ingrought, overgrought and mucosal hiperplassia.Biliar encrustation is founded in MCS 32.1%, in group of MNS 44.8% (table 6).Th ere is no signifi cant diferensis between groups, but there is compering to literature.In most studies encrustation as biliary tract stenting complication is founded in 2-6% complication reported [15][16][17][18].
Recurrent biliary obstruction caused by migration or stent occlusion remains the most important issue.It is still unproven whether coveredself-expandable metal stent (CSEMS) will be a better solution than uncovered SEMS as evidenced by 2 recently pub-lished randomized studies [21,25].Over the years the concept of covering metal stents with membranes has been discussed but controversiesexists, such as whether covered metal stents actually off er more durable biliary drainage and whether they lead to stent migration or complication and whether biocompatible to human body.
From all that reasons, we can conclude that covered metal stents are biocompatible with the human body.Biocompatibility of covered metal stents in the treatment of irreversible halt bile is evident if we consider that it is a very complex pathological entity, which in the case of selected patients malignant etiology, followed by a very severe clinical picture, which is very fast due to hemodynamic imbalance can result in vital vulnerability, regardless of the stage of disease.Such conditions require prompt medical attention by choosing eff ective treatment methods to eliminate vital threat in the shortest possible time, without having to be less invasive and harmful to the patient.Judging by the results of applied new generation stents, stents meet a number of quality that they can be placed in order to measure the most eff ective treatment now.
Qualities that favor covered biliary stents over all previous methods of interventional radiology treatment as an earlier generation stents and other are: 1. Provide long-term lumen patency and ingrowth into the wall of the gall road or obstruction secondary proliferative tissue is physically possible; 2. Well tolerated non-irritant; 3.Not change position aft er installation-not migrate; 4. Stent implantation is performed on an outpatient under local anesthesia.
Insertion success, duration of adequate clinical palliation, and complications were all superior or comparable to most published data on self-expanding biliary stents.Results are visible immediately, depending on the severity of cholestasis, return to normal skin color in patients to improve the general condition and hemodynamic stabilization performed promptly, in the same time with the establishment of runoff captured bile juices.Th e scientifi c contribution is justifi ed by the fact that this generation of stents has never before been applied, so it provides a genuine therapeutic solution.

Table 2 .
Distribution of periprocedural complication

Table 4 .
Distribution of early postptrocedural complication nant etiology are covered stents.

Table 5 .
Distribution of late postptrocedural complication

Table 6 .
Causes of stent dysfunctional